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nord_657_1
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Symptoms of Kallmann Syndrome
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The clinical hallmark of IGD is the failure of onset of puberty. This lack of pubertal maturation, i.e. hypogonadism, occurs in both sexes and is characterized by reduced blood levels of the sex hormone levels (testosterone and estrogen) as well as gonadotropins (LH and FSH) and infertility. In boys, the onset of normal pubertal development is heralded by testicular enlargement that is then followed by penile growth and the appearance of pubic hair. Affected men complain of absence of secondary sexual characteristics (facial hair growth, body hair growth, decreased pubic hair growth and genital enlargement) and a delayed growth spurt in comparison to their peers. In addition, an absence of sexual interest (libido) and poor sexual function (inability to attain or sustain an erection) may also be present. Unusual growth of breasts may also be rarely seen in these subjects although this more typically occurs during treatment of this condition and is often transient (see below).Clinical examinations in these subjects usually confirms the incomplete sexual maturation (e.g. prepubertal testicular volume [< 4ml]), a eunuchoid body habitus (disproportionally long arms when compared to height) and decreased muscle mass. The degree of pubertal maturation can vary considerably with some individuals lacking any sign of puberty whereas others may have partial pubertal features that do not progress normally. Although IGD in males is typically diagnosed at puberty, this diagnosis can be made in infancy due to a small genital size (micropenis/microphallus) and/or lack of descent of testes (undescended testes or referred to as cryptorchidism). As mentioned earlier, pulsatile GnRH secretion and evidence of a normal reproductive axis occurs during the neonatal period. Hence, timely biochemical testing during the first 6 months or so of life may also confirm the presence of hypogonadism with low gonadotropin levels, i.e. the biochemical hallmarks of this condition during this critical window of normal development. However, if this brief developmental window of diagnostic testing is missed, a definite diagnostic confirmation may have to wait until the expected time of puberty although the increasing knowledge of the genetic basis of this condition may enable confirmation by specific genetic testing (see below).In girls, the first sign of normal puberty is the onset of breast budding (thelarche), followed by a growth spurt, the appearance of pubic hair growth, and then only later, the onset of menstrual flow, i.e. menarche. IGD females typically report absence of breast development, an attenuated growth spurt, decreased pubic hair growth, and lack of initiation of menses (primary amenorrhea). However, some females may exhibit some evidence of a partial puberty with thelarche that fails to progress. Very occasionally, some IGD females may report onset of menses at the appropriate time period in adolescence that ceases after a few cycles. Clinical exam in IGD females usually confirms their immature sexual characteristics and enuchoid habitus. It is important to note that development of pubic hair can be normal in both sexes as it is controlled by secretion of androgens from the adrenal glands, i.e. adrenarche, which is unaffected in IGD subjects.As mentioned earlier, ~50% IGD subjects have KS and exhibit either anosmia (complete lack of smell) or hyposmia (reduced ability to smell). Many IGD subjects also exhibit a spectrum of other non-reproductive features and these features may offer clues to the underlying genetic etiology of IGD (see below). Commonly recognized non-reproductive features that may be present in IGD subjects include:·Midline facial defects such as cleft lip and/ or palate·Renal agenesis (One kidney does not develop)·Short metacarpals (short fingers, especially the 4th finger)·Deafness·Mirror movements (synkinesia)·Eye movement abnormalities·Poor balance due to cerebellar ataxia·Scoliosis (bent spine)
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Symptoms of Kallmann Syndrome. The clinical hallmark of IGD is the failure of onset of puberty. This lack of pubertal maturation, i.e. hypogonadism, occurs in both sexes and is characterized by reduced blood levels of the sex hormone levels (testosterone and estrogen) as well as gonadotropins (LH and FSH) and infertility. In boys, the onset of normal pubertal development is heralded by testicular enlargement that is then followed by penile growth and the appearance of pubic hair. Affected men complain of absence of secondary sexual characteristics (facial hair growth, body hair growth, decreased pubic hair growth and genital enlargement) and a delayed growth spurt in comparison to their peers. In addition, an absence of sexual interest (libido) and poor sexual function (inability to attain or sustain an erection) may also be present. Unusual growth of breasts may also be rarely seen in these subjects although this more typically occurs during treatment of this condition and is often transient (see below).Clinical examinations in these subjects usually confirms the incomplete sexual maturation (e.g. prepubertal testicular volume [< 4ml]), a eunuchoid body habitus (disproportionally long arms when compared to height) and decreased muscle mass. The degree of pubertal maturation can vary considerably with some individuals lacking any sign of puberty whereas others may have partial pubertal features that do not progress normally. Although IGD in males is typically diagnosed at puberty, this diagnosis can be made in infancy due to a small genital size (micropenis/microphallus) and/or lack of descent of testes (undescended testes or referred to as cryptorchidism). As mentioned earlier, pulsatile GnRH secretion and evidence of a normal reproductive axis occurs during the neonatal period. Hence, timely biochemical testing during the first 6 months or so of life may also confirm the presence of hypogonadism with low gonadotropin levels, i.e. the biochemical hallmarks of this condition during this critical window of normal development. However, if this brief developmental window of diagnostic testing is missed, a definite diagnostic confirmation may have to wait until the expected time of puberty although the increasing knowledge of the genetic basis of this condition may enable confirmation by specific genetic testing (see below).In girls, the first sign of normal puberty is the onset of breast budding (thelarche), followed by a growth spurt, the appearance of pubic hair growth, and then only later, the onset of menstrual flow, i.e. menarche. IGD females typically report absence of breast development, an attenuated growth spurt, decreased pubic hair growth, and lack of initiation of menses (primary amenorrhea). However, some females may exhibit some evidence of a partial puberty with thelarche that fails to progress. Very occasionally, some IGD females may report onset of menses at the appropriate time period in adolescence that ceases after a few cycles. Clinical exam in IGD females usually confirms their immature sexual characteristics and enuchoid habitus. It is important to note that development of pubic hair can be normal in both sexes as it is controlled by secretion of androgens from the adrenal glands, i.e. adrenarche, which is unaffected in IGD subjects.As mentioned earlier, ~50% IGD subjects have KS and exhibit either anosmia (complete lack of smell) or hyposmia (reduced ability to smell). Many IGD subjects also exhibit a spectrum of other non-reproductive features and these features may offer clues to the underlying genetic etiology of IGD (see below). Commonly recognized non-reproductive features that may be present in IGD subjects include:·Midline facial defects such as cleft lip and/ or palate·Renal agenesis (One kidney does not develop)·Short metacarpals (short fingers, especially the 4th finger)·Deafness·Mirror movements (synkinesia)·Eye movement abnormalities·Poor balance due to cerebellar ataxia·Scoliosis (bent spine)
| 657 |
Kallmann Syndrome
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nord_657_2
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Causes of Kallmann Syndrome
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IGD is caused by mutations in a number of different genes and to-date, ~50% of patients have a demonstrable genetic mutation that is identifiable. While some genes primarily cause the KS form of IGD, others cause nIHH only, and some can cause both forms of this disorder. Mutations in genes that are thought to disrupt the development and migration of GnRH neurons from the olfactory epithelium to hypothalamus result in the KS phenotype. These include: KAL1, NELF, FGFR1, FGF8, PROK2, PROKR2, HS6ST1, CHD7, WDR11 and SEMA3A. Genes that primarily interfere with the normal secretion of GnRH (GNRH1, KISS1, KISS1R (GPR54), TAC3, TACR3) or its action on the pituitary (GNRHR) cause nIHH. The “overlap genes” ie. the ones that cause both KS and nIHH include FGFR1, FGF8, PROK2, PROKR2, HS6ST1, CHD7, WDR11 and SEMA3A. Presumably, these genes may have multiple roles in GnRH biology including both migration and their normal secretory function.Each of these genes have varied pattern of affecting families, i.e. inheritance (the way that the disorder passes from parents to offspring). All forms of Mendelian inheritance (autosomal dominant, autosomal recessive, and X-lined recessive) as well more complex oligogenic inheritance patterns are now recognized. Understanding the genetic basis of the disorder is crucial not only for genetic counseling for determine the risk of transmission to the next generation, but also for fostering new gene discovery as well as bench-to-bedside research.General notes on inheritance of genetic diseases:Genes for any particular trait are located on chromosomes (rod-shaped organelles consisting of DNA in the nucleus of each cell) and each individual receives 23 chromosomes (22 autosomes and one sex-chromosome like the X and Y chromosomes), each from the father and the mother. Knowing which gene is located on which chromosome allows a prediction of the inheritance pattern of each gene and based on this pattern of inheritance, the probability of passing the disease from parents to their children. A brief summary of the common modes of inheritance are discussed below:Autosomal dominant inheritance: Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary and sufficient to cause a particular disease. Thus the risk of transmitting a dominant gene is the same for males and females and hence can be inherited from either parent. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy.Autosomal recessive inheritance: Recessive genetic disorders also affect both sexes equally but differ from dominant inheritance in that a disease only occurs when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms of that condition. Marriages within close relatives (consanguineous marriages) thus have a higher risk of having children with a recessive genetic disorder than unrelated parents, as they are more likely to carry the same abnormal gene. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. Although consanguineous families with intermarriage are much more likely to experience these recessive diseases, these disorders can also arise in non-consanguineous (i.e. non-related) parents who happen to carry mutations in the same gene.X-linked inheritance: In X-linked recessive inheritance, females with a mutation in a gene on the X chromosome usually do not display symptoms of the disease linked to the genetic mutation since females have two X chromosomes and the normal gene on the second X chromosome can compensate for the mutated one. However, since males have only one X chromosome that is inherited from their mother (i.e. they are hemizygous), if they inherit an X chromosome that contains a defective gene, they will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will then be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Hence any condition in which a father passes a disease on to his son is, by definition, not an X-linked condition.Oligogenic inheritance: Oligogenic inheritance refers to a newly recognized inheritance pattern in which mutations in more than one gene synergistically interact and function in an additive manner to cause a disease phenotype. Both genes may have mutations (i.e. this is a digenic condition) in only one copy (i.e. it is a bi-allelic condition) or occasionally, one gene may have two mutations, each in a different allele they carry and the other may harbor a single mutation giving triallelic-digenic inheritance. Approximately, 10-15% of IGD patients have been shown to display this form of inheritance.The genes linked to IGD include:KAL1The first gene found responsible for KS was initially localized to the distal portion of X chromosome (Xp22.3) by studying patients with a “contiguous gene syndrome” (i.e. multiple genes lost due to large deletion of a portion of a chromosome resulting in multiple clinical phenotypes). This cluster of phenotypes included: short stature, chondrodysplasia punctata, intellectual disability, icthyosis and KS. By mapping the genes within this large deletion, the KAL1 gene was identified as the cause of KS. KAL1 is an X-linked gene and IGD is inherited in an X-linked recessive manner. KAL1 is comprised by 14 exons and encodes a secreted extracellular matrix protein called anosmin-1. Anosmin-1 plays an important role in the neuronal migration of both the GnRH neurons as well as the olfactory structures. This dual defect results in the characteristic combination of GnRH deficiency and anosmia, respectively. In addition, patients with KAL1 mutations may have additional non-reproductive phenotypes such as unilateral renal agenesis (absence of one kidney) and mirror movements. It is known that anosmin is also involved in kidney development, thus explaining why some patients with KS have renal agenesis. In addition, anosmin is also important for the crossing of the neurons in the developing brain across the midline, and this accounts for the mirror movements. Although KAL1 is a prototypical X-linked recessive gene, it is now known that some female carriers of KAL1 gene may also manifest IGD, suggesting other genetic mechanisms in these female carriers.KISS1R (GPR54)/KISS1In 2003, two independent groups indentified autosomal recessive mutations in KISS1R (formerly called GPR54) as a cause of nIHH form of IGD. The KISS1R encodes the kisspeptin receptor, a cognate G-protein-couple receptor for the ligand, kisspeptin. Kisspeptin is a secreted neuropeptide and it is now well-established the kisspeptin signaling system is an upstream regulator of the GnRH neurons. Recently, mutations in the gene KISS1 encoding kisspeptin itself, was also found to underlie autosomal recessive nIHH. Both KISS1 and KISS1R mutations affect the secretion of GnRH rather than the migration of GnRH neurons, thus resulting in nIHH exclusively. These human genetic observations and other supportive data from both humans and other species, now confirm that kisspeptin signaling is the most robust stimulator of GnRH secretion known currently.FGF8/FGFR1Using an IGD patient with a chromosomal breakpoint on 8p11.2-p11.1, FGFR1 (KAL2), a gene encoding the tyrosine kinase receptor, fibroblast growth factor receptor 1, was identified as a cause of KS. Subsequently, this was confirmed and in addition, mutations in FGFR1 were also identified in nIHH subjects, thus implicating this gene as an “overlap” gene causing both forms of IGD. Since then a large number of mutations of this gene have been uncovered as a cause of IGD. In mice that lack FGFR1, although the connection between the olfactory axons and the forebrain does occur, the olfactory bulb that is responsible for the sense of smell cannot evaginate from the epithelial wall. This observation could explain GnRH neuronal and olfactory migrational defect in patients with mutations in the FGFR1. Although there are 23 known FGF ligands, using the crystallographic modeling information of these ligands and by studying a single FGFR1 mutation, FGF8 was then identified as the ligand responsible for GnRH neuronal migration and mutations in FGF8 have now indentified in IGD patients. Typically, although both FGF8 and FGFR1 mutations are inherited in an autosomal dominant manner considerable variable penterance/expressivity characterizes pedigrees with these mutations. Amongst their clinical characteristics, patients with mutations in this pathway exhibit unique non-reproductive features such as dental agenesis, midline facial defects (cleft lip/palate) and digital bony abnormalities.PROK2/PROKR2 (Prokineticin 2/Prokineticin 2 receptor)Following the demonstration of deletions of Prok2 and Prokr2 as genetic causes of KS in mice, mutations in their respective human homologs, PROK2 and PROKR2 have been identified to cause both KS and nIHH. Both these genes are critical regulators of both GnRH neuronal development as well as the GnRH release. It is important to recognize that the majority of those mutations in these two genes have been found in the heterozygous states in humans, whereas heterozygous mice for these mutations don't present with a similar phenotype. In addition, human harboring mutations in PROK2 and PROKR2 also present with variable clinical characteristics, ranging from severe IGD to seemingly unaffected healthy subjects. This fact indicates that a combination of mutations in different genes may be required for the eventual expression the IGD phenotype and argues strongly for oligogenicity as the inheritance mode for the PROK2 pathway.GNRH1/GNRHRBoth GNRH1 and GNRHR are obvious candidate genes to cause IGD. IGD patients with mutations in GNRHR were the first to be described. GNRHR mutations are relatively common and cause the nIHH form of IGD. Studies in patients with GNRHR mutations reveal a heterogeneous clinical presentation, with both autosomal recessive and oligogenic inheritance patterns. After several years of investigation, GNRH1 mutations were eventually shown to be a cause of GnRH deficiency in 2009. While GNRHR mutations are fairly common, mutations in GNRH1 are extremely rare and mutations were only identified after genetic studies were done in over 400 patients with IGD. No specific non-reproductive feature is seen in this group of patients.TAC3 and TACR3Using homozygosity mapping in consanguineous pedigrees (families where couples marry with closely related individuals), two novel genes involved in tachykinin signaling, TAC3 (encoding neurokinin B) and its receptor (TACR3) were identified as causes of nIHH. Subsequently, mutations in these two genes were also identified in non-endogamous IGD patients and show the neurokinin pathway plays an important role both in ‘mini-puberty’ as well as the GnRH activation in puberty. However, longitudinal studies have revealed that several subjects with TAC3/TACR3 mutations eventually reverse their GnRH deficiency in adulthood, suggesting that this pathway may be dispensable for adult reproductive function. No specific non-reproductive feature is seen in this group of patients.CHD7Mutations in gene CHD7 cause a severe CHARGE syndrome (eye coloboma, heart anomalies, choanal atresia, growth and developmental retardation, genitourinary anomalies and ear abnormalities) (OMIM #214800). The “G” in CHARGE related to hypogonadism occurring secondary to IGD. Recently, milder allelic variants in CHD7 have been linked to a non-syndromic presentation of IGD (both KS and nIHH), and surprisingly accounts for ~7% of IGD patients. These mutations are typically inherited milder missense mutations vs. CHARGE syndrome mutations which are de novo truncating/frameshift mutations, suggesting a genotype-phenotype correlation (unpublished data from the author's clinical center). IGD patients with CHD7 mutations may also have additional CHARGE related features and ~30% of patients may display hearing loss (unpublished data from the author's clinical center). Therefore, physicians as well as genetic counselors should perform extensive clinical evaluation to exclude these features.NELFThe human nasal embryonic LHRH factor gene, NELF, has been shown to function as a guidance molecule for olfactory axon projections and neurophilic migration of GnRH cells in mice. Mutations in NELF have been identified in IGD patients (both KS and nIHH), primarily in an oligogenic inheritance pattern.WDR11The WDR11 gene encodes for WD Repeat Containing Protein 11. Heterozygous mutations in WDR11 were recently identified as a cause of IGD. While both KS and nIHH subjects harbored variants in WDR11, murine studies show interaction of WDR11 with EMX1, a homeodomain transcription factor in olfactory neuronal development, thus accounting for its implication in KS. The precise biologic role of WDR11 in neuroendocrine regulation of GnRH is yet to be established.HS6ST1Mutations in HS6ST1 gene, encoding heparan sulfate (HS) 6-O-sulfotransferase, a member if heparan sulfate (HS) polysaccharides were recently identified as an oligogenic cause of IGD (both KS and nIHH). HS6ST1 catalyzes the transfer of sulfate from 3-prime-phosphoadenosine 5-prime-phosphosulfate to position 6 of the N-sulfoglucosamine residue of heparan sulfate and plays a crucial role in cell-cell communication and neuronal development. Genetics experiments in the worm, (C. elegans) also revealed that reveal that HS cell specifically regulates neural branching in vivo in concert with other IHH-associated genes, such as KAL1, FGFR1 and FGF8. These findings are consistent with a model in which anosmin-1 can act as a modulatory coligand with FGF8 to activate the FGFR1 receptor in an HS-dependent manner.SEMA3AMost recently, mutations as well as partial deletions in SEMA3A, encoding a secreted axonal guidance molecule, semaphorin 3A, were identified in ~6% of KS patients. Semaphorin 3A, a class 3 semaphorin, activates the neuropilin-plexin-A1 holoreceptor complex and acts as an axonal repulsive cue to the axonal growth cone during embryonic development. Supportive data from both murine deletions of Sema3a as well as mice with specific mutation in the semaphorin binding domain of its receptor show abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain.In conclusion, IGD is caused by a large number of mutations in many different genes, which now explain ~50% of the genetic causes of the disorder. While most are inherited in a strict Mendelian pattern, several of these genes are shown to interact with each other in an oligogenic manner, which means that patients with IGD may carry mutations in more than one gene, contributing to the complexity of the disease as well as its inheritance to the next generations. Thus, IGD patients require formal genetic counseling to both assess the etiology of their condition as well as the risk of transmission to subsequent generations.
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Causes of Kallmann Syndrome. IGD is caused by mutations in a number of different genes and to-date, ~50% of patients have a demonstrable genetic mutation that is identifiable. While some genes primarily cause the KS form of IGD, others cause nIHH only, and some can cause both forms of this disorder. Mutations in genes that are thought to disrupt the development and migration of GnRH neurons from the olfactory epithelium to hypothalamus result in the KS phenotype. These include: KAL1, NELF, FGFR1, FGF8, PROK2, PROKR2, HS6ST1, CHD7, WDR11 and SEMA3A. Genes that primarily interfere with the normal secretion of GnRH (GNRH1, KISS1, KISS1R (GPR54), TAC3, TACR3) or its action on the pituitary (GNRHR) cause nIHH. The “overlap genes” ie. the ones that cause both KS and nIHH include FGFR1, FGF8, PROK2, PROKR2, HS6ST1, CHD7, WDR11 and SEMA3A. Presumably, these genes may have multiple roles in GnRH biology including both migration and their normal secretory function.Each of these genes have varied pattern of affecting families, i.e. inheritance (the way that the disorder passes from parents to offspring). All forms of Mendelian inheritance (autosomal dominant, autosomal recessive, and X-lined recessive) as well more complex oligogenic inheritance patterns are now recognized. Understanding the genetic basis of the disorder is crucial not only for genetic counseling for determine the risk of transmission to the next generation, but also for fostering new gene discovery as well as bench-to-bedside research.General notes on inheritance of genetic diseases:Genes for any particular trait are located on chromosomes (rod-shaped organelles consisting of DNA in the nucleus of each cell) and each individual receives 23 chromosomes (22 autosomes and one sex-chromosome like the X and Y chromosomes), each from the father and the mother. Knowing which gene is located on which chromosome allows a prediction of the inheritance pattern of each gene and based on this pattern of inheritance, the probability of passing the disease from parents to their children. A brief summary of the common modes of inheritance are discussed below:Autosomal dominant inheritance: Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary and sufficient to cause a particular disease. Thus the risk of transmitting a dominant gene is the same for males and females and hence can be inherited from either parent. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy.Autosomal recessive inheritance: Recessive genetic disorders also affect both sexes equally but differ from dominant inheritance in that a disease only occurs when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms of that condition. Marriages within close relatives (consanguineous marriages) thus have a higher risk of having children with a recessive genetic disorder than unrelated parents, as they are more likely to carry the same abnormal gene. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. Although consanguineous families with intermarriage are much more likely to experience these recessive diseases, these disorders can also arise in non-consanguineous (i.e. non-related) parents who happen to carry mutations in the same gene.X-linked inheritance: In X-linked recessive inheritance, females with a mutation in a gene on the X chromosome usually do not display symptoms of the disease linked to the genetic mutation since females have two X chromosomes and the normal gene on the second X chromosome can compensate for the mutated one. However, since males have only one X chromosome that is inherited from their mother (i.e. they are hemizygous), if they inherit an X chromosome that contains a defective gene, they will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will then be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Hence any condition in which a father passes a disease on to his son is, by definition, not an X-linked condition.Oligogenic inheritance: Oligogenic inheritance refers to a newly recognized inheritance pattern in which mutations in more than one gene synergistically interact and function in an additive manner to cause a disease phenotype. Both genes may have mutations (i.e. this is a digenic condition) in only one copy (i.e. it is a bi-allelic condition) or occasionally, one gene may have two mutations, each in a different allele they carry and the other may harbor a single mutation giving triallelic-digenic inheritance. Approximately, 10-15% of IGD patients have been shown to display this form of inheritance.The genes linked to IGD include:KAL1The first gene found responsible for KS was initially localized to the distal portion of X chromosome (Xp22.3) by studying patients with a “contiguous gene syndrome” (i.e. multiple genes lost due to large deletion of a portion of a chromosome resulting in multiple clinical phenotypes). This cluster of phenotypes included: short stature, chondrodysplasia punctata, intellectual disability, icthyosis and KS. By mapping the genes within this large deletion, the KAL1 gene was identified as the cause of KS. KAL1 is an X-linked gene and IGD is inherited in an X-linked recessive manner. KAL1 is comprised by 14 exons and encodes a secreted extracellular matrix protein called anosmin-1. Anosmin-1 plays an important role in the neuronal migration of both the GnRH neurons as well as the olfactory structures. This dual defect results in the characteristic combination of GnRH deficiency and anosmia, respectively. In addition, patients with KAL1 mutations may have additional non-reproductive phenotypes such as unilateral renal agenesis (absence of one kidney) and mirror movements. It is known that anosmin is also involved in kidney development, thus explaining why some patients with KS have renal agenesis. In addition, anosmin is also important for the crossing of the neurons in the developing brain across the midline, and this accounts for the mirror movements. Although KAL1 is a prototypical X-linked recessive gene, it is now known that some female carriers of KAL1 gene may also manifest IGD, suggesting other genetic mechanisms in these female carriers.KISS1R (GPR54)/KISS1In 2003, two independent groups indentified autosomal recessive mutations in KISS1R (formerly called GPR54) as a cause of nIHH form of IGD. The KISS1R encodes the kisspeptin receptor, a cognate G-protein-couple receptor for the ligand, kisspeptin. Kisspeptin is a secreted neuropeptide and it is now well-established the kisspeptin signaling system is an upstream regulator of the GnRH neurons. Recently, mutations in the gene KISS1 encoding kisspeptin itself, was also found to underlie autosomal recessive nIHH. Both KISS1 and KISS1R mutations affect the secretion of GnRH rather than the migration of GnRH neurons, thus resulting in nIHH exclusively. These human genetic observations and other supportive data from both humans and other species, now confirm that kisspeptin signaling is the most robust stimulator of GnRH secretion known currently.FGF8/FGFR1Using an IGD patient with a chromosomal breakpoint on 8p11.2-p11.1, FGFR1 (KAL2), a gene encoding the tyrosine kinase receptor, fibroblast growth factor receptor 1, was identified as a cause of KS. Subsequently, this was confirmed and in addition, mutations in FGFR1 were also identified in nIHH subjects, thus implicating this gene as an “overlap” gene causing both forms of IGD. Since then a large number of mutations of this gene have been uncovered as a cause of IGD. In mice that lack FGFR1, although the connection between the olfactory axons and the forebrain does occur, the olfactory bulb that is responsible for the sense of smell cannot evaginate from the epithelial wall. This observation could explain GnRH neuronal and olfactory migrational defect in patients with mutations in the FGFR1. Although there are 23 known FGF ligands, using the crystallographic modeling information of these ligands and by studying a single FGFR1 mutation, FGF8 was then identified as the ligand responsible for GnRH neuronal migration and mutations in FGF8 have now indentified in IGD patients. Typically, although both FGF8 and FGFR1 mutations are inherited in an autosomal dominant manner considerable variable penterance/expressivity characterizes pedigrees with these mutations. Amongst their clinical characteristics, patients with mutations in this pathway exhibit unique non-reproductive features such as dental agenesis, midline facial defects (cleft lip/palate) and digital bony abnormalities.PROK2/PROKR2 (Prokineticin 2/Prokineticin 2 receptor)Following the demonstration of deletions of Prok2 and Prokr2 as genetic causes of KS in mice, mutations in their respective human homologs, PROK2 and PROKR2 have been identified to cause both KS and nIHH. Both these genes are critical regulators of both GnRH neuronal development as well as the GnRH release. It is important to recognize that the majority of those mutations in these two genes have been found in the heterozygous states in humans, whereas heterozygous mice for these mutations don't present with a similar phenotype. In addition, human harboring mutations in PROK2 and PROKR2 also present with variable clinical characteristics, ranging from severe IGD to seemingly unaffected healthy subjects. This fact indicates that a combination of mutations in different genes may be required for the eventual expression the IGD phenotype and argues strongly for oligogenicity as the inheritance mode for the PROK2 pathway.GNRH1/GNRHRBoth GNRH1 and GNRHR are obvious candidate genes to cause IGD. IGD patients with mutations in GNRHR were the first to be described. GNRHR mutations are relatively common and cause the nIHH form of IGD. Studies in patients with GNRHR mutations reveal a heterogeneous clinical presentation, with both autosomal recessive and oligogenic inheritance patterns. After several years of investigation, GNRH1 mutations were eventually shown to be a cause of GnRH deficiency in 2009. While GNRHR mutations are fairly common, mutations in GNRH1 are extremely rare and mutations were only identified after genetic studies were done in over 400 patients with IGD. No specific non-reproductive feature is seen in this group of patients.TAC3 and TACR3Using homozygosity mapping in consanguineous pedigrees (families where couples marry with closely related individuals), two novel genes involved in tachykinin signaling, TAC3 (encoding neurokinin B) and its receptor (TACR3) were identified as causes of nIHH. Subsequently, mutations in these two genes were also identified in non-endogamous IGD patients and show the neurokinin pathway plays an important role both in ‘mini-puberty’ as well as the GnRH activation in puberty. However, longitudinal studies have revealed that several subjects with TAC3/TACR3 mutations eventually reverse their GnRH deficiency in adulthood, suggesting that this pathway may be dispensable for adult reproductive function. No specific non-reproductive feature is seen in this group of patients.CHD7Mutations in gene CHD7 cause a severe CHARGE syndrome (eye coloboma, heart anomalies, choanal atresia, growth and developmental retardation, genitourinary anomalies and ear abnormalities) (OMIM #214800). The “G” in CHARGE related to hypogonadism occurring secondary to IGD. Recently, milder allelic variants in CHD7 have been linked to a non-syndromic presentation of IGD (both KS and nIHH), and surprisingly accounts for ~7% of IGD patients. These mutations are typically inherited milder missense mutations vs. CHARGE syndrome mutations which are de novo truncating/frameshift mutations, suggesting a genotype-phenotype correlation (unpublished data from the author's clinical center). IGD patients with CHD7 mutations may also have additional CHARGE related features and ~30% of patients may display hearing loss (unpublished data from the author's clinical center). Therefore, physicians as well as genetic counselors should perform extensive clinical evaluation to exclude these features.NELFThe human nasal embryonic LHRH factor gene, NELF, has been shown to function as a guidance molecule for olfactory axon projections and neurophilic migration of GnRH cells in mice. Mutations in NELF have been identified in IGD patients (both KS and nIHH), primarily in an oligogenic inheritance pattern.WDR11The WDR11 gene encodes for WD Repeat Containing Protein 11. Heterozygous mutations in WDR11 were recently identified as a cause of IGD. While both KS and nIHH subjects harbored variants in WDR11, murine studies show interaction of WDR11 with EMX1, a homeodomain transcription factor in olfactory neuronal development, thus accounting for its implication in KS. The precise biologic role of WDR11 in neuroendocrine regulation of GnRH is yet to be established.HS6ST1Mutations in HS6ST1 gene, encoding heparan sulfate (HS) 6-O-sulfotransferase, a member if heparan sulfate (HS) polysaccharides were recently identified as an oligogenic cause of IGD (both KS and nIHH). HS6ST1 catalyzes the transfer of sulfate from 3-prime-phosphoadenosine 5-prime-phosphosulfate to position 6 of the N-sulfoglucosamine residue of heparan sulfate and plays a crucial role in cell-cell communication and neuronal development. Genetics experiments in the worm, (C. elegans) also revealed that reveal that HS cell specifically regulates neural branching in vivo in concert with other IHH-associated genes, such as KAL1, FGFR1 and FGF8. These findings are consistent with a model in which anosmin-1 can act as a modulatory coligand with FGF8 to activate the FGFR1 receptor in an HS-dependent manner.SEMA3AMost recently, mutations as well as partial deletions in SEMA3A, encoding a secreted axonal guidance molecule, semaphorin 3A, were identified in ~6% of KS patients. Semaphorin 3A, a class 3 semaphorin, activates the neuropilin-plexin-A1 holoreceptor complex and acts as an axonal repulsive cue to the axonal growth cone during embryonic development. Supportive data from both murine deletions of Sema3a as well as mice with specific mutation in the semaphorin binding domain of its receptor show abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain.In conclusion, IGD is caused by a large number of mutations in many different genes, which now explain ~50% of the genetic causes of the disorder. While most are inherited in a strict Mendelian pattern, several of these genes are shown to interact with each other in an oligogenic manner, which means that patients with IGD may carry mutations in more than one gene, contributing to the complexity of the disease as well as its inheritance to the next generations. Thus, IGD patients require formal genetic counseling to both assess the etiology of their condition as well as the risk of transmission to subsequent generations.
| 657 |
Kallmann Syndrome
|
nord_657_3
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Affects of Kallmann Syndrome
|
Both KS and nIHH are relatively rare, can affect both males and females, with a clear male predominance (~4:1). According to a recent retrospective study, to identify all diagnosed KS cases throughout Finland born during a defined time period, the minimal incidence of KS in Finland was approximately 1 in 48,000 newborns. There was a clear difference in estimates between boys (1 in 30,000) and girls (1 in 125,000). The reason for this sex ratio relates in part to the genetics and in part due to a bias of ascertainment wherein males with delayed puberty tend to seek care more frequently than do their female counterparts. A precise estimate of prevalence remains a challenge as there may be differences in different populations.
|
Affects of Kallmann Syndrome. Both KS and nIHH are relatively rare, can affect both males and females, with a clear male predominance (~4:1). According to a recent retrospective study, to identify all diagnosed KS cases throughout Finland born during a defined time period, the minimal incidence of KS in Finland was approximately 1 in 48,000 newborns. There was a clear difference in estimates between boys (1 in 30,000) and girls (1 in 125,000). The reason for this sex ratio relates in part to the genetics and in part due to a bias of ascertainment wherein males with delayed puberty tend to seek care more frequently than do their female counterparts. A precise estimate of prevalence remains a challenge as there may be differences in different populations.
| 657 |
Kallmann Syndrome
|
nord_657_4
|
Related disorders of Kallmann Syndrome
|
Occasionally, GnRH deficiency may present as adult-onset GnRH deficiency, wherein there is a history of an age-appropriate normal puberty followed by decrease in libido and fertility in adult life. These patients have usually normal testicular size and historical or physical evidence of normal spontaneous maturation, with documented fertility in several cases.Delayed puberty is characterized by delay of initiating puberty, but subsequent normal progression of sexual development. In contrast with the incidence in general population (<1%), delayed puberty has been observed much more frequently in families of patients with GnRH deficiency.IGD must be also distinguished from other forms of functional deficiency of GnRH, which present more commonly in women in the setting of excessive extreme exercise, severe weight loss, stress or dietary restriction (e.g. anorexia nervosa). This form of GnRH deficiency is referred to as hypothalamic amenorrhea (HA) and recent evidence suggests that genetic mutations in genes causing IGD may also be present in these women.Structural lesions of hypothalamus, such as tumors can interfere in the normal pattern of GnRH secretion. It is for that reason that normal radiographic appearance of the pituitary and hypothalamus is required for the diagnosis of IGD.In addition, various multisystem disorders (syndromic patients) with overlapping features of KS/nIHH have been reported. These include: CHARGE Syndrome (due to CHD7 mutations (see above), adrenal hypoplasia congenita (AHC) (due to DAX1 mutations), congenital obesity syndromes (due to LEP/LEPR mutations), Bartlet-Biedl Syndrome (several genes) and Moebius Syndrome.
|
Related disorders of Kallmann Syndrome. Occasionally, GnRH deficiency may present as adult-onset GnRH deficiency, wherein there is a history of an age-appropriate normal puberty followed by decrease in libido and fertility in adult life. These patients have usually normal testicular size and historical or physical evidence of normal spontaneous maturation, with documented fertility in several cases.Delayed puberty is characterized by delay of initiating puberty, but subsequent normal progression of sexual development. In contrast with the incidence in general population (<1%), delayed puberty has been observed much more frequently in families of patients with GnRH deficiency.IGD must be also distinguished from other forms of functional deficiency of GnRH, which present more commonly in women in the setting of excessive extreme exercise, severe weight loss, stress or dietary restriction (e.g. anorexia nervosa). This form of GnRH deficiency is referred to as hypothalamic amenorrhea (HA) and recent evidence suggests that genetic mutations in genes causing IGD may also be present in these women.Structural lesions of hypothalamus, such as tumors can interfere in the normal pattern of GnRH secretion. It is for that reason that normal radiographic appearance of the pituitary and hypothalamus is required for the diagnosis of IGD.In addition, various multisystem disorders (syndromic patients) with overlapping features of KS/nIHH have been reported. These include: CHARGE Syndrome (due to CHD7 mutations (see above), adrenal hypoplasia congenita (AHC) (due to DAX1 mutations), congenital obesity syndromes (due to LEP/LEPR mutations), Bartlet-Biedl Syndrome (several genes) and Moebius Syndrome.
| 657 |
Kallmann Syndrome
|
nord_657_5
|
Diagnosis of Kallmann Syndrome
|
The diagnosis of Kallmann syndrome is based on the clinical evidence of arrested sexual maturation or hypogonadism and the incomplete sexual maturation by Tanner staging on physical examination. Tanner staging is an established way used during the physical examination by endocrinologists and pediatric endocrinologists worldwide to evaluate the maturation of the primary and secondary sexual characteristics:STAGE 1Pubic Hair. NoneMale Genitalia. Childhood appearance of testes, scrotum, and penis (testicular volume <4 mL)Female Breast Development. No breast bud, small areola, slight elevation of papillaSTAGE IIPubic Hair. Sparse hair that is long and slightly pigmentedMale Genitalia. Enlargement of testes; reddish discoloration of scrotumFemale Breast Development. Formation of the breast bud; areolar enlargementSTAGE IIIPubic Hair. Darker, coarser, curly hairMale Genitalia. Continued growth of testes and elongation of penisFemale Breast Development. Continued growth of the breast bud and areola; areola confluent with breastSTAGE IVPubic Hair. Adult hair covering pubisMale Genitalia. Continued growth of testes, widening of the penis with growth of the glans penis; scrotal darkeningFemale Breast Development. Continued growth; areola and papilla form secondary mound projecting above breast contourSTAGE VPubic Hair. Laterally distributed adult- type hairMale Genitalia. Mature adult genitalia (testicular volume >15mL)Female Breast Development. Mature (areola again confluent with breast contour; only papilla projects)Typically, Tanner staging in IGD patients show:·Stage I-II genitalia in males, stage I-II breasts in females·Stage II-III pubic hair in both males and females, since it is controlled in part by adrenal androgens·Pre-pubertal testicular volume (stage I; <4mL) in malesHowever, the degree of sexual maturation can vary considerably between subjects. Occasionally, males with IGD can present with a partial pubertal phenotype, termed as the ‘fertile eunuch syndrome', first described in 1950's by Paqualini and Bur. These patients are hypogonodal with eunuchoid body proportions but their testicular measurements and spermatogenesis are nearly normal, suggesting an element of spontaneous testicular maturation. Similarly, in females, partial phenotypes with variable degree of breast development and in some extreme cases, menses may occur which then ceases. These partial phenotypes may be seen across all genetic forms of the disease and indicate some attenuated activity of their GnRH neuronal secretory activity.Apart from the physical examination, biochemical testing is also critical for diagnosis of IGD. As GnRH is not measurable, serum concentration of the gonadotropins (LH and FSH (secreted by the pituitary) and sex steroids are used for diagnosis. In patients with IGD, LH and FSH serum concentrations can be either low or normal, which is highly inappropriate in the presence of low testosterone (in males) and estradiol (in females). In addition, radiographic imaging of the hypothalamus-pituitary region using MRI scans is undertaken to rule any anatomical structural abnormalities. In addition the MRI exam may also indicate the absence of the olfactory structures in KS patients.Sense of smell can be evaluated by history and by formal diagnostic smell tests, such as the University of Pennsylvania smell identification test (UPSIT). This “scratch and sniff” test evaluates an individual's ability to identify 40 microencapsulated odorants and can be easily performed in most clinical settings. Identification of anosmia, hyposmia, or normosmia is based on the individual's score, age at testing and gender and is interpreted using a standard normogram in the UPSIT manual.As it has been already mentioned, molecular genetic testing for specifying the genes responsible for each affected individual indicates the way that other family members can be affected. Currently, clinical molecular genetic testing for mutations in KAL1,GNRHR, KISS1R, FGFR1, PROKR2, PROK2, CHD7, FGF8, GNRH1 and TACR3 genes are available to confirm the diagnosis. (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTests).
|
Diagnosis of Kallmann Syndrome. The diagnosis of Kallmann syndrome is based on the clinical evidence of arrested sexual maturation or hypogonadism and the incomplete sexual maturation by Tanner staging on physical examination. Tanner staging is an established way used during the physical examination by endocrinologists and pediatric endocrinologists worldwide to evaluate the maturation of the primary and secondary sexual characteristics:STAGE 1Pubic Hair. NoneMale Genitalia. Childhood appearance of testes, scrotum, and penis (testicular volume <4 mL)Female Breast Development. No breast bud, small areola, slight elevation of papillaSTAGE IIPubic Hair. Sparse hair that is long and slightly pigmentedMale Genitalia. Enlargement of testes; reddish discoloration of scrotumFemale Breast Development. Formation of the breast bud; areolar enlargementSTAGE IIIPubic Hair. Darker, coarser, curly hairMale Genitalia. Continued growth of testes and elongation of penisFemale Breast Development. Continued growth of the breast bud and areola; areola confluent with breastSTAGE IVPubic Hair. Adult hair covering pubisMale Genitalia. Continued growth of testes, widening of the penis with growth of the glans penis; scrotal darkeningFemale Breast Development. Continued growth; areola and papilla form secondary mound projecting above breast contourSTAGE VPubic Hair. Laterally distributed adult- type hairMale Genitalia. Mature adult genitalia (testicular volume >15mL)Female Breast Development. Mature (areola again confluent with breast contour; only papilla projects)Typically, Tanner staging in IGD patients show:·Stage I-II genitalia in males, stage I-II breasts in females·Stage II-III pubic hair in both males and females, since it is controlled in part by adrenal androgens·Pre-pubertal testicular volume (stage I; <4mL) in malesHowever, the degree of sexual maturation can vary considerably between subjects. Occasionally, males with IGD can present with a partial pubertal phenotype, termed as the ‘fertile eunuch syndrome', first described in 1950's by Paqualini and Bur. These patients are hypogonodal with eunuchoid body proportions but their testicular measurements and spermatogenesis are nearly normal, suggesting an element of spontaneous testicular maturation. Similarly, in females, partial phenotypes with variable degree of breast development and in some extreme cases, menses may occur which then ceases. These partial phenotypes may be seen across all genetic forms of the disease and indicate some attenuated activity of their GnRH neuronal secretory activity.Apart from the physical examination, biochemical testing is also critical for diagnosis of IGD. As GnRH is not measurable, serum concentration of the gonadotropins (LH and FSH (secreted by the pituitary) and sex steroids are used for diagnosis. In patients with IGD, LH and FSH serum concentrations can be either low or normal, which is highly inappropriate in the presence of low testosterone (in males) and estradiol (in females). In addition, radiographic imaging of the hypothalamus-pituitary region using MRI scans is undertaken to rule any anatomical structural abnormalities. In addition the MRI exam may also indicate the absence of the olfactory structures in KS patients.Sense of smell can be evaluated by history and by formal diagnostic smell tests, such as the University of Pennsylvania smell identification test (UPSIT). This “scratch and sniff” test evaluates an individual's ability to identify 40 microencapsulated odorants and can be easily performed in most clinical settings. Identification of anosmia, hyposmia, or normosmia is based on the individual's score, age at testing and gender and is interpreted using a standard normogram in the UPSIT manual.As it has been already mentioned, molecular genetic testing for specifying the genes responsible for each affected individual indicates the way that other family members can be affected. Currently, clinical molecular genetic testing for mutations in KAL1,GNRHR, KISS1R, FGFR1, PROKR2, PROK2, CHD7, FGF8, GNRH1 and TACR3 genes are available to confirm the diagnosis. (http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab?db=GeneTests).
| 657 |
Kallmann Syndrome
|
nord_657_6
|
Therapies of Kallmann Syndrome
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TreatmentThe standard forms of medical treatment involve hormone replacement therapies and this is usually tailored the clinical need of the patients. Typically, once the diagnosis is made, in both sexes, treatment is aimed at inducing puberty and maintaining normal hormonal levels. Subsequently, treatment may also be need for inducing fertility for achieving pregnancy.In males, puberty is usually initiated using testosterone therapy and various formulations of testosterone are currently available for this purpose. The most commonly used modes of treatment include testosterone injections given intramuscularly every 2 or 3 weeks depending on the particular injection) or topical testosterone formulations (patches, gels, liquids etc). Once puberty is initiated, testosterone therapy is continued to maintain secondary sex characteristics as well as to normalize biochemical testosterone levels in the blood. When fertility is desired, gonadotropin therapy (hCG and human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) can be administered to stimulate testicular growth and initiate sperm production (spermatogenesis). Typically, sperm is rarely seen in the semen analysis until testicular volume reaches at least 8 mL. In most IGD individuals without a history of cryptorchidism (undescended testes), sperm function is usually normal and conception can occur even with relatively low sperm counts.In females, estrogen and progestin therapy is used to induce the secondary sex characteristics, whereas gonadotropins or pulsatile GnRH therapy can be utilized to stimulate production of mature egg cells (folliculogenesis). If spontaneous pregnancy fails to occur despite normal folliculogenesis, in vitro fertilization may be considered with conception rates reported to be approximately 30% per ovulatory cycle.In addition to treating hypogonadism, potential deterioration in bone health that may have resulted from periods of low circulating sex hormones should be addressed. Depending on the history (the timing of puberty, duration of hypogonadism, and other osteoporotic risk factors [e.g., glucocorticoid excess, smoking) and bone mineral density measurement, measurement, specific treatment for decreased bone mass should be considered.Finally, it is really important to be reminded that since ~10-15 % of male patients studied in a referral IGD clinical center have been noted to have reversal of their hypogonadism, IGD patients must be evaluated serially for evidence of this reversibility. Features indicative of reversal include: testicular volume growth despite being on testosterone therapy and normalization of testosterone levels without adequate hormone replacement.
|
Therapies of Kallmann Syndrome. TreatmentThe standard forms of medical treatment involve hormone replacement therapies and this is usually tailored the clinical need of the patients. Typically, once the diagnosis is made, in both sexes, treatment is aimed at inducing puberty and maintaining normal hormonal levels. Subsequently, treatment may also be need for inducing fertility for achieving pregnancy.In males, puberty is usually initiated using testosterone therapy and various formulations of testosterone are currently available for this purpose. The most commonly used modes of treatment include testosterone injections given intramuscularly every 2 or 3 weeks depending on the particular injection) or topical testosterone formulations (patches, gels, liquids etc). Once puberty is initiated, testosterone therapy is continued to maintain secondary sex characteristics as well as to normalize biochemical testosterone levels in the blood. When fertility is desired, gonadotropin therapy (hCG and human menopausal gonadotropins [hMG] or recombinant FSH [rFSH]) can be administered to stimulate testicular growth and initiate sperm production (spermatogenesis). Typically, sperm is rarely seen in the semen analysis until testicular volume reaches at least 8 mL. In most IGD individuals without a history of cryptorchidism (undescended testes), sperm function is usually normal and conception can occur even with relatively low sperm counts.In females, estrogen and progestin therapy is used to induce the secondary sex characteristics, whereas gonadotropins or pulsatile GnRH therapy can be utilized to stimulate production of mature egg cells (folliculogenesis). If spontaneous pregnancy fails to occur despite normal folliculogenesis, in vitro fertilization may be considered with conception rates reported to be approximately 30% per ovulatory cycle.In addition to treating hypogonadism, potential deterioration in bone health that may have resulted from periods of low circulating sex hormones should be addressed. Depending on the history (the timing of puberty, duration of hypogonadism, and other osteoporotic risk factors [e.g., glucocorticoid excess, smoking) and bone mineral density measurement, measurement, specific treatment for decreased bone mass should be considered.Finally, it is really important to be reminded that since ~10-15 % of male patients studied in a referral IGD clinical center have been noted to have reversal of their hypogonadism, IGD patients must be evaluated serially for evidence of this reversibility. Features indicative of reversal include: testicular volume growth despite being on testosterone therapy and normalization of testosterone levels without adequate hormone replacement.
| 657 |
Kallmann Syndrome
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nord_658_0
|
Overview of Kasabach-Merritt Phenomenon
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Kasabach-Merritt phenomenon (KMP) is a rare condition that is associated with two rare vascular tumors: kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). It is characterized by a coagulopathy with features including profound low platelets (thrombocytopenia), low fibrinogen (hypofibrinogenemia) and low level of red blood cells (anemia). The rare vascular tumors associated with this phenomenon usually occur in infants and young children and can be life-threatening secondary to the risk of bleeding and organ dysfunction.
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Overview of Kasabach-Merritt Phenomenon. Kasabach-Merritt phenomenon (KMP) is a rare condition that is associated with two rare vascular tumors: kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). It is characterized by a coagulopathy with features including profound low platelets (thrombocytopenia), low fibrinogen (hypofibrinogenemia) and low level of red blood cells (anemia). The rare vascular tumors associated with this phenomenon usually occur in infants and young children and can be life-threatening secondary to the risk of bleeding and organ dysfunction.
| 658 |
Kasabach-Merritt Phenomenon
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nord_658_1
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Symptoms of Kasabach-Merritt Phenomenon
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Initially a vascular lesion is usually noted on the skin which can be firm and hard (indurated). Areas of tiny red dots (petechiae) can appear around the lesion or on other parts of the body. If the vascular lesion is internal, these petechiae and bruising can be seen on the skin. Bruising and spontaneous bleeding can also occur. The tumors are not hemangiomas. They usually present in young infants, less than three months of age, but have also been reported in the toddler age group. These tumors occur in the extremities, chest, neck, abdomen and pelvis. They infiltrate across tissue and can be aggravated by interventions, infection and trauma. When the tumors associated with KMP are internal such as in the chest or abdomen, they can cause significant illness and can be life-threatening due to bleeding. Internal lesions can take a longer time to diagnose.
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Symptoms of Kasabach-Merritt Phenomenon. Initially a vascular lesion is usually noted on the skin which can be firm and hard (indurated). Areas of tiny red dots (petechiae) can appear around the lesion or on other parts of the body. If the vascular lesion is internal, these petechiae and bruising can be seen on the skin. Bruising and spontaneous bleeding can also occur. The tumors are not hemangiomas. They usually present in young infants, less than three months of age, but have also been reported in the toddler age group. These tumors occur in the extremities, chest, neck, abdomen and pelvis. They infiltrate across tissue and can be aggravated by interventions, infection and trauma. When the tumors associated with KMP are internal such as in the chest or abdomen, they can cause significant illness and can be life-threatening due to bleeding. Internal lesions can take a longer time to diagnose.
| 658 |
Kasabach-Merritt Phenomenon
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nord_658_2
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Causes of Kasabach-Merritt Phenomenon
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The cause of KMP is unknown. It is believed to be secondary to sequestration or trapping of platelets and proteins into the tumor. These tumors are made up of abnormal endothelial cells (spindle cells) and abnormal lymphatic tissue. It is unclear why the KMP occurs and if it is caused by the spindle cells or the lymphatic component. A cause for the tumor (KHE and or TA) is also unknown but possibly secondary to a change in a gene in the tissue involved (somatic gene mutation).
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Causes of Kasabach-Merritt Phenomenon. The cause of KMP is unknown. It is believed to be secondary to sequestration or trapping of platelets and proteins into the tumor. These tumors are made up of abnormal endothelial cells (spindle cells) and abnormal lymphatic tissue. It is unclear why the KMP occurs and if it is caused by the spindle cells or the lymphatic component. A cause for the tumor (KHE and or TA) is also unknown but possibly secondary to a change in a gene in the tissue involved (somatic gene mutation).
| 658 |
Kasabach-Merritt Phenomenon
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nord_658_3
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Affects of Kasabach-Merritt Phenomenon
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KMP is a rare disorder that affects males and females equally. The diagnosis is most often made during infancy. The pnenomenon occurs much less often in older children. KHE and TA tumors can occur without KMP. The reason for this is still unknown and may be secondary to a smaller size of the tumor, an older age at presentation or other clinical features.
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Affects of Kasabach-Merritt Phenomenon. KMP is a rare disorder that affects males and females equally. The diagnosis is most often made during infancy. The pnenomenon occurs much less often in older children. KHE and TA tumors can occur without KMP. The reason for this is still unknown and may be secondary to a smaller size of the tumor, an older age at presentation or other clinical features.
| 658 |
Kasabach-Merritt Phenomenon
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nord_658_4
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Related disorders of Kasabach-Merritt Phenomenon
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Symptoms of the following disorders can be similar to those of Kasabach-Merritt phenomenon. Comparisons may be useful for a differential diagnosis:Vascular MalformationsLarge malformations such as venous or venous lymphatic lesions and multiple venous malformations can causes coagulopathies with low platelet counts and other coagulation proteins. This coagulopathy is not KMP. This coagulopathy is not secondary to trapping but secondary to a deficit of the proteins needed for coagulation.HemangiomasThe rare vascular tumors associated with KMP were misdiagnosed as hemangiomas in the past. Hemangiomas are benign tumors with endothelial proliferation which are usually not present at birth but proliferate and grow over a 4 to 6-month period of time and then stabilize and roll inward (involute). Hemangiomas are not associated with any coagulopathy or thrombocytopenia.Other Vascular TumorsLow platelets and low fibrinogen can be associated with other vascular tumors such as angiosarcomas. These tumors have physical and radiologic characteristics that are different than KHE and TA and should not be classified KPM.
|
Related disorders of Kasabach-Merritt Phenomenon. Symptoms of the following disorders can be similar to those of Kasabach-Merritt phenomenon. Comparisons may be useful for a differential diagnosis:Vascular MalformationsLarge malformations such as venous or venous lymphatic lesions and multiple venous malformations can causes coagulopathies with low platelet counts and other coagulation proteins. This coagulopathy is not KMP. This coagulopathy is not secondary to trapping but secondary to a deficit of the proteins needed for coagulation.HemangiomasThe rare vascular tumors associated with KMP were misdiagnosed as hemangiomas in the past. Hemangiomas are benign tumors with endothelial proliferation which are usually not present at birth but proliferate and grow over a 4 to 6-month period of time and then stabilize and roll inward (involute). Hemangiomas are not associated with any coagulopathy or thrombocytopenia.Other Vascular TumorsLow platelets and low fibrinogen can be associated with other vascular tumors such as angiosarcomas. These tumors have physical and radiologic characteristics that are different than KHE and TA and should not be classified KPM.
| 658 |
Kasabach-Merritt Phenomenon
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nord_658_5
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Diagnosis of Kasabach-Merritt Phenomenon
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The diagnosis of KMP is made in association with the tumors kaposiform hemangioendothelioma and tufted angioma. If a characteristic lesion is seen on the skin or an infant has signs of coagulopathy and bleeding, laboratory evaluation should be completed. Blood work including a CBC with differential and platelets, fibrinogen, D-dimer, PT, and PTT should be ordered. The best imaging modality to assess the extent of the lesion is a MRI with contrast though ultrasound can reveal an infiltrative high flow lesion. A biopsy will confirm the diagnosis.
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Diagnosis of Kasabach-Merritt Phenomenon. The diagnosis of KMP is made in association with the tumors kaposiform hemangioendothelioma and tufted angioma. If a characteristic lesion is seen on the skin or an infant has signs of coagulopathy and bleeding, laboratory evaluation should be completed. Blood work including a CBC with differential and platelets, fibrinogen, D-dimer, PT, and PTT should be ordered. The best imaging modality to assess the extent of the lesion is a MRI with contrast though ultrasound can reveal an infiltrative high flow lesion. A biopsy will confirm the diagnosis.
| 658 |
Kasabach-Merritt Phenomenon
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nord_658_6
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Therapies of Kasabach-Merritt Phenomenon
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TreatmentThe focus is treating the underlying tumor. Treatment of these tumors is best done at centers familiar with these tumors or who have an interdisciplinary vascular anomaly center. Medical management has included corticosteroids, interferon, chemotherapeutic agents such as vincristineaspirin, and antiplatelet drugs such as Ticlopidine. Sometimes a combination of medications has been used. Other adjuvant therapies have included interventional embolization. If the lesion can be surgically removed, that is the treatment of choice.In 2013, a consensus statement was published as a result on an interdisciplinary meeting that stated vincristine and steroids were the first line treatment for KHE/TA with KMP. Since that statement there have been a significant number of papers published regarding the use of sirolimus for the treatment of these tumors with impressive results especially in improving KMP. A series of 10 patients with KHE and KMP were treated with sirolimus in a prospective FDA sponsored phase II study and all responded. (1RO1FD-03712). About 50% of patients need to remain on a low dose of sirolimus to prevent reoccurrence of symptoms such as pain. Follow-up studies are needed to evaluate this medication as a treatment for KMP.
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Therapies of Kasabach-Merritt Phenomenon. TreatmentThe focus is treating the underlying tumor. Treatment of these tumors is best done at centers familiar with these tumors or who have an interdisciplinary vascular anomaly center. Medical management has included corticosteroids, interferon, chemotherapeutic agents such as vincristineaspirin, and antiplatelet drugs such as Ticlopidine. Sometimes a combination of medications has been used. Other adjuvant therapies have included interventional embolization. If the lesion can be surgically removed, that is the treatment of choice.In 2013, a consensus statement was published as a result on an interdisciplinary meeting that stated vincristine and steroids were the first line treatment for KHE/TA with KMP. Since that statement there have been a significant number of papers published regarding the use of sirolimus for the treatment of these tumors with impressive results especially in improving KMP. A series of 10 patients with KHE and KMP were treated with sirolimus in a prospective FDA sponsored phase II study and all responded. (1RO1FD-03712). About 50% of patients need to remain on a low dose of sirolimus to prevent reoccurrence of symptoms such as pain. Follow-up studies are needed to evaluate this medication as a treatment for KMP.
| 658 |
Kasabach-Merritt Phenomenon
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nord_659_0
|
Overview of KAT6A Syndrome
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Summary
KAT6A syndrome is an extremely rare genetic neurodevelopmental disorder in which there is a variation (mutation) in the KAT6A gene. Variations in the KAT6A gene can potentially cause a wide variety of signs and symptoms; how the disorder affects one child can be very different from how it affects another. Neurodevelopmental disorders are ones that impair or alter the growth and development of the brain and the central nervous system. Common symptoms include varying degrees of intellectual disability, delays in reaching developmental milestones (developmental delays), delays in being able to speak and communicate (speech delays) and diminished muscle tone (hypotonia). Additional symptoms including abnormalities affecting the heart, eyes and gastrointestinal system can also occur. In most instances, variations in the KAT6A gene occur spontaneously and there is no family history of the disorder (de novo variations). Treatment is based on the specific symptoms present in each individual.
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Overview of KAT6A Syndrome. Summary
KAT6A syndrome is an extremely rare genetic neurodevelopmental disorder in which there is a variation (mutation) in the KAT6A gene. Variations in the KAT6A gene can potentially cause a wide variety of signs and symptoms; how the disorder affects one child can be very different from how it affects another. Neurodevelopmental disorders are ones that impair or alter the growth and development of the brain and the central nervous system. Common symptoms include varying degrees of intellectual disability, delays in reaching developmental milestones (developmental delays), delays in being able to speak and communicate (speech delays) and diminished muscle tone (hypotonia). Additional symptoms including abnormalities affecting the heart, eyes and gastrointestinal system can also occur. In most instances, variations in the KAT6A gene occur spontaneously and there is no family history of the disorder (de novo variations). Treatment is based on the specific symptoms present in each individual.
| 659 |
KAT6A Syndrome
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nord_659_1
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Symptoms of KAT6A Syndrome
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Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about KAT6A syndrome is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of additional genes, environmental factors, or other factors influencing the disorder have prevented physicians and researchers from developing a complete picture of associated symptoms and prognosis.The potential symptoms associated with a variation in the KAT6A gene are numerous and highly variable. With genetic disorders, the specific type of variation (e.g., type of mutation, or location in the gene) can be associated more often with specific symptoms. This is called genotype-phenotype correlation. Researchers continue to determine whether there are any specific genotype-phenotype correlations in KAT6A syndrome. It is important to note that every child is unique and that affected individuals may not have all the symptoms discussed below. How the disorder affects one child can be very different from how it affects another child.Almost all children with KAT6A syndrome have intellectual disability. Intellectual disability can range from mild to severe. The degree of intellectual disability may be hard to determine at first, because other symptoms may make evaluation difficult. Standardized measures used to assess intellectual functions often rely on speech and communication abilities. With delays in these abilities, it is challenging to fully map out the neuropsychological profile of children with KAT6A gene variation. Most children experience delays in reaching developmental milestones like sitting up or crawling. Severe speech, language and communication difficulties are present in KAT6A syndrome. Most children are minimally verbal and alternative/augmentative communication approaches are required for many into adult life. Receptive language skills are relatively better than expressive language skills, which means that children with KAT6A gene variation can understand more information spoken to them than they are able to speak themselves. Some children may improve language skills, more in the receptive domain compared to the expressive, but others may remain relatively limited in their speech abilities or nonverbal through adulthood. Affected infants may have microcephaly, a condition in which the circumference of the head is smaller than would otherwise be expected based on age and gender. Less often, affected infants have craniosynostosis, which is a general term for the improper development of the bones of the skull, which can result in an abnormal head shape in affected individuals. Craniosynostosis refers to the premature fusion of the fibrous joints (sutures) between certain bones of the skull. The severity of primary craniosynostosis can vary from one person to another.As affected infants age, they may experience feeding difficulties because of problems with the movements of the muscles of the face (oromotor dysfunction). Some children have difficulty swallowing (dysphagia), and there can be a risk of food, liquid or other foreign material accidentally going into the lungs (aspiration). Infants can have additional symptoms involving the gastrointestinal tract including backflow of the contents of the stomach into the esophagus (gastroesophageal reflux), constipation, and abnormally twisting or rotation of the intestines (intestinal malrotation), which can cause pain and bowel obstruction. Bowel obstruction can be life-threating if not treated promptly. Based on a parent report published on the KAT6 Foundation’s page, untreated bowel obstructions are the leading cause of death among children affected by the KAT6A gene variation.Some affected individuals have heart defects that are present from birth (congenital heart defects). These can include atrial and ventricular septal defects. Septal defects are when there is a ‘hole’ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles, or in the membrane that separates the two upper chambers of the heart, called the atria. The size of these ‘holes will determine whether any symptoms are present, and how severe these symptoms may be. Additional congenital heart defects can include an abnormal opening between the main artery of the lungs (pulmonary artery) and the aorta (patent ductus arteriosus), and patent foreman ovale, in which the normal hole between the two atria that allows blood to bypass the fetal lungs, fails to close as it normally should.Some infants and children have distinctive facial features. This can include a broad tip of the nose, which can become more pronounced as a child grows older. Additional features include a thin upper lip, low-set ears, a prominent bridge of the nose, and narrowing of the temporal bones that make up the sides and base of the skull. Additional features include a droopy eyelid (ptosis), downturned corners of the mouth and an abnormally small jaw (micrognathia). The eyes can be misaligned (strabismus), and sometimes vision may be reduced because the eye and brain are not working together properly (amblyopia). Less often, additional eye symptoms can occur including nearsightedness (myopia), farsightedness (hypermetropia), and rapid, involuntary eye movements (nystagmus). Teeth abnormalities are common and include peg-shaped teeth, abnormally small teeth, extra (supernumerary) teeth, and crowding of the teeth.Behavioral issues are common in KAT6A syndrome. Some children display some of the signs and symptoms that are seen in children on the autism spectrum. Such behavioral issues can include temper tantrums, hand flapping and other repetitive behaviors, inappropriate laughing, frustration, and anxiety. Coping with everyday demands that includes self-care and interacting with others can be challenging for children with KAT6A gene variation. According to the KAT6 Foundation and the medical literature, many parents have reported that their children are happy, sociable and good natured.Many affected individuals have difficulties with sleep such as difficult falling asleep and remaining asleep. A few individuals have developed obstructive sleep apnea. Sleep apnea is a condition characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms include frequent interruptions of sleep at night and excessive sleepiness during the day. To manage sleep issues, parents of children with KAT6A gene variation often seek medical advice and rely on medications. Additional symptoms that have been reported include cleft palate and weakened cartilage of the walls of the bronchial tubes (bronchomalacia). Some individuals experience recurrent infections, including repeated middle ear infections (otitis media) or respiratory infections. Some individuals have developed seizures, complex movement disorders, or an excessive startle reaction. There are also a few children who have had pinkies that are fixed or “locked” in a bent or curved position (clinodactyly) or abnormally short fingers (brachydactyly). In boys, there may be a delay or failure of the testes to descend into the scrotum (cryptorchidism).There are several different symptoms that have been identified in only one or a few individuals. Researchers are not sure yet whether these are potential symptoms of KAT6A syndrome, or coincidental findings resulting from another cause. Such symptoms include food allergy or intolerance, short stature and abnormalities associated with the pituitary gland. Deficiency or abnormality of the immune system, which can contribute to repeated infections, has been suspected in some individuals, but is unproven.It is not necessary for the KAT6A syndrome’s clinical features to have a strong association with the type or location of the gene variation. However, for core features such as intellectual disability, speech and communication delays, microcephaly, cardiac anomalies and gastrointestinal complications, studies on genotype-phenotype correlations have shown that these core features are more prevalent in late truncating mutations.
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Symptoms of KAT6A Syndrome. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about KAT6A syndrome is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of additional genes, environmental factors, or other factors influencing the disorder have prevented physicians and researchers from developing a complete picture of associated symptoms and prognosis.The potential symptoms associated with a variation in the KAT6A gene are numerous and highly variable. With genetic disorders, the specific type of variation (e.g., type of mutation, or location in the gene) can be associated more often with specific symptoms. This is called genotype-phenotype correlation. Researchers continue to determine whether there are any specific genotype-phenotype correlations in KAT6A syndrome. It is important to note that every child is unique and that affected individuals may not have all the symptoms discussed below. How the disorder affects one child can be very different from how it affects another child.Almost all children with KAT6A syndrome have intellectual disability. Intellectual disability can range from mild to severe. The degree of intellectual disability may be hard to determine at first, because other symptoms may make evaluation difficult. Standardized measures used to assess intellectual functions often rely on speech and communication abilities. With delays in these abilities, it is challenging to fully map out the neuropsychological profile of children with KAT6A gene variation. Most children experience delays in reaching developmental milestones like sitting up or crawling. Severe speech, language and communication difficulties are present in KAT6A syndrome. Most children are minimally verbal and alternative/augmentative communication approaches are required for many into adult life. Receptive language skills are relatively better than expressive language skills, which means that children with KAT6A gene variation can understand more information spoken to them than they are able to speak themselves. Some children may improve language skills, more in the receptive domain compared to the expressive, but others may remain relatively limited in their speech abilities or nonverbal through adulthood. Affected infants may have microcephaly, a condition in which the circumference of the head is smaller than would otherwise be expected based on age and gender. Less often, affected infants have craniosynostosis, which is a general term for the improper development of the bones of the skull, which can result in an abnormal head shape in affected individuals. Craniosynostosis refers to the premature fusion of the fibrous joints (sutures) between certain bones of the skull. The severity of primary craniosynostosis can vary from one person to another.As affected infants age, they may experience feeding difficulties because of problems with the movements of the muscles of the face (oromotor dysfunction). Some children have difficulty swallowing (dysphagia), and there can be a risk of food, liquid or other foreign material accidentally going into the lungs (aspiration). Infants can have additional symptoms involving the gastrointestinal tract including backflow of the contents of the stomach into the esophagus (gastroesophageal reflux), constipation, and abnormally twisting or rotation of the intestines (intestinal malrotation), which can cause pain and bowel obstruction. Bowel obstruction can be life-threating if not treated promptly. Based on a parent report published on the KAT6 Foundation’s page, untreated bowel obstructions are the leading cause of death among children affected by the KAT6A gene variation.Some affected individuals have heart defects that are present from birth (congenital heart defects). These can include atrial and ventricular septal defects. Septal defects are when there is a ‘hole’ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles, or in the membrane that separates the two upper chambers of the heart, called the atria. The size of these ‘holes will determine whether any symptoms are present, and how severe these symptoms may be. Additional congenital heart defects can include an abnormal opening between the main artery of the lungs (pulmonary artery) and the aorta (patent ductus arteriosus), and patent foreman ovale, in which the normal hole between the two atria that allows blood to bypass the fetal lungs, fails to close as it normally should.Some infants and children have distinctive facial features. This can include a broad tip of the nose, which can become more pronounced as a child grows older. Additional features include a thin upper lip, low-set ears, a prominent bridge of the nose, and narrowing of the temporal bones that make up the sides and base of the skull. Additional features include a droopy eyelid (ptosis), downturned corners of the mouth and an abnormally small jaw (micrognathia). The eyes can be misaligned (strabismus), and sometimes vision may be reduced because the eye and brain are not working together properly (amblyopia). Less often, additional eye symptoms can occur including nearsightedness (myopia), farsightedness (hypermetropia), and rapid, involuntary eye movements (nystagmus). Teeth abnormalities are common and include peg-shaped teeth, abnormally small teeth, extra (supernumerary) teeth, and crowding of the teeth.Behavioral issues are common in KAT6A syndrome. Some children display some of the signs and symptoms that are seen in children on the autism spectrum. Such behavioral issues can include temper tantrums, hand flapping and other repetitive behaviors, inappropriate laughing, frustration, and anxiety. Coping with everyday demands that includes self-care and interacting with others can be challenging for children with KAT6A gene variation. According to the KAT6 Foundation and the medical literature, many parents have reported that their children are happy, sociable and good natured.Many affected individuals have difficulties with sleep such as difficult falling asleep and remaining asleep. A few individuals have developed obstructive sleep apnea. Sleep apnea is a condition characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms include frequent interruptions of sleep at night and excessive sleepiness during the day. To manage sleep issues, parents of children with KAT6A gene variation often seek medical advice and rely on medications. Additional symptoms that have been reported include cleft palate and weakened cartilage of the walls of the bronchial tubes (bronchomalacia). Some individuals experience recurrent infections, including repeated middle ear infections (otitis media) or respiratory infections. Some individuals have developed seizures, complex movement disorders, or an excessive startle reaction. There are also a few children who have had pinkies that are fixed or “locked” in a bent or curved position (clinodactyly) or abnormally short fingers (brachydactyly). In boys, there may be a delay or failure of the testes to descend into the scrotum (cryptorchidism).There are several different symptoms that have been identified in only one or a few individuals. Researchers are not sure yet whether these are potential symptoms of KAT6A syndrome, or coincidental findings resulting from another cause. Such symptoms include food allergy or intolerance, short stature and abnormalities associated with the pituitary gland. Deficiency or abnormality of the immune system, which can contribute to repeated infections, has been suspected in some individuals, but is unproven.It is not necessary for the KAT6A syndrome’s clinical features to have a strong association with the type or location of the gene variation. However, for core features such as intellectual disability, speech and communication delays, microcephaly, cardiac anomalies and gastrointestinal complications, studies on genotype-phenotype correlations have shown that these core features are more prevalent in late truncating mutations.
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KAT6A Syndrome
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Causes of KAT6A Syndrome
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KAT6A syndrome is caused by a variation (mutation) in the KAT6A gene. This gene is also known as the MOZ or MYST3 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.The KAT6A gene contains instructions for creating (encoding) a protein (or enzyme) that is vitally important to the body. This enzyme is believed to have multiple jobs in the body. It is classified as a type of histone acetyltransferase. These enzymes modify histones, which are structural proteins that bind to DNA and help to give chromosomes their normal shape. The KAT6A enzyme helps to control the expression of other genes and the activity and expression of other proteins in the body. This enzyme helps to regulate a wide variety of chemical processes in the body. Consequently, this enzyme is involved in various aspects of health and development, and a variation in the KAT6A gene can lead to a wide variety of issues.The variation in the KAT6A gene almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent.If a person with KAT6A syndrome were to have a child, they could pass the altered KAT6A gene on to their children through autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy.
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Causes of KAT6A Syndrome. KAT6A syndrome is caused by a variation (mutation) in the KAT6A gene. This gene is also known as the MOZ or MYST3 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body, including the brain.The KAT6A gene contains instructions for creating (encoding) a protein (or enzyme) that is vitally important to the body. This enzyme is believed to have multiple jobs in the body. It is classified as a type of histone acetyltransferase. These enzymes modify histones, which are structural proteins that bind to DNA and help to give chromosomes their normal shape. The KAT6A enzyme helps to control the expression of other genes and the activity and expression of other proteins in the body. This enzyme helps to regulate a wide variety of chemical processes in the body. Consequently, this enzyme is involved in various aspects of health and development, and a variation in the KAT6A gene can lead to a wide variety of issues.The variation in the KAT6A gene almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent.If a person with KAT6A syndrome were to have a child, they could pass the altered KAT6A gene on to their children through autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy.
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KAT6A Syndrome
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Affects of KAT6A Syndrome
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KAT6A syndrome is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to the KAT6 Foundation, as of December 2022, there are 350 individuals known to have the disorder. Rare disorders like KAT6A syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. KAT6A syndrome is often underdiagnosed, and a 2015 report suggests that the disorder may account for as much as 1% of undiagnosed individuals with syndromic developmental delay.
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Affects of KAT6A Syndrome. KAT6A syndrome is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to the KAT6 Foundation, as of December 2022, there are 350 individuals known to have the disorder. Rare disorders like KAT6A syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. KAT6A syndrome is often underdiagnosed, and a 2015 report suggests that the disorder may account for as much as 1% of undiagnosed individuals with syndromic developmental delay.
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Related disorders of KAT6A Syndrome
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Symptoms of the following disorders can be similar to those of KAT6A syndrome. Comparisons may be useful for a differential diagnosis.There are many disorders that can cause signs and symptoms similar to those seen in people with KAT6A syndrome. These include better known disorders such as cerebral palsy, and a wide variety of other genetic neurodevelopmental disorders such as the KAT6B syndrome. The signs and symptoms of KAT6A syndrome alone are not varied enough to distinguish the disorder from many of these other, similar disorders. Some affected individuals have symptoms that are consistent with those for individuals with an autism spectrum disorder.
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Related disorders of KAT6A Syndrome. Symptoms of the following disorders can be similar to those of KAT6A syndrome. Comparisons may be useful for a differential diagnosis.There are many disorders that can cause signs and symptoms similar to those seen in people with KAT6A syndrome. These include better known disorders such as cerebral palsy, and a wide variety of other genetic neurodevelopmental disorders such as the KAT6B syndrome. The signs and symptoms of KAT6A syndrome alone are not varied enough to distinguish the disorder from many of these other, similar disorders. Some affected individuals have symptoms that are consistent with those for individuals with an autism spectrum disorder.
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KAT6A Syndrome
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Diagnosis of KAT6A Syndrome
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A diagnosis of KAT6A syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There are no formal diagnostic criteria established for this disorder. A diagnosis is confirmed through molecular genetic testing.Clinical Testing and Workup
Molecular genetic testing can detect disease-causing variations in the KAT6A gene but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having KAT6A syndrome and the sample will undergo whole exome sequencing (WES). WES is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variations in the KAT6A gene that are known to cause disease, or variations in other genes known to cause symptoms like this syndrome.Affected individuals may undergo additional tests to assess the extent of the disease. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An MRI of the brain can reveal degeneration or damage to the brain. An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects sometimes associated with the disorder. An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with KAT6A syndrome.Neurologic examination is important for individuals with the symptoms of KAT6A syndrome. Neurologic examination helps identify the specific features affecting a person. Laboratory tests, neurophysiologic testing, and neuroimaging; routine laboratory studies (such as blood counts, serum electrolytes, and tests of kidney, liver, and endocrine functions); and analysis of cerebrospinal fluid (obtained by “spinal tap”) may be conducted to help exclude alternate and co-existing diagnoses.
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Diagnosis of KAT6A Syndrome. A diagnosis of KAT6A syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There are no formal diagnostic criteria established for this disorder. A diagnosis is confirmed through molecular genetic testing.Clinical Testing and Workup
Molecular genetic testing can detect disease-causing variations in the KAT6A gene but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having KAT6A syndrome and the sample will undergo whole exome sequencing (WES). WES is a molecular genetic testing method that examines the genes in humans that contain instructions for creating proteins (protein-encoding genes). This is called the exome. WES can detect variations in the KAT6A gene that are known to cause disease, or variations in other genes known to cause symptoms like this syndrome.Affected individuals may undergo additional tests to assess the extent of the disease. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An MRI of the brain can reveal degeneration or damage to the brain. An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects sometimes associated with the disorder. An eye doctor will conduct a thorough, extensive eye examination to look for eye abnormalities that may be associated with KAT6A syndrome.Neurologic examination is important for individuals with the symptoms of KAT6A syndrome. Neurologic examination helps identify the specific features affecting a person. Laboratory tests, neurophysiologic testing, and neuroimaging; routine laboratory studies (such as blood counts, serum electrolytes, and tests of kidney, liver, and endocrine functions); and analysis of cerebrospinal fluid (obtained by “spinal tap”) may be conducted to help exclude alternate and co-existing diagnoses.
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KAT6A Syndrome
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Therapies of KAT6A Syndrome
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Treatment
Infants with KAT6A syndrome should be evaluated for feeding issues and treated with standard methods if necessary. This can include insertion of a nasogastric feeding tube, which is a thin tube that delivers food to the stomach via the nose and esophagus. Constipation can be severe and may result in multiple hospital admissions. About 50% of children with congenital heart disease require surgery. Regular examination of the eyes is recommended to detect potential eye complications such as misalignment (strabismus).Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Speech therapy is required. Affected children have benefited from the use of augmentative and alternative communication strategies such as sign language, picture boards, smart phone applications and speech-generating devices. Periodic reassessments and adjustment of services should be provided to all children. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.The treatment of KAT6A syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including, but not limited to, surgeons, cardiologists, ophthalmologists, gastroenterologists, speech therapists and physical therapists. A metabolic genetic specialist has an important role in managing the overall care of the patient, communicating with all the specialists and providing genetic counseling to the affected individuals and their families. Psychosocial support for the entire family is also recommended.
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Therapies of KAT6A Syndrome. Treatment
Infants with KAT6A syndrome should be evaluated for feeding issues and treated with standard methods if necessary. This can include insertion of a nasogastric feeding tube, which is a thin tube that delivers food to the stomach via the nose and esophagus. Constipation can be severe and may result in multiple hospital admissions. About 50% of children with congenital heart disease require surgery. Regular examination of the eyes is recommended to detect potential eye complications such as misalignment (strabismus).Following an initial diagnosis, a developmental assessment may be performed and appropriate occupational, physical, speech and feeding therapies be instituted. Speech therapy is required. Affected children have benefited from the use of augmentative and alternative communication strategies such as sign language, picture boards, smart phone applications and speech-generating devices. Periodic reassessments and adjustment of services should be provided to all children. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.The treatment of KAT6A syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists including, but not limited to, surgeons, cardiologists, ophthalmologists, gastroenterologists, speech therapists and physical therapists. A metabolic genetic specialist has an important role in managing the overall care of the patient, communicating with all the specialists and providing genetic counseling to the affected individuals and their families. Psychosocial support for the entire family is also recommended.
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KAT6A Syndrome
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Overview of KAT6B-Related Disorders
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SummaryKAT6B-related disorders are extremely rare genetic neurodevelopmental disorders caused by changes (pathogenic variants or mutations) in the KAT6B gene. Neurodevelopmental disorders impair or alter the growth and development of the brain and the central nervous system. Variants in the KAT6B gene can lead to a broad spectrum of signs and symptoms, some of which can be grouped into genitopatellar syndrome (GPS) or a type of Ohdo syndrome called Say-Barber-Biesecker-Young-Simpson (SBBYS) but features very frequently overlap. Commonly, these include varying degrees of intellectual disability, delays in reaching developmental milestones (developmental delays), feeding difficulties, diminished muscle tone (hypotonia), abnormalities affecting the heart, hips or knees and growth problems. Less common features include hearing impairment, seizures and autism-like behaviors, and abnormalities of the thyroid gland, skull, genitals, kidneys and teeth. In most instances, variants in the KAT6B gene occur spontaneously and there is no family history of the disorder (de novo variants). Treatment is based on the specific symptoms present in each individual.
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Overview of KAT6B-Related Disorders. SummaryKAT6B-related disorders are extremely rare genetic neurodevelopmental disorders caused by changes (pathogenic variants or mutations) in the KAT6B gene. Neurodevelopmental disorders impair or alter the growth and development of the brain and the central nervous system. Variants in the KAT6B gene can lead to a broad spectrum of signs and symptoms, some of which can be grouped into genitopatellar syndrome (GPS) or a type of Ohdo syndrome called Say-Barber-Biesecker-Young-Simpson (SBBYS) but features very frequently overlap. Commonly, these include varying degrees of intellectual disability, delays in reaching developmental milestones (developmental delays), feeding difficulties, diminished muscle tone (hypotonia), abnormalities affecting the heart, hips or knees and growth problems. Less common features include hearing impairment, seizures and autism-like behaviors, and abnormalities of the thyroid gland, skull, genitals, kidneys and teeth. In most instances, variants in the KAT6B gene occur spontaneously and there is no family history of the disorder (de novo variants). Treatment is based on the specific symptoms present in each individual.
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KAT6B-Related Disorders
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Symptoms of KAT6B-Related Disorders
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Variants in the KAT6B gene can lead to a broad spectrum of signs and symptoms. On either side of the spectrum are some clinical features that are associated more often with either genitopatellar syndrome (GPS) or a type of Ohdo syndrome called Say-Barber-Biesecker-Young-Simpson (SBBYS). But individuals affected by KAT6B-related disorders frequently have intermediate clinical features that are a mixture or overlap between these two syndromes. Some individuals have clinical features that do not overlap with either syndrome at all.The potential symptoms associated with a variation in the KAT6B gene are numerous and highly variable and can depend on the specific type of variant (e.g., type of mutation, or location in the gene). This is called genotype-phenotype correlation. It is important to note that every child is unique and how the disorder affects one child can be very different from how it affects another.Neurologic features are present in most individuals affected by KAT6B-related disorders. A child's progression through predictable developmental phases, like sitting up and crawling, may be slowed, stopped or reversed (developmental delays). Global developmental delays can affect both motor functions, like walking, and intellectual development ranging from mild to severe. Speech delays and language disorders are frequent, though some individuals can communicate through vocalization or manipulating objects. Some brain anomalies are more common in individuals affected by GPS including an absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum) that can contribute to developmental delays and can sometimes cause seizures. Less frequently, an unusual amount of cerebrospinal fluid can increase pressure on the brain and cause damage or seizures. Individuals affected by SBBYS are more likely to have an underdeveloped or damaged optic nerve, and impairments in the region of the brain that processes visual information (cortical visual impairment). These can lead to visual deficiencies in one eye (lazy eye) or nearsightedness.Most individuals affected by KAT6B-related disorders have feeding difficulties and gastrointestinal features. Feeding challenges can include difficulty coordinating motor functions and swallowing (dysphagia) which can lead to choking or breathing food, liquid or other foreign material into the lungs (aspiration). Most individuals, especially infants, can have a backflow of the contents of the stomach into the esophagus (gastroesophageal reflux). In some individuals, improper development of the intestines may cause them to settle in the wrong parts of the abdomen, which can cause them to become blocked or twisted (small bowel malrotation) and lead to frequent vomiting or constipation. Additionally, individuals with GPS are more likely to have anal abnormalities, including no anus (anal atresia), a narrowing of the anal canal (anal stenosis), or mispositioning of the anus closer to the front of the body. These conditions can lead to serious health complications from a failure to pass stool. Some individuals affected by KAT6B-related disorders have low muscle tone (hypotonia) and muscle abnormalities. For infants especially this can further complicate feeding and breathing, but often difficulties resolve in infancy. In GPS, infants are more likely to have an abnormality where tissue located above the voice box flops back over the upper-airway (laryngomalacia) and obstructs breathing. Beyond infancy, hypotonia of extremities and the trunk may continue. Nearly all individuals affected with GPS have permanently short and tight muscles (contractures), primarily in the knees and hip, that significantly restrict flexibility and movement. In SBBYS, contractures only occasionally occur.Skeletal and growth abnormalities can also occur. Affected infants may have a condition in which head circumference is smaller than would otherwise be expected based on age and gender (microcephaly). Rarely, flexible sutures in spaces typically found between bones of a baby’s skull turn into bone and join prematurely (craniosynostosis). This can cause changes in skull growth patterns that often result in a misshapen head. In children, additional growth abnormalities can include varying degrees of poor weight gain, diminished physical growth and below average height. More common in individuals affected by GPS are underdeveloped (hypoplastic), dislocated or absent kneecap (patella), clubfoot, and bone abnormalities of the spine, ribs and pelvis. Individuals affected by SBBYS are more likely to have toe and finger abnormalities, and most individuals will have long thumbs and great toes.Roughly half of affected individuals have heart defects that are present from birth (congenital heart defects). These can include atrial and ventricular septal defects. Septal defects are when there is a ‘hole’ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles, or in the membrane that separates the two upper chambers of the heart, called the atria. Additionally, normal openings in the fetal heart may fail to close at birth (patent ductus arteriosus and patent foramen ovale). Incomplete closure of these holes can allow varying amounts of blood to bypass the lungs where they would normally pick up oxygen. The size of these ‘holes will determine whether any symptoms are present, and how severe these symptoms may be.Distinct facial features associated with KAT6B-related disorders commonly include low-set ears, prominent cheeks, a flat and broad nasal bridge, a longer than usual vertical indentation that extends from the middle area of the upper lip to the nose (philtrum), a thin upper lip and jawbone abnormalities like an abnormally small jaw (micrognathia) or the lower jawbone set further back than expected on the face (retrognathia). More common in individuals affected by GPS are prominent eyes (proptosis), a cone-head shaped head and a nose with either a bulbous end or a broad or prominent base. More common in individuals affected by SBBYS are immobile faces that show less expression (mask-like facies). Eye anomalies are also more frequent and can impact visual function including abnormalities of the ducts that supply tears to keep eyes moist (lacrimal ducts), drooping eyes (ptosis) and underdevelopment of eyelids (blepharophimosis) that prevent the eyelids from fully opening and permanently cover part of the eyes.An opening at the top of the mouth (cleft palate) is present in about a third of individuals affected by KAT6B-related disorders. A few individuals with a cleft palate also have jawbone abnormalities and tongue displacement (glossoptosis) that form a cluster of features called Pierre Robin sequence. Tongue displacement can cause additional breathing, eating or swallowing difficulties in infants, but typically improves as the infant grows up.Hearing loss is often present in individuals affected with KAT6B-related disorders. It can be caused by both sound waves incorrectly traveling through the ear (conductive) and damage to the inner ear or hearing nerves (sensorineural).A minority of individuals with KAT6B-related disorders may have thyroid gland function abnormalities that cause less thyroid hormone to be produced (hypothyroidism). Some individuals may have an underdeveloped (hypoplasia) or absent (agenesis) thyroid gland.Most individuals affected by KAT6B-related disorders have genital abnormalities. A male baby may be born with a urethra opening not at its usual location at the head of the penis (hypospadias) and may experience a delay or failure of the testes to descend into the scrotum (cryptorchidism). Females may have an enlarged clitoris and developmental abnormalities of the labia. Males with GPS are more likely to have developmental abnormalities of the scrotum, penis and testes and most females will have a delay in puberty.Some individuals affected by KAT6B-related disorders can experience behavioral or psychiatric issues that can include anxiety, aggressive behavior, attention problems and features suggestive of autism spectrum disorder.Kidney (renal) abnormalities occur in many individuals affected by GPS including kidney swelling, multiple cysts and functional anomalies that can rarely lead to kidney failure in infants.Occasionally, teeth abnormalities may occur in affect individuals with KAT6B-related disorders and can include underdeveloped or absent teeth, a baby being born with teeth (natal teeth), and a child not losing their baby teeth as expected (retained primary dentition). A delay in the eruption of teeth tends to occur more in SBBYS.
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Symptoms of KAT6B-Related Disorders. Variants in the KAT6B gene can lead to a broad spectrum of signs and symptoms. On either side of the spectrum are some clinical features that are associated more often with either genitopatellar syndrome (GPS) or a type of Ohdo syndrome called Say-Barber-Biesecker-Young-Simpson (SBBYS). But individuals affected by KAT6B-related disorders frequently have intermediate clinical features that are a mixture or overlap between these two syndromes. Some individuals have clinical features that do not overlap with either syndrome at all.The potential symptoms associated with a variation in the KAT6B gene are numerous and highly variable and can depend on the specific type of variant (e.g., type of mutation, or location in the gene). This is called genotype-phenotype correlation. It is important to note that every child is unique and how the disorder affects one child can be very different from how it affects another.Neurologic features are present in most individuals affected by KAT6B-related disorders. A child's progression through predictable developmental phases, like sitting up and crawling, may be slowed, stopped or reversed (developmental delays). Global developmental delays can affect both motor functions, like walking, and intellectual development ranging from mild to severe. Speech delays and language disorders are frequent, though some individuals can communicate through vocalization or manipulating objects. Some brain anomalies are more common in individuals affected by GPS including an absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum) that can contribute to developmental delays and can sometimes cause seizures. Less frequently, an unusual amount of cerebrospinal fluid can increase pressure on the brain and cause damage or seizures. Individuals affected by SBBYS are more likely to have an underdeveloped or damaged optic nerve, and impairments in the region of the brain that processes visual information (cortical visual impairment). These can lead to visual deficiencies in one eye (lazy eye) or nearsightedness.Most individuals affected by KAT6B-related disorders have feeding difficulties and gastrointestinal features. Feeding challenges can include difficulty coordinating motor functions and swallowing (dysphagia) which can lead to choking or breathing food, liquid or other foreign material into the lungs (aspiration). Most individuals, especially infants, can have a backflow of the contents of the stomach into the esophagus (gastroesophageal reflux). In some individuals, improper development of the intestines may cause them to settle in the wrong parts of the abdomen, which can cause them to become blocked or twisted (small bowel malrotation) and lead to frequent vomiting or constipation. Additionally, individuals with GPS are more likely to have anal abnormalities, including no anus (anal atresia), a narrowing of the anal canal (anal stenosis), or mispositioning of the anus closer to the front of the body. These conditions can lead to serious health complications from a failure to pass stool. Some individuals affected by KAT6B-related disorders have low muscle tone (hypotonia) and muscle abnormalities. For infants especially this can further complicate feeding and breathing, but often difficulties resolve in infancy. In GPS, infants are more likely to have an abnormality where tissue located above the voice box flops back over the upper-airway (laryngomalacia) and obstructs breathing. Beyond infancy, hypotonia of extremities and the trunk may continue. Nearly all individuals affected with GPS have permanently short and tight muscles (contractures), primarily in the knees and hip, that significantly restrict flexibility and movement. In SBBYS, contractures only occasionally occur.Skeletal and growth abnormalities can also occur. Affected infants may have a condition in which head circumference is smaller than would otherwise be expected based on age and gender (microcephaly). Rarely, flexible sutures in spaces typically found between bones of a baby’s skull turn into bone and join prematurely (craniosynostosis). This can cause changes in skull growth patterns that often result in a misshapen head. In children, additional growth abnormalities can include varying degrees of poor weight gain, diminished physical growth and below average height. More common in individuals affected by GPS are underdeveloped (hypoplastic), dislocated or absent kneecap (patella), clubfoot, and bone abnormalities of the spine, ribs and pelvis. Individuals affected by SBBYS are more likely to have toe and finger abnormalities, and most individuals will have long thumbs and great toes.Roughly half of affected individuals have heart defects that are present from birth (congenital heart defects). These can include atrial and ventricular septal defects. Septal defects are when there is a ‘hole’ in the membrane (septum) that separates the two lower chambers of the heart, called the ventricles, or in the membrane that separates the two upper chambers of the heart, called the atria. Additionally, normal openings in the fetal heart may fail to close at birth (patent ductus arteriosus and patent foramen ovale). Incomplete closure of these holes can allow varying amounts of blood to bypass the lungs where they would normally pick up oxygen. The size of these ‘holes will determine whether any symptoms are present, and how severe these symptoms may be.Distinct facial features associated with KAT6B-related disorders commonly include low-set ears, prominent cheeks, a flat and broad nasal bridge, a longer than usual vertical indentation that extends from the middle area of the upper lip to the nose (philtrum), a thin upper lip and jawbone abnormalities like an abnormally small jaw (micrognathia) or the lower jawbone set further back than expected on the face (retrognathia). More common in individuals affected by GPS are prominent eyes (proptosis), a cone-head shaped head and a nose with either a bulbous end or a broad or prominent base. More common in individuals affected by SBBYS are immobile faces that show less expression (mask-like facies). Eye anomalies are also more frequent and can impact visual function including abnormalities of the ducts that supply tears to keep eyes moist (lacrimal ducts), drooping eyes (ptosis) and underdevelopment of eyelids (blepharophimosis) that prevent the eyelids from fully opening and permanently cover part of the eyes.An opening at the top of the mouth (cleft palate) is present in about a third of individuals affected by KAT6B-related disorders. A few individuals with a cleft palate also have jawbone abnormalities and tongue displacement (glossoptosis) that form a cluster of features called Pierre Robin sequence. Tongue displacement can cause additional breathing, eating or swallowing difficulties in infants, but typically improves as the infant grows up.Hearing loss is often present in individuals affected with KAT6B-related disorders. It can be caused by both sound waves incorrectly traveling through the ear (conductive) and damage to the inner ear or hearing nerves (sensorineural).A minority of individuals with KAT6B-related disorders may have thyroid gland function abnormalities that cause less thyroid hormone to be produced (hypothyroidism). Some individuals may have an underdeveloped (hypoplasia) or absent (agenesis) thyroid gland.Most individuals affected by KAT6B-related disorders have genital abnormalities. A male baby may be born with a urethra opening not at its usual location at the head of the penis (hypospadias) and may experience a delay or failure of the testes to descend into the scrotum (cryptorchidism). Females may have an enlarged clitoris and developmental abnormalities of the labia. Males with GPS are more likely to have developmental abnormalities of the scrotum, penis and testes and most females will have a delay in puberty.Some individuals affected by KAT6B-related disorders can experience behavioral or psychiatric issues that can include anxiety, aggressive behavior, attention problems and features suggestive of autism spectrum disorder.Kidney (renal) abnormalities occur in many individuals affected by GPS including kidney swelling, multiple cysts and functional anomalies that can rarely lead to kidney failure in infants.Occasionally, teeth abnormalities may occur in affect individuals with KAT6B-related disorders and can include underdeveloped or absent teeth, a baby being born with teeth (natal teeth), and a child not losing their baby teeth as expected (retained primary dentition). A delay in the eruption of teeth tends to occur more in SBBYS.
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Causes of KAT6B-Related Disorders
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KAT6B-related disorders are caused by a pathogenic variant (mutation) in the KAT6B gene. This gene is also known as the MORF or MYST4 gene. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a variant occurs, the protein that is created may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many parts of the body.The KAT6B gene contains instructions for creating a type of protein (enzyme) that is classified as a histone acetyltransferase. Its function is to modify histones, which are structural proteins that bind to and tightly wrap DNA, similar to a spool wrapped with thread. Histones help to give chromosomes their signature shape. They also help to control when gene instructions are read (expressed) so the right proteins are produced at the right time for our bodies to function properly. By modifying histones, the KAT6B enzyme helps to control and regulate the expression of many other genes and their proteins throughout the body and, consequently, is involved in many aspects of health and development. A variation in the KAT6B gene that affects its enzyme's ability to work correctly can lead to a wide range of health issues.Researchers are finding that the location of a disease-causing variant within the KAT6B gene can be associated more often with either GPS or SBBYS (genotype-phenotype correlations). Variants that cause GPS are commonly found at the beginning of a set of instructions (exon) in the KAT6B gene called exon 18. It is suspected these variants may cause the KAT6B enzyme to gain the ability to function in inappropriate ways. Variants that cause SBBYS are commonly found at the end of exon 18 and within exons 3, 7, 11, or 14-17. It is suspected these variants may cause the KAT6B enzyme to lose its ability to function.In cases where a variation in the KAT6B gene causes a disorder, it almost always occurs as a new (sporadic or de novo) mutation, which means it occurred randomly in that child without either parent having the mutation. Since the disorder is usually not inherited from or “carried” by a parent, it's estimated there is a 1% risk of the mutation reoccurring in another child from the same parents.If a person with a KAT6B-related disorder were to have a child, they could pass the altered KAT6B gene on to their children through autosomal dominant inheritance. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary for the appearance of the disease. The non-working gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the non-working gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of KAT6B-Related Disorders. KAT6B-related disorders are caused by a pathogenic variant (mutation) in the KAT6B gene. This gene is also known as the MORF or MYST4 gene. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a variant occurs, the protein that is created may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the protein, this can affect many parts of the body.The KAT6B gene contains instructions for creating a type of protein (enzyme) that is classified as a histone acetyltransferase. Its function is to modify histones, which are structural proteins that bind to and tightly wrap DNA, similar to a spool wrapped with thread. Histones help to give chromosomes their signature shape. They also help to control when gene instructions are read (expressed) so the right proteins are produced at the right time for our bodies to function properly. By modifying histones, the KAT6B enzyme helps to control and regulate the expression of many other genes and their proteins throughout the body and, consequently, is involved in many aspects of health and development. A variation in the KAT6B gene that affects its enzyme's ability to work correctly can lead to a wide range of health issues.Researchers are finding that the location of a disease-causing variant within the KAT6B gene can be associated more often with either GPS or SBBYS (genotype-phenotype correlations). Variants that cause GPS are commonly found at the beginning of a set of instructions (exon) in the KAT6B gene called exon 18. It is suspected these variants may cause the KAT6B enzyme to gain the ability to function in inappropriate ways. Variants that cause SBBYS are commonly found at the end of exon 18 and within exons 3, 7, 11, or 14-17. It is suspected these variants may cause the KAT6B enzyme to lose its ability to function.In cases where a variation in the KAT6B gene causes a disorder, it almost always occurs as a new (sporadic or de novo) mutation, which means it occurred randomly in that child without either parent having the mutation. Since the disorder is usually not inherited from or “carried” by a parent, it's estimated there is a 1% risk of the mutation reoccurring in another child from the same parents.If a person with a KAT6B-related disorder were to have a child, they could pass the altered KAT6B gene on to their children through autosomal dominant inheritance. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary for the appearance of the disease. The non-working gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the non-working gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
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Affects of KAT6B-Related Disorders
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KAT6B-related disorders affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to the KAT6 Foundation, as of February 2023, there are 150 individuals around the world known to have a KAT6B gene variant. Rare disorders like KAT6B-related disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population but it is estimated that fewer than one in a million individuals may be affected.
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Affects of KAT6B-Related Disorders. KAT6B-related disorders affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to the KAT6 Foundation, as of February 2023, there are 150 individuals around the world known to have a KAT6B gene variant. Rare disorders like KAT6B-related disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population but it is estimated that fewer than one in a million individuals may be affected.
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Related disorders of KAT6B-Related Disorders
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Clinical features of the following disorders can be similar to those of KAT6B-related disorders. Comparisons may be useful for a differential diagnosis.Meier-Gorlin syndrome is a rare genetic disorder primarily characterized by short stature. Features it can share with KAT6B-related disorders include short or tight muscle fibers that reduce flexibility and movement (contracture) and abnormalities of the knee, skull and genitals. But its differential features can include a severely low birth weight (severe intrauterine and postnatal growth restriction) and under-developed external ears (bilateral microtia). (For more information on this disorder, choose “Meier-Gorlin syndrome” as your search term in the Rare Disease Database.)Cerebro-oculo-facio-skeletal syndrome is a rare degenerative disorder that primarily involves the brain, eyes and spinal cord. Features it can share with KAT6B-related disorders include a smaller than expected head circumference based on age and gender (microcephaly) and intellectual disabilities. But its differential features can include progressive neurodegeneration, clouding of vision (cataracts) and distinctive facial features like low-set ears and small eyes. (For more information on this disorder, choose “Cerebro-oculo-facio-skeletal syndrome” as your search term in the Rare Disease Database.)Congenital contractural arachnodactyly is a rare connective tissue disorder. Features it can share with KAT6B-related disorders include short or tight muscle fibers that reduce flexibility and movement (contracture). But its differential features can include a tall and slender body shape (Marfan-like body habitus), abnormally long and slender fingers and toes (arachnodactyly) and underdeveloped (hypoplastic) calf muscles. (For more information on this disorder, choose “Congenital contractural arachnodactyly Congenital contractural arachnodactyly” as your search term in the Rare Disease Database.)Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare developmental condition. Features it can share with KAT6B-related disorders include underdeveloped and drooping eyelids (blepharophimosis and ptosis). But a differential feature is an upward fold of skin of the inner lower eyelids (epicanthus inversus). (For more information on this disorder, choose “Blepharophimosis, ptosis, epicanthus inversus syndrome” as your search term in the Rare Disease Database.)Nail-patella syndrome is a rare genetic disorder primarily characterized by nail and skeletal abnormalities. Features it can share with KAT6B-related disorders include an absent kneecap, clubfoot and limited mobility of the knees and hips. But its differential features can include high levels of protein in the urine (proteinuria), nail changes and abnormal eye pressures that can lead to optic nerve damage and reduced vision or blindness (open-angle glaucoma). (For more information on this disorder, choose “Nail-patella syndrome“ as your search term in the Rare Disease Database.)RAPADILINO syndrome is a rare condition that affects many parts of the body and bone development. Features it can share with KAT6B-related disorders include an underdeveloped kneecap (hypoplasia), hearing loss and a cleft palate. But its differential features can include irregular light-brown spots on the skin, underdevelopment or absence of the bones in the forearms and the thumbs (radial ray defects) and a lack of intellectual disabilities. (For more information on this disorder, choose “RAPADILINO“ as your search term in the Rare Disease Database.)Small patella syndrome is a rare syndrome mainly characterized by the abnormal development of certain bones. Features it can share with KAT6B-related disorders include a small underdeveloped or missing kneecap (patellar aplasia or hypoplasia). But a differential feature can include severe pelvic bone abnormalities. (For more information on this disorder, choose “Small patella syndrome“ as your search term in the Rare Disease Database.)Mowat-Wilson syndrome is a rare genetic disorder that is characterized by intellectual disability, distinctive facial features and seizures. In addition to intellectual disability, features it can share with KAT6B-related disorders include abnormalities of the heart and genitals, a smaller than expected head circumference based on age and gender (microcephaly) and an absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum). But a differential feature can include the intestinal disorder Hirschsprung disease. (For more information on this disorder, choose “Mowat-Wilson syndrome” as your search term in the Rare Disease Database.)Dubowitz syndrome is a very rare developmental disorder. It shares many features with KAT6B-related disorders not limited to intellectual disability, growth abnormalities, a smaller than expected head circumference based on age and gender (microcephaly), underdeveloped and drooping eyelids (blepharophimosis and ptosis) and genital abnormalities. But differential features can include the skin condition eczema, sparse hair and eyebrows, and frequent infections. (For more information on this disorder, choose “Dubowitz syndrome” as your search term in the Rare Disease Database.)Fetal alcohol spectrum disorders are associated with alcohol exposure during fetal development in utero. Features it can share with KAT6B-related disorders include intellectual disability, underdeveloped eyelids (blepharophimosis) and a smaller than expected head circumference based on age and gender (microcephaly). But a differential feature can include severely low birth weight and much more severe growth restrictions.Toriello-Carey syndrome is a rare condition characterized by multiple anomalies at birth. Features it can share with KAT6B-related disorders include developmental delays, intellectual disability, an absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum), diminished muscle tone (hypotonia), a smaller than expected head circumference based on age and gender (microcephaly) and genital abnormalities. But differential features can include more pronounced and more frequent abnormalities of the jawbone and tongue that cause more frequent obstructions of the upper airways leading to breathing difficulties. (For more information on this disorder, choose “Toriello-Carey syndrome” as your search term in the Rare Disease Database.)
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Related disorders of KAT6B-Related Disorders. Clinical features of the following disorders can be similar to those of KAT6B-related disorders. Comparisons may be useful for a differential diagnosis.Meier-Gorlin syndrome is a rare genetic disorder primarily characterized by short stature. Features it can share with KAT6B-related disorders include short or tight muscle fibers that reduce flexibility and movement (contracture) and abnormalities of the knee, skull and genitals. But its differential features can include a severely low birth weight (severe intrauterine and postnatal growth restriction) and under-developed external ears (bilateral microtia). (For more information on this disorder, choose “Meier-Gorlin syndrome” as your search term in the Rare Disease Database.)Cerebro-oculo-facio-skeletal syndrome is a rare degenerative disorder that primarily involves the brain, eyes and spinal cord. Features it can share with KAT6B-related disorders include a smaller than expected head circumference based on age and gender (microcephaly) and intellectual disabilities. But its differential features can include progressive neurodegeneration, clouding of vision (cataracts) and distinctive facial features like low-set ears and small eyes. (For more information on this disorder, choose “Cerebro-oculo-facio-skeletal syndrome” as your search term in the Rare Disease Database.)Congenital contractural arachnodactyly is a rare connective tissue disorder. Features it can share with KAT6B-related disorders include short or tight muscle fibers that reduce flexibility and movement (contracture). But its differential features can include a tall and slender body shape (Marfan-like body habitus), abnormally long and slender fingers and toes (arachnodactyly) and underdeveloped (hypoplastic) calf muscles. (For more information on this disorder, choose “Congenital contractural arachnodactyly Congenital contractural arachnodactyly” as your search term in the Rare Disease Database.)Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare developmental condition. Features it can share with KAT6B-related disorders include underdeveloped and drooping eyelids (blepharophimosis and ptosis). But a differential feature is an upward fold of skin of the inner lower eyelids (epicanthus inversus). (For more information on this disorder, choose “Blepharophimosis, ptosis, epicanthus inversus syndrome” as your search term in the Rare Disease Database.)Nail-patella syndrome is a rare genetic disorder primarily characterized by nail and skeletal abnormalities. Features it can share with KAT6B-related disorders include an absent kneecap, clubfoot and limited mobility of the knees and hips. But its differential features can include high levels of protein in the urine (proteinuria), nail changes and abnormal eye pressures that can lead to optic nerve damage and reduced vision or blindness (open-angle glaucoma). (For more information on this disorder, choose “Nail-patella syndrome“ as your search term in the Rare Disease Database.)RAPADILINO syndrome is a rare condition that affects many parts of the body and bone development. Features it can share with KAT6B-related disorders include an underdeveloped kneecap (hypoplasia), hearing loss and a cleft palate. But its differential features can include irregular light-brown spots on the skin, underdevelopment or absence of the bones in the forearms and the thumbs (radial ray defects) and a lack of intellectual disabilities. (For more information on this disorder, choose “RAPADILINO“ as your search term in the Rare Disease Database.)Small patella syndrome is a rare syndrome mainly characterized by the abnormal development of certain bones. Features it can share with KAT6B-related disorders include a small underdeveloped or missing kneecap (patellar aplasia or hypoplasia). But a differential feature can include severe pelvic bone abnormalities. (For more information on this disorder, choose “Small patella syndrome“ as your search term in the Rare Disease Database.)Mowat-Wilson syndrome is a rare genetic disorder that is characterized by intellectual disability, distinctive facial features and seizures. In addition to intellectual disability, features it can share with KAT6B-related disorders include abnormalities of the heart and genitals, a smaller than expected head circumference based on age and gender (microcephaly) and an absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum). But a differential feature can include the intestinal disorder Hirschsprung disease. (For more information on this disorder, choose “Mowat-Wilson syndrome” as your search term in the Rare Disease Database.)Dubowitz syndrome is a very rare developmental disorder. It shares many features with KAT6B-related disorders not limited to intellectual disability, growth abnormalities, a smaller than expected head circumference based on age and gender (microcephaly), underdeveloped and drooping eyelids (blepharophimosis and ptosis) and genital abnormalities. But differential features can include the skin condition eczema, sparse hair and eyebrows, and frequent infections. (For more information on this disorder, choose “Dubowitz syndrome” as your search term in the Rare Disease Database.)Fetal alcohol spectrum disorders are associated with alcohol exposure during fetal development in utero. Features it can share with KAT6B-related disorders include intellectual disability, underdeveloped eyelids (blepharophimosis) and a smaller than expected head circumference based on age and gender (microcephaly). But a differential feature can include severely low birth weight and much more severe growth restrictions.Toriello-Carey syndrome is a rare condition characterized by multiple anomalies at birth. Features it can share with KAT6B-related disorders include developmental delays, intellectual disability, an absence of the area of the brain which connects the two cerebral hemispheres (agenesis of the corpus callosum), diminished muscle tone (hypotonia), a smaller than expected head circumference based on age and gender (microcephaly) and genital abnormalities. But differential features can include more pronounced and more frequent abnormalities of the jawbone and tongue that cause more frequent obstructions of the upper airways leading to breathing difficulties. (For more information on this disorder, choose “Toriello-Carey syndrome” as your search term in the Rare Disease Database.)
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Diagnosis of KAT6B-Related Disorders
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A diagnosis of a KAT6B-related disorder is based upon identification of characteristic clinical features, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. No formal diagnostic criteria have been established for KAT6B-related disorders, even if clinical features cause suspicion that an individual may have GPS or SBBYS. A diagnosis can only be confirmed through molecular genetic testing.Clinical Testing and WorkupMolecular genetic testing can detect disease-causing variants in the KAT6B gene but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having a KAT6B-related disorder for a type of molecular genetic test called whole exome sequencing (WES). WES examines the parts of genes that provide instructions to create proteins (exons) and evaluates all the exons within the genome (exome) at the same time. WES can then detect variants in the KAT6B gene or in other genes that may have overlapping clinical features. More recently, the KAT6B gene has been added to a molecular genetic test known as the intellectual disability next generation sequencing (NGS) panel. This test only examines genes throughout the genome that have known associations to intellectual disabilities. This more targeted approach means the test can be less expensive.Affected individuals may undergo additional tests to assess the extent of the disease. Developmental examinations can help assess any developmental delays, including motor function and speech or language delays. Neuropsychological assessments can help evaluate brain function and its impact on cognition and behaviors. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects sometimes associated with the disorder. A test that measures electrical activity in the brain, called an electroencephalogram (EEG), may be recommended if seizures are a concern for the affected individual. Swallow tests to detect feeding issues, routine laboratory blood tests to evaluate kidney and thyroid function, and a physical exam to reveal abnormalities of the knees, muscles, genitalia or anus may also be conducted.
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Diagnosis of KAT6B-Related Disorders. A diagnosis of a KAT6B-related disorder is based upon identification of characteristic clinical features, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. No formal diagnostic criteria have been established for KAT6B-related disorders, even if clinical features cause suspicion that an individual may have GPS or SBBYS. A diagnosis can only be confirmed through molecular genetic testing.Clinical Testing and WorkupMolecular genetic testing can detect disease-causing variants in the KAT6B gene but is available only as a diagnostic service at specialized laboratories. Doctors will take a blood sample of individuals suspected of having a KAT6B-related disorder for a type of molecular genetic test called whole exome sequencing (WES). WES examines the parts of genes that provide instructions to create proteins (exons) and evaluates all the exons within the genome (exome) at the same time. WES can then detect variants in the KAT6B gene or in other genes that may have overlapping clinical features. More recently, the KAT6B gene has been added to a molecular genetic test known as the intellectual disability next generation sequencing (NGS) panel. This test only examines genes throughout the genome that have known associations to intellectual disabilities. This more targeted approach means the test can be less expensive.Affected individuals may undergo additional tests to assess the extent of the disease. Developmental examinations can help assess any developmental delays, including motor function and speech or language delays. Neuropsychological assessments can help evaluate brain function and its impact on cognition and behaviors. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues. An echocardiogram is a test that uses reflected sound waves to create images of the heart and can reveal structural heart defects sometimes associated with the disorder. A test that measures electrical activity in the brain, called an electroencephalogram (EEG), may be recommended if seizures are a concern for the affected individual. Swallow tests to detect feeding issues, routine laboratory blood tests to evaluate kidney and thyroid function, and a physical exam to reveal abnormalities of the knees, muscles, genitalia or anus may also be conducted.
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Therapies of KAT6B-Related Disorders
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TreatmentThe treatment of KAT6B-related disorders is directed toward the specific symptoms that are apparent in each individual. There are no standardized treatment protocols or guidelines, but the coordinated efforts of a team of specialists can help tailor treatments to the affected individual. It is appropriate to routinely evaluate body systems affected by KAT6B-related disorders. Regular, routine evaluation by healthcare professionals can track symptoms as they change or develop over time and treatments can be adjusted by the appropriate to best support current needs.Healthcare professionals that may be part of the care team can include pediatricians, surgeons and physicians who specialize in diagnosing and treating of developmental neurological disorders (neurologists) and disorders of the heart (cardiologists), eye (ophthalmologists), digestive system (gastroenterologists), musculoskeletal system (orthopedists), ears (otolaryngologists), kidneys (nephrologists), and thyroid (endocrinologists). Additionally, physical medicine and rehabilitation therapists (physical, occupational and speech therapists), developmental and neuropsychologists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is also recommended.At infancy and continuing at each clinic visit, feeding, breathing and swallowing issues should be evaluated and appropriately addressed. Feeding therapy may help resolve coordination or other feeding issues. A nasogastric or gastrostomy feeding tube, which delivers food directly to the stomach, may be most appropriate in some situations. Constipation can be severe and requires close on-going monitoring. Many children with congenital heart disease require corrective surgery.Following an initial diagnosis, a developmental assessment may be performed, and appropriate physical medicine and rehabilitation therapies may be instituted. Mobility and flexibility can be addressed by physical and occupational therapy. In some cases, surgery to release muscles, orthopedic devices for proper positioning or durable medical devices for mobility assistance may be required. Behavioral concerns may be addressed by a developmental pediatrician. Speech therapy is often required. Affected children have benefited from the use of sign language and various communication devices. Additional medical, social, or vocational services including specialized learning programs may be necessary, including an individualized learning plan (IEP) and 504 plan that are updated regularly.
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Therapies of KAT6B-Related Disorders. TreatmentThe treatment of KAT6B-related disorders is directed toward the specific symptoms that are apparent in each individual. There are no standardized treatment protocols or guidelines, but the coordinated efforts of a team of specialists can help tailor treatments to the affected individual. It is appropriate to routinely evaluate body systems affected by KAT6B-related disorders. Regular, routine evaluation by healthcare professionals can track symptoms as they change or develop over time and treatments can be adjusted by the appropriate to best support current needs.Healthcare professionals that may be part of the care team can include pediatricians, surgeons and physicians who specialize in diagnosing and treating of developmental neurological disorders (neurologists) and disorders of the heart (cardiologists), eye (ophthalmologists), digestive system (gastroenterologists), musculoskeletal system (orthopedists), ears (otolaryngologists), kidneys (nephrologists), and thyroid (endocrinologists). Additionally, physical medicine and rehabilitation therapists (physical, occupational and speech therapists), developmental and neuropsychologists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is also recommended.At infancy and continuing at each clinic visit, feeding, breathing and swallowing issues should be evaluated and appropriately addressed. Feeding therapy may help resolve coordination or other feeding issues. A nasogastric or gastrostomy feeding tube, which delivers food directly to the stomach, may be most appropriate in some situations. Constipation can be severe and requires close on-going monitoring. Many children with congenital heart disease require corrective surgery.Following an initial diagnosis, a developmental assessment may be performed, and appropriate physical medicine and rehabilitation therapies may be instituted. Mobility and flexibility can be addressed by physical and occupational therapy. In some cases, surgery to release muscles, orthopedic devices for proper positioning or durable medical devices for mobility assistance may be required. Behavioral concerns may be addressed by a developmental pediatrician. Speech therapy is often required. Affected children have benefited from the use of sign language and various communication devices. Additional medical, social, or vocational services including specialized learning programs may be necessary, including an individualized learning plan (IEP) and 504 plan that are updated regularly.
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Overview of Kawasaki Disease
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Kawasaki disease is an acute multisystem inflammatory disease of blood vessels (vasculitis) that most commonly affects infants and young children. The disease may be characterized by a high fever, inflammation of the mucous membranes of the mouth and throat, a reddish skin rash, and swelling of lymph nodes (lymphadenopathy). In addition, individuals with Kawasaki disease may develop inflammation of arteries that transport blood to heart muscle (coronary arteritis), associated widening or bulging (aneurysms) of the walls of affected coronary arteries, inflammation of heart muscle (myocarditis), and/or other symptoms and findings. Kawasaki disease is the primary cause of acquired heart disease in children in the United States. Although the cause of the disease is unknown, it is widely thought to be due to infection or an abnormal immune response to infection.
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Overview of Kawasaki Disease. Kawasaki disease is an acute multisystem inflammatory disease of blood vessels (vasculitis) that most commonly affects infants and young children. The disease may be characterized by a high fever, inflammation of the mucous membranes of the mouth and throat, a reddish skin rash, and swelling of lymph nodes (lymphadenopathy). In addition, individuals with Kawasaki disease may develop inflammation of arteries that transport blood to heart muscle (coronary arteritis), associated widening or bulging (aneurysms) of the walls of affected coronary arteries, inflammation of heart muscle (myocarditis), and/or other symptoms and findings. Kawasaki disease is the primary cause of acquired heart disease in children in the United States. Although the cause of the disease is unknown, it is widely thought to be due to infection or an abnormal immune response to infection.
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Symptoms of Kawasaki Disease
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In many affected children, the initial symptom associated with Kawasaki disease is a high fever that typically rises and falls (remittent fever) and lasts for approximately one to two weeks without treatment. In some cases, fever may persist for up to about three to four weeks. Additional characteristic features include inflammation of the whites of the eyes (bilateral conjunctivitis); inflammation of mucous membranes of the mouth and throat, resulting in dry, red, cracked lips and a strawberry-red tongue; swelling of lymph nodes in the neck (cervical lymphadenopathy); redness and swelling of the hands and feet; and a reddish rash, typically affecting the trunk and often involving the groin area. By about the second or third week, skin tissue may peel (desquamate) from the tips of the fingers and toes and may progress to involve the hands and feet.In many cases, affected children may have additional symptoms and findings, such as irritability, diarrhea, vomiting, coughing, and/or joint inflammation (arthritis), pain, and swelling. Other associated abnormalities may include enlargement of the liver and spleen (hepatosplenomegaly), inflammation of the protective membranes covering the brain (aseptic meningitis), inflammation of the middle ear (otitis media), and/or other findings. Many individuals with Kawasaki disease may also have heart (cardiac) involvement. Up to 50 percent may develop inflammation of heart muscle (myocarditis), which may be associated with an abnormally increased heart rate (tachycardia), decreased ventricular (lower heart chamber) functioning, and, in severe cases, impaired ability of the heart to effectively pump blood to the lungs and the rest of the body (heart failure). In addition, in some cases, heart involvement may include inflammation of the membranous sac surrounding the heart (pericarditis), leakage of certain heart valves (aortic or mitral valve insufficiency), or other abnormalities. The most serious cardiac complication is inflammation of arteries that provide oxygen-rich blood to heart muscle (coronary arteritis) and possible weakening, widening (dilation), and bulging (aneurysms) of affected arterial walls. Dilation and aneurysm formation occur in approximately three to 20 percent of patients. In severe cases, complications may include the development of blood clots in the ballooned area with obstruction of blood flow, bursting (rupture) of an aneurysm, or heart attack, leading to potentially life-threatening complications. Some cases have also been reported in which patients, particularly infants, have fever with fewer than four other features of the disease (see “Diagnosis” below) and subsequently develop coronary artery disease.
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Symptoms of Kawasaki Disease. In many affected children, the initial symptom associated with Kawasaki disease is a high fever that typically rises and falls (remittent fever) and lasts for approximately one to two weeks without treatment. In some cases, fever may persist for up to about three to four weeks. Additional characteristic features include inflammation of the whites of the eyes (bilateral conjunctivitis); inflammation of mucous membranes of the mouth and throat, resulting in dry, red, cracked lips and a strawberry-red tongue; swelling of lymph nodes in the neck (cervical lymphadenopathy); redness and swelling of the hands and feet; and a reddish rash, typically affecting the trunk and often involving the groin area. By about the second or third week, skin tissue may peel (desquamate) from the tips of the fingers and toes and may progress to involve the hands and feet.In many cases, affected children may have additional symptoms and findings, such as irritability, diarrhea, vomiting, coughing, and/or joint inflammation (arthritis), pain, and swelling. Other associated abnormalities may include enlargement of the liver and spleen (hepatosplenomegaly), inflammation of the protective membranes covering the brain (aseptic meningitis), inflammation of the middle ear (otitis media), and/or other findings. Many individuals with Kawasaki disease may also have heart (cardiac) involvement. Up to 50 percent may develop inflammation of heart muscle (myocarditis), which may be associated with an abnormally increased heart rate (tachycardia), decreased ventricular (lower heart chamber) functioning, and, in severe cases, impaired ability of the heart to effectively pump blood to the lungs and the rest of the body (heart failure). In addition, in some cases, heart involvement may include inflammation of the membranous sac surrounding the heart (pericarditis), leakage of certain heart valves (aortic or mitral valve insufficiency), or other abnormalities. The most serious cardiac complication is inflammation of arteries that provide oxygen-rich blood to heart muscle (coronary arteritis) and possible weakening, widening (dilation), and bulging (aneurysms) of affected arterial walls. Dilation and aneurysm formation occur in approximately three to 20 percent of patients. In severe cases, complications may include the development of blood clots in the ballooned area with obstruction of blood flow, bursting (rupture) of an aneurysm, or heart attack, leading to potentially life-threatening complications. Some cases have also been reported in which patients, particularly infants, have fever with fewer than four other features of the disease (see “Diagnosis” below) and subsequently develop coronary artery disease.
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Causes of Kawasaki Disease
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Although the exact cause of Kawasaki disease is not known, evidence indicates an infection or an inappropriate immune response to infection. However, despite much research in this area, a specific infectious cause has not been identified. Recent evidence by Yale University investigators (2005) suggests that a newly discovered coronavirus may have a role in Kawasaki disease. Additional research is needed. Some researchers suggest that the disease may be caused by certain toxic substances, called bacterial “superantigens,” that are produced by particular types of bacteria, such as streptococci or staphylococci. They indicate that such superantigens may trigger an exaggerated response of the immune system, resulting in infiltration of blood vessel walls with certain white blood cells, associated blood vessel inflammation (vasculitis), and cardiovascular damage. However, other researchers suggest that one or more conventional antigens may be involved in causing the inflammatory disease process. (An antigen is any substance that may trigger a particular immune response, such as foreign proteins, including microorganisms.) Further research is necessary to determine the role specific antigens or “superantigens” may play in causing Kawasaki disease.
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Causes of Kawasaki Disease. Although the exact cause of Kawasaki disease is not known, evidence indicates an infection or an inappropriate immune response to infection. However, despite much research in this area, a specific infectious cause has not been identified. Recent evidence by Yale University investigators (2005) suggests that a newly discovered coronavirus may have a role in Kawasaki disease. Additional research is needed. Some researchers suggest that the disease may be caused by certain toxic substances, called bacterial “superantigens,” that are produced by particular types of bacteria, such as streptococci or staphylococci. They indicate that such superantigens may trigger an exaggerated response of the immune system, resulting in infiltration of blood vessel walls with certain white blood cells, associated blood vessel inflammation (vasculitis), and cardiovascular damage. However, other researchers suggest that one or more conventional antigens may be involved in causing the inflammatory disease process. (An antigen is any substance that may trigger a particular immune response, such as foreign proteins, including microorganisms.) Further research is necessary to determine the role specific antigens or “superantigens” may play in causing Kawasaki disease.
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Affects of Kawasaki Disease
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Kawasaki disease most frequently affects children five years of age or younger. In extremely rare cases, Kawasaki disease may occur during adolescence or adulthood. First reported in Japanese children in the 1960s, the disease is now recognized worldwide and occurs in individuals in all racial and ethnic groups. However, Kawasaki disease appears to affect Asian children most frequently. Estimates indicate that at least 3,000 cases of Kawasaki disease are diagnosed each year in the United States. Males appear to be affected more frequently than females by a ratio of approximately 1.5 to 1.
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Affects of Kawasaki Disease. Kawasaki disease most frequently affects children five years of age or younger. In extremely rare cases, Kawasaki disease may occur during adolescence or adulthood. First reported in Japanese children in the 1960s, the disease is now recognized worldwide and occurs in individuals in all racial and ethnic groups. However, Kawasaki disease appears to affect Asian children most frequently. Estimates indicate that at least 3,000 cases of Kawasaki disease are diagnosed each year in the United States. Males appear to be affected more frequently than females by a ratio of approximately 1.5 to 1.
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Related disorders of Kawasaki Disease
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Symptoms of the following disorders may be similar to those of Kawasaki disease. Comparisons may be useful for a differential diagnosis:Measles is a highly contagious viral disease occurring primarily in children. Symptoms may include fever, cough, sore throat, runny nose, redness of the eyes (conjunctivitis), and increased sensitivity to light (photophobia). Small red spots with bluish or whitish centers may appear on the inner cheeks (Koplik's spots). In addition, a characteristic red skin rash develops.Scarlet fever is an infectious disease of childhood caused by toxins produced by Streptococcal bacteria. It may be characterized by fever, vomiting, headache, sore throat, enlarged lymph nodes in the neck, a flushed face, a pale area around the mouth, an inflamed tongue, and a widespread red rash, often with peeling of the skin.Toxic shock syndrome is a rare infectious disease caused by toxins produced by the bacterium Staphylococcus aureus. Symptoms may include a sudden high fever, vomiting, diarrhea, headache, sore throat, red eyes, and/or a characteristic sunburn-like skin rash with peeling of the skin, particularly of the palms and soles. With disease progression, affected individuals may develop dangerously low blood pressure (hypotension), liver and kidney failure, and dysfunction of other organs. Without early diagnosis and appropriate treatment, life-threatening complications may result. Toxic shock syndrome is most common in menstruating women who use highly absorbent tampons. Other cases have been reported in association with postoperative wound infections, nasal packing, or other factors. (For more information on this disorder, choose “toxic shock” as your search term in the Rare Disease Database.)A number of additional infectious and non-infectious diseases may be associated with certain symptoms similar to those potentially associated with Kawasaki disease. (For further information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Related disorders of Kawasaki Disease. Symptoms of the following disorders may be similar to those of Kawasaki disease. Comparisons may be useful for a differential diagnosis:Measles is a highly contagious viral disease occurring primarily in children. Symptoms may include fever, cough, sore throat, runny nose, redness of the eyes (conjunctivitis), and increased sensitivity to light (photophobia). Small red spots with bluish or whitish centers may appear on the inner cheeks (Koplik's spots). In addition, a characteristic red skin rash develops.Scarlet fever is an infectious disease of childhood caused by toxins produced by Streptococcal bacteria. It may be characterized by fever, vomiting, headache, sore throat, enlarged lymph nodes in the neck, a flushed face, a pale area around the mouth, an inflamed tongue, and a widespread red rash, often with peeling of the skin.Toxic shock syndrome is a rare infectious disease caused by toxins produced by the bacterium Staphylococcus aureus. Symptoms may include a sudden high fever, vomiting, diarrhea, headache, sore throat, red eyes, and/or a characteristic sunburn-like skin rash with peeling of the skin, particularly of the palms and soles. With disease progression, affected individuals may develop dangerously low blood pressure (hypotension), liver and kidney failure, and dysfunction of other organs. Without early diagnosis and appropriate treatment, life-threatening complications may result. Toxic shock syndrome is most common in menstruating women who use highly absorbent tampons. Other cases have been reported in association with postoperative wound infections, nasal packing, or other factors. (For more information on this disorder, choose “toxic shock” as your search term in the Rare Disease Database.)A number of additional infectious and non-infectious diseases may be associated with certain symptoms similar to those potentially associated with Kawasaki disease. (For further information on such disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
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Diagnosis of Kawasaki Disease
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Kawasaki disease is diagnosed based on a thorough clinical evaluation; a detailed patient history; and detection of characteristic features, including fever of at least five days and at least four of five characteristic signs (reddened eyes; changes of the lips and mouth; reddish, swollen extremities; rash; and swollen lymph nodes). Laboratory tests may reveal certain non-specific, though characteristic findings, including increased numbers of white blood cells (leukocytosis) and low levels of red blood cells (anemia) during early illness, with a rapidly rising blood platelet count by the second to third week after onset.In addition, diagnostic tests should be conducted in all individuals with Kawasaki disease to detect possible heart involvement. Such testing may include echocardiography at diagnosis as well as at recommended intervals (e.g., at two to three weeks, six to eight weeks, and potentially six to 12 months after onset). During an echocardiogram, high-frequency sound waves are directed toward the heart, enabling physicians to study cardiac structure and function. Electrocardiograms (EKGs) are often performed along with echocardiograms. An EKG records the electrical activities of heart muscle. For children who develop coronary artery abnormalities, physicians may advise more frequent echocardiography and additional cardiac tests (e.g., stress testing, coronary angiography, and/or other tests). The recommended frequency and the specific tests used during long-term follow-up will be based on various factors, including clinical course, degree of coronary artery involvement, and patient age.
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Diagnosis of Kawasaki Disease. Kawasaki disease is diagnosed based on a thorough clinical evaluation; a detailed patient history; and detection of characteristic features, including fever of at least five days and at least four of five characteristic signs (reddened eyes; changes of the lips and mouth; reddish, swollen extremities; rash; and swollen lymph nodes). Laboratory tests may reveal certain non-specific, though characteristic findings, including increased numbers of white blood cells (leukocytosis) and low levels of red blood cells (anemia) during early illness, with a rapidly rising blood platelet count by the second to third week after onset.In addition, diagnostic tests should be conducted in all individuals with Kawasaki disease to detect possible heart involvement. Such testing may include echocardiography at diagnosis as well as at recommended intervals (e.g., at two to three weeks, six to eight weeks, and potentially six to 12 months after onset). During an echocardiogram, high-frequency sound waves are directed toward the heart, enabling physicians to study cardiac structure and function. Electrocardiograms (EKGs) are often performed along with echocardiograms. An EKG records the electrical activities of heart muscle. For children who develop coronary artery abnormalities, physicians may advise more frequent echocardiography and additional cardiac tests (e.g., stress testing, coronary angiography, and/or other tests). The recommended frequency and the specific tests used during long-term follow-up will be based on various factors, including clinical course, degree of coronary artery involvement, and patient age.
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Therapies of Kawasaki Disease
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TreatmentExperts indicate that children with Kawasaki disease should be treated by or in consultation with pediatricians who specialize in the diagnosis and treatment of heart disorders (pediatric cardiologists).Research has shown that early diagnosis and treatment speeds the resolution of fever and other acute symptoms and significantly lowers the risk of heart damage. Treatment is started as soon as possible after diagnosis and may include high-dose intravenous immune globulin (IGIV) and high-dose aspirin therapy. Immune globulin is a special preparation containing antibodies obtained from the fluid portion of the blood. Evidence indicates that, when given within the first 10 days of onset, IGIV reduces the incidence of coronary artery abnormalities from about 20 percent in patients receiving aspirin alone to three to four percent.In rare cases, patients may have an insufficient response to initial IGIV treatment and may require re-treatment.The Food and Drug Administration (FDA) has approved the following IGIV products (immune globulin intravenous [human]) for the treatment of Kawasaki disease: Gammagard S/D, manufactured by Baxter Healthcare; Venoglobulin-S, manufactured by Alpha Therapeutic; Venoglobulin-I, manufactured by Alpha Therapeutic; and Iveegam, manufactured by Baxter Healthcare.By the 14th day of illness or after resolution of fever, a lower dose of aspirin is typically given for its antiplatelet effect to help prevent blood clots from forming. Such therapy may be continued for up to eight weeks after onset in children without abnormalities detected by echocardiography. However, physicians may advise that aspirin therapy be continued indefinitely for those with coronary artery abnormalities. In some cases, individuals who have multiple or large coronary aneurysms may also receive therapy with anticlotting medications, such as dipyridamole or warfarin.Due to a small risk of Reye syndrome during outbreaks of flu (influenza) and chickenpox, physicians may recommend annual influenza vaccination for children who require long-term aspirin therapy. (Reye syndrome is a rare disorder of childhood characterized by fatty changes of the liver and acute swelling of the brain. There appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications [salicylates] in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections [e.g., influenza B] or, in some cases, chickenpox.. If affected children develop symptoms of flu or chickenpox, parents should immediately alert their child's physician, who may recommend temporary interruption of aspirin therapy or temporary substitution with dipyridamole.In rare cases, coronary artery bypass surgery or heart transplantation may be recommended for individuals with severe heart involvement. Treatment with corticosteroid drugs is not recommended for children with Kawasaki disease. Other treatment for affected individuals is symptomatic and supportive.
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Therapies of Kawasaki Disease. TreatmentExperts indicate that children with Kawasaki disease should be treated by or in consultation with pediatricians who specialize in the diagnosis and treatment of heart disorders (pediatric cardiologists).Research has shown that early diagnosis and treatment speeds the resolution of fever and other acute symptoms and significantly lowers the risk of heart damage. Treatment is started as soon as possible after diagnosis and may include high-dose intravenous immune globulin (IGIV) and high-dose aspirin therapy. Immune globulin is a special preparation containing antibodies obtained from the fluid portion of the blood. Evidence indicates that, when given within the first 10 days of onset, IGIV reduces the incidence of coronary artery abnormalities from about 20 percent in patients receiving aspirin alone to three to four percent.In rare cases, patients may have an insufficient response to initial IGIV treatment and may require re-treatment.The Food and Drug Administration (FDA) has approved the following IGIV products (immune globulin intravenous [human]) for the treatment of Kawasaki disease: Gammagard S/D, manufactured by Baxter Healthcare; Venoglobulin-S, manufactured by Alpha Therapeutic; Venoglobulin-I, manufactured by Alpha Therapeutic; and Iveegam, manufactured by Baxter Healthcare.By the 14th day of illness or after resolution of fever, a lower dose of aspirin is typically given for its antiplatelet effect to help prevent blood clots from forming. Such therapy may be continued for up to eight weeks after onset in children without abnormalities detected by echocardiography. However, physicians may advise that aspirin therapy be continued indefinitely for those with coronary artery abnormalities. In some cases, individuals who have multiple or large coronary aneurysms may also receive therapy with anticlotting medications, such as dipyridamole or warfarin.Due to a small risk of Reye syndrome during outbreaks of flu (influenza) and chickenpox, physicians may recommend annual influenza vaccination for children who require long-term aspirin therapy. (Reye syndrome is a rare disorder of childhood characterized by fatty changes of the liver and acute swelling of the brain. There appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications [salicylates] in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections [e.g., influenza B] or, in some cases, chickenpox.. If affected children develop symptoms of flu or chickenpox, parents should immediately alert their child's physician, who may recommend temporary interruption of aspirin therapy or temporary substitution with dipyridamole.In rare cases, coronary artery bypass surgery or heart transplantation may be recommended for individuals with severe heart involvement. Treatment with corticosteroid drugs is not recommended for children with Kawasaki disease. Other treatment for affected individuals is symptomatic and supportive.
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Overview of KBG Syndrome
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KBG syndrome (KBGS) is a rare genetic disorder characterized by large front teeth (macrodontia), characteristic facial features, short to normal stature, developmental delay or intellectual disability (the level of intellectual disability is usually mild, and there are also people with KBGS who have a normal development). Behavioral issues are common. People with KBGS can have skeletal abnormalities (such as short fingers, delayed closure of the fontanelle or scoliosis), hearing loss and feeding difficulties (particularly in infancy), and some have epilepsy (seizures) or brain malformations. The specific symptoms may vary from one person to another. KBG syndrome is caused by a change (variant or mutation) in the ANKRD11 gene or a loss of genetic material (microdeletion) on chromosome 16q that involves the ANKRD11 gene. Variants of this gene can occur spontaneously with no family history or be inherited in an autosomal dominant manner. KBG syndrome is named after the initials of the last names of the first three families identified with this disorder in the medical literature in 1975.
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Overview of KBG Syndrome. KBG syndrome (KBGS) is a rare genetic disorder characterized by large front teeth (macrodontia), characteristic facial features, short to normal stature, developmental delay or intellectual disability (the level of intellectual disability is usually mild, and there are also people with KBGS who have a normal development). Behavioral issues are common. People with KBGS can have skeletal abnormalities (such as short fingers, delayed closure of the fontanelle or scoliosis), hearing loss and feeding difficulties (particularly in infancy), and some have epilepsy (seizures) or brain malformations. The specific symptoms may vary from one person to another. KBG syndrome is caused by a change (variant or mutation) in the ANKRD11 gene or a loss of genetic material (microdeletion) on chromosome 16q that involves the ANKRD11 gene. Variants of this gene can occur spontaneously with no family history or be inherited in an autosomal dominant manner. KBG syndrome is named after the initials of the last names of the first three families identified with this disorder in the medical literature in 1975.
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Symptoms of KBG Syndrome
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Children with KBG syndrome may display characteristic physical abnormalities of the head and face (craniofacial dysmorphism). The shape of the skull can be abnormal, with a flat back of the head (brachycephaly). Characteristic facial features may include eyes that appear widely spaced apart (hypertelorism) or crossed (strabismus); wide, bushy eyebrows; thin, bow-shaped lips; prominent ears; and/or a triangularly shaped face. There is typically a full tip of the nose with upturned nostrils. Characteristic features may also include large teeth (macrodontia). Macrodontia is particularly common in KBG syndrome and often affects the two upper middle teeth (upper central incisors) and sometimes other teeth as well. Affected individuals may also have jagged, crowded or misaligned teeth and/or unusually short, flattened, supporting bones or sockets of the jaw (mandible) that house the teeth (alveolar ridges). Microcephaly has been described in some children. Microcephaly is a condition in which the circumference of the head is smaller than would be otherwise expected based on age and gender. However, most children with KBG syndrome have a normal head size.A child with KBG syndrome may also have speech and hearing impairments, and/or have mild to moderate levels of intellectual disability. Children with intellectual disability may experience delays in reaching developmental milestones. Most children will only experience mild learning disabilities. Other children will not have intellectual disabilities and have no issues with learning or thinking that are related to KBG syndrome. Part of the adults with KBG syndrome can live independently, but other adults with KBG need external help or live in assisted facilities.People (especially children) with KBGS may have hearing loss. This can be sensorineural or perceptive and might require treatment such as hearing aids. Children experience recurrent ear infections (otitis media), which may contribute to hearing loss.Some children have behavioral issues such as impulsivity or poor concentration, sometimes with a diagnosis of attention deficit hyperactivity disorder (ADHD), temper tantrums, anxiety or shyness, or compulsive and sometimes aggressive behavior. Autism spectrum disorder or autistic traits can also be present in children with KBG syndrome. The nature of the behavioral issues is variable.Some children have epilepsy, usually during childhood. The type of epilepsy can vary from generalized or partial seizures that respond well to therapy, to more complex forms of epilepsy that are difficult to treat. Some children also have EEG abnormalities without signs of seizures. Sometimes MRI scans of the brain show abnormalities.About 40% of people with KBGS have a short stature. Affected children may have delayed bone age, which means that a child’s bones mature at a slower rate. Other malformations of the bones can be present, such as spinal abnormalities (abnormal vertebrae or ribs); the shortened middle portion of the thigh bones (femoral neck); abnormally developed hip bones (hip dysplasia/Perthes disease); and/or shortened, hollow finger bones (metacarpals). Scoliosis (sideways curve of the spine) is quite common. In some children, associated features may include a sunken, pushed-in appearance of the chest (pectus excavatum or “funnel chest”); a single deep crease across the palms of the hands (simian crease); certain bones of the hands may be short (short tubular bones of the hands), pinkies that are unusually short (brachydactyly) and/or that may be stuck in a bent position (clinodactyly). Less commonly, additional findings have been reported in some children including congenital heart defects, defects affecting the roof of the mouth (palate), webbing or fusion (syndactyly) of the middle toes and a webbed, short neck. Some males may have undescended testicles (cryptorchidism). Advanced puberty has been reported in some children. Some infants have sleep difficulties. Feeding difficulties are present in about 20% of people with KBGS and can include vomiting, constipation and gastroesophageal reflux disease.Some children with KBGS have been reported to have incomplete closure of certain bones of the spinal column (spina bifida) or inelastic tissue on the caudal spinal cord (tethered cord). People with KBG might have various eye and vision problems such as crossed eyes (strabismus), cloudy lenses of the eyes (congenital cataracts), blurred vision or other vision problems. Some patients have skin or hair differences including dark spots on the skin (hyperpigmentation); dry, itchy skin; excess body hair (hypertrichosis); abnormal hair patterns on the scalp and/or deformed, thickened or discolored nails.Delayed closure of the ‘soft spots’ or fontanelles has also been reported. An infant’s skull has seven bones and several joints called sutures. Sutures are made of tough, elastic fibrous tissue and separate the bones from one another. Sutures meet up (intersect) at two spots on the skull called fontanelles, which are better known as an infant’s “soft spots”. The seven bones of an infant’s skull normally do not fuse together until around age two or later. The sutures normally remain flexible until this point. In some infants, this fusion is delayed. The fontanelle can also be unusually large at birth.
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Symptoms of KBG Syndrome. Children with KBG syndrome may display characteristic physical abnormalities of the head and face (craniofacial dysmorphism). The shape of the skull can be abnormal, with a flat back of the head (brachycephaly). Characteristic facial features may include eyes that appear widely spaced apart (hypertelorism) or crossed (strabismus); wide, bushy eyebrows; thin, bow-shaped lips; prominent ears; and/or a triangularly shaped face. There is typically a full tip of the nose with upturned nostrils. Characteristic features may also include large teeth (macrodontia). Macrodontia is particularly common in KBG syndrome and often affects the two upper middle teeth (upper central incisors) and sometimes other teeth as well. Affected individuals may also have jagged, crowded or misaligned teeth and/or unusually short, flattened, supporting bones or sockets of the jaw (mandible) that house the teeth (alveolar ridges). Microcephaly has been described in some children. Microcephaly is a condition in which the circumference of the head is smaller than would be otherwise expected based on age and gender. However, most children with KBG syndrome have a normal head size.A child with KBG syndrome may also have speech and hearing impairments, and/or have mild to moderate levels of intellectual disability. Children with intellectual disability may experience delays in reaching developmental milestones. Most children will only experience mild learning disabilities. Other children will not have intellectual disabilities and have no issues with learning or thinking that are related to KBG syndrome. Part of the adults with KBG syndrome can live independently, but other adults with KBG need external help or live in assisted facilities.People (especially children) with KBGS may have hearing loss. This can be sensorineural or perceptive and might require treatment such as hearing aids. Children experience recurrent ear infections (otitis media), which may contribute to hearing loss.Some children have behavioral issues such as impulsivity or poor concentration, sometimes with a diagnosis of attention deficit hyperactivity disorder (ADHD), temper tantrums, anxiety or shyness, or compulsive and sometimes aggressive behavior. Autism spectrum disorder or autistic traits can also be present in children with KBG syndrome. The nature of the behavioral issues is variable.Some children have epilepsy, usually during childhood. The type of epilepsy can vary from generalized or partial seizures that respond well to therapy, to more complex forms of epilepsy that are difficult to treat. Some children also have EEG abnormalities without signs of seizures. Sometimes MRI scans of the brain show abnormalities.About 40% of people with KBGS have a short stature. Affected children may have delayed bone age, which means that a child’s bones mature at a slower rate. Other malformations of the bones can be present, such as spinal abnormalities (abnormal vertebrae or ribs); the shortened middle portion of the thigh bones (femoral neck); abnormally developed hip bones (hip dysplasia/Perthes disease); and/or shortened, hollow finger bones (metacarpals). Scoliosis (sideways curve of the spine) is quite common. In some children, associated features may include a sunken, pushed-in appearance of the chest (pectus excavatum or “funnel chest”); a single deep crease across the palms of the hands (simian crease); certain bones of the hands may be short (short tubular bones of the hands), pinkies that are unusually short (brachydactyly) and/or that may be stuck in a bent position (clinodactyly). Less commonly, additional findings have been reported in some children including congenital heart defects, defects affecting the roof of the mouth (palate), webbing or fusion (syndactyly) of the middle toes and a webbed, short neck. Some males may have undescended testicles (cryptorchidism). Advanced puberty has been reported in some children. Some infants have sleep difficulties. Feeding difficulties are present in about 20% of people with KBGS and can include vomiting, constipation and gastroesophageal reflux disease.Some children with KBGS have been reported to have incomplete closure of certain bones of the spinal column (spina bifida) or inelastic tissue on the caudal spinal cord (tethered cord). People with KBG might have various eye and vision problems such as crossed eyes (strabismus), cloudy lenses of the eyes (congenital cataracts), blurred vision or other vision problems. Some patients have skin or hair differences including dark spots on the skin (hyperpigmentation); dry, itchy skin; excess body hair (hypertrichosis); abnormal hair patterns on the scalp and/or deformed, thickened or discolored nails.Delayed closure of the ‘soft spots’ or fontanelles has also been reported. An infant’s skull has seven bones and several joints called sutures. Sutures are made of tough, elastic fibrous tissue and separate the bones from one another. Sutures meet up (intersect) at two spots on the skull called fontanelles, which are better known as an infant’s “soft spots”. The seven bones of an infant’s skull normally do not fuse together until around age two or later. The sutures normally remain flexible until this point. In some infants, this fusion is delayed. The fontanelle can also be unusually large at birth.
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Causes of KBG Syndrome
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KBG syndrome is caused by either an alteration (variant or mutation) in the ANKRD11 gene or a loss of genetic material from chromosome 16q that includes the ANKRD11 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.The ANKRD11 gene contains instructions for creating a protein that is active in nerve cells (neurons). The exact role of this protein is not fully understood. When the ANKRD11 gene is altered or missing, individuals cannot produce enough functional copies of this protein. More research is necessary to determine how low levels of the protein product of the ANKRD11 gene causes the symptoms of KBG syndrome.KBG syndrome is inherited in an autosomal dominant pattern. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered or missing gene is necessary to cause a particular disease. The affected gene can be inherited from either parent or can be the result of a new, spontaneous gene change in the affected individual. This may be referred to as a “de novo” change. The risk of passing the altered gene or missing chromosome segment from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of KBG Syndrome. KBG syndrome is caused by either an alteration (variant or mutation) in the ANKRD11 gene or a loss of genetic material from chromosome 16q that includes the ANKRD11 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.The ANKRD11 gene contains instructions for creating a protein that is active in nerve cells (neurons). The exact role of this protein is not fully understood. When the ANKRD11 gene is altered or missing, individuals cannot produce enough functional copies of this protein. More research is necessary to determine how low levels of the protein product of the ANKRD11 gene causes the symptoms of KBG syndrome.KBG syndrome is inherited in an autosomal dominant pattern. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered or missing gene is necessary to cause a particular disease. The affected gene can be inherited from either parent or can be the result of a new, spontaneous gene change in the affected individual. This may be referred to as a “de novo” change. The risk of passing the altered gene or missing chromosome segment from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Affects of KBG Syndrome
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KBG syndrome is a rare disorder that affects males and females. Currently, more than 150 cases have been reported in the medical literature. The actual number of patients worldwide is much higher. The disorder can go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of KBG syndrome in the general population.
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Affects of KBG Syndrome. KBG syndrome is a rare disorder that affects males and females. Currently, more than 150 cases have been reported in the medical literature. The actual number of patients worldwide is much higher. The disorder can go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of KBG syndrome in the general population.
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Related disorders of KBG Syndrome
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Symptoms of the following disorders can be similar to those of KBG syndrome. Comparisons may be useful for a differential diagnosis:Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth delay); characteristic differences of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly); a prominent vertical groove between the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils (anteverted nares); and a protruding upper jaw (maxillary prognathism) with small chin (micrognathia). Additional characteristic facial abnormalities may include thin, downturned lips; low-set ears; arched, well-defined eyebrows that grow together across the base of the nose (synophrys); an unusually low hairline on the forehead and the back of the neck; and curly, unusually long eyelashes. Affected individuals may also have distinctive malformations of the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers, and webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands, and fingers. Infants with CdLS may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched “growling” cry and low voice; heart defects; delayed skeletal maturation; hearing loss; or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from person to person. (For more information, choose “Cornelia de Lange” as your search term in the Rare Disease Database).
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Related disorders of KBG Syndrome. Symptoms of the following disorders can be similar to those of KBG syndrome. Comparisons may be useful for a differential diagnosis:Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth delay); characteristic differences of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly); a prominent vertical groove between the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils (anteverted nares); and a protruding upper jaw (maxillary prognathism) with small chin (micrognathia). Additional characteristic facial abnormalities may include thin, downturned lips; low-set ears; arched, well-defined eyebrows that grow together across the base of the nose (synophrys); an unusually low hairline on the forehead and the back of the neck; and curly, unusually long eyelashes. Affected individuals may also have distinctive malformations of the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers, and webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands, and fingers. Infants with CdLS may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched “growling” cry and low voice; heart defects; delayed skeletal maturation; hearing loss; or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from person to person. (For more information, choose “Cornelia de Lange” as your search term in the Rare Disease Database).
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Diagnosis of KBG Syndrome
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A diagnosis of KBG syndrome may be suspected after a thorough clinical evaluation, a detailed patient and family history, and the identification of characteristic physical findings. The diagnosis can also be made by gene panel analysis or next generation sequencing techniques, where multiple genetic causes of intellectual disability are investigated at the same time.
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Diagnosis of KBG Syndrome. A diagnosis of KBG syndrome may be suspected after a thorough clinical evaluation, a detailed patient and family history, and the identification of characteristic physical findings. The diagnosis can also be made by gene panel analysis or next generation sequencing techniques, where multiple genetic causes of intellectual disability are investigated at the same time.
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Therapies of KBG Syndrome
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Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, orthopedic surgeons, (pediatric) neurologists, physical therapists, speech therapists, orthodontists or dentists and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family may be beneficial as well.Orthopedic surgery may be particularly helpful to correct hip and spine abnormalities of affected individuals. Hearing aids, speech therapy and comprehensive dental care may also be beneficial.
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Therapies of KBG Syndrome. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, orthopedic surgeons, (pediatric) neurologists, physical therapists, speech therapists, orthodontists or dentists and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family may be beneficial as well.Orthopedic surgery may be particularly helpful to correct hip and spine abnormalities of affected individuals. Hearing aids, speech therapy and comprehensive dental care may also be beneficial.
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Overview of KCNB1 Encephalopathy
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SummaryKCNB1 encephalopathy is a rare autosomal dominant genetic disorder caused by a change in the KCNB1 gene. Patients have developmental delay starting in infancy or early childhood, often with prominent language impairment. Most children develop multiple types of seizures that can be frequent and hard to control with standard treatments. However, a few patients do not have seizures but may still have abnormal patterns on EEG. Some children may have features of autism or Rett syndrome or have a diagnosis of Lennox-Gastaut syndrome. Broadly patients with KCNB1 encephalopathy may be classified as having a developmental and epileptic encephalopathy since features of developmental delay and epilepsy are the most common.IntroductionKCNB1 encephalopathy was first identified in 2014 in three patients with severe early onset seizures and developmental delay. Over the last few years, with increasing availability of genetic testing, additional patients have been identified with a broader range of clinical features (see the Signs & Symptoms section for further explanation).
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Overview of KCNB1 Encephalopathy. SummaryKCNB1 encephalopathy is a rare autosomal dominant genetic disorder caused by a change in the KCNB1 gene. Patients have developmental delay starting in infancy or early childhood, often with prominent language impairment. Most children develop multiple types of seizures that can be frequent and hard to control with standard treatments. However, a few patients do not have seizures but may still have abnormal patterns on EEG. Some children may have features of autism or Rett syndrome or have a diagnosis of Lennox-Gastaut syndrome. Broadly patients with KCNB1 encephalopathy may be classified as having a developmental and epileptic encephalopathy since features of developmental delay and epilepsy are the most common.IntroductionKCNB1 encephalopathy was first identified in 2014 in three patients with severe early onset seizures and developmental delay. Over the last few years, with increasing availability of genetic testing, additional patients have been identified with a broader range of clinical features (see the Signs & Symptoms section for further explanation).
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Symptoms of KCNB1 Encephalopathy
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Due to the recent identification of the syndrome and limited number of patients with detailed clinical characterization, the full extent of symptoms has yet to be described. To date, the largest patient cohort was published in 2017 and including 26 patients. All 26 patients had developmental delay with speech/language more affected than other aspects of development. About half of children with KCNB1 encephalopathy have features of autism, abnormal behavior, or attention deficit/hyperactivity disorder (ADHD). A little less than half of patients have hypotonia, or low muscle tone that may contribute to delayed motor skills. A few patients have movement disorders or involuntary movements, vision changes (either strabismus or cortical visual impairment), GI issues, and sleep disturbances. Some patients also have borderline long QT and/or autonomic nervous system abnormalities. The QT interval represents the time it takes for the heart ventricles to squeeze and relax. A long QT interval is associated with an increased risk of abnormal heart rhythms and even sudden cardiac death in some cases. The autonomic nervous system is important for regulating unconscious body functions including heart rate, blood pressure, breathing rate, sweating, and digestion. The specific changes to the autonomic nervous system function have not been well described yet.With regard to epilepsy, the majority of patients with KCNB1 encephalopathy also have difficult to control epilepsy with seizure onset usually in late infancy to early childhood. Most patients have multiple seizure types including myoclonic, atonic, generalized tonic-clonic, infantile spasms, tonic, drop attacks, absence, and focal dyscognitive seizures. The initial seizure type may be focal dyscognitive seizures that are subtle and difficult to recognize especially in young children. Up to one quarter of patients, including those without discrete seizures may have an abnormal pattern on EEG during sleep called continuous spike wave during slow-wave sleep (CSWS) or electrical status epilepticus during slow-wave sleep (ESES). This EEG pattern can be seen in patients with other genetic changes and is sometimes associated with developmental regression or expressive language difficulties (see Landau-Kleffner in Related Disorders section).
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Symptoms of KCNB1 Encephalopathy. Due to the recent identification of the syndrome and limited number of patients with detailed clinical characterization, the full extent of symptoms has yet to be described. To date, the largest patient cohort was published in 2017 and including 26 patients. All 26 patients had developmental delay with speech/language more affected than other aspects of development. About half of children with KCNB1 encephalopathy have features of autism, abnormal behavior, or attention deficit/hyperactivity disorder (ADHD). A little less than half of patients have hypotonia, or low muscle tone that may contribute to delayed motor skills. A few patients have movement disorders or involuntary movements, vision changes (either strabismus or cortical visual impairment), GI issues, and sleep disturbances. Some patients also have borderline long QT and/or autonomic nervous system abnormalities. The QT interval represents the time it takes for the heart ventricles to squeeze and relax. A long QT interval is associated with an increased risk of abnormal heart rhythms and even sudden cardiac death in some cases. The autonomic nervous system is important for regulating unconscious body functions including heart rate, blood pressure, breathing rate, sweating, and digestion. The specific changes to the autonomic nervous system function have not been well described yet.With regard to epilepsy, the majority of patients with KCNB1 encephalopathy also have difficult to control epilepsy with seizure onset usually in late infancy to early childhood. Most patients have multiple seizure types including myoclonic, atonic, generalized tonic-clonic, infantile spasms, tonic, drop attacks, absence, and focal dyscognitive seizures. The initial seizure type may be focal dyscognitive seizures that are subtle and difficult to recognize especially in young children. Up to one quarter of patients, including those without discrete seizures may have an abnormal pattern on EEG during sleep called continuous spike wave during slow-wave sleep (CSWS) or electrical status epilepticus during slow-wave sleep (ESES). This EEG pattern can be seen in patients with other genetic changes and is sometimes associated with developmental regression or expressive language difficulties (see Landau-Kleffner in Related Disorders section).
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Causes of KCNB1 Encephalopathy
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KCNB1 encephalopathy is caused by a change (variant/mutation) in one copy of the KCNB1 gene that prevents it from working properly. Genetic variation affecting the coding sequence of this gene in the general or unaffected population is extremely rare. KCNB1 is the gene that codes for KV2.1, an ion channel that helps potassium (K) flow out of the cell and has a role in the cell’s ability to make and transmit electrical signals. KCNB1 is a voltage gated potassium channel meaning that it opens based on the charge around it. Variants in a few other potassium channels are also associated with epilepsy and developmental delay (see Related Disorders section for KCNQ2). Two types of KCNB1 variants have been identified in patients with KCNB1 encephalopathy. The most common are point mutations, single base pair changes in the DNA sequence that result in a different amino acid in the KV2.1 protein. There are a few specific point mutations that have occurred in different, unrelated patients and the clinical features of these patients can be different. A few patients also have the same location of the point mutation but with a different substitution resulting in different proteins and different clinical features. Less commonly, there are truncating or frameshift variants that stop the protein product early and often cause a nonfunctional potassium channel. Most of the KCNB1 encephalopathy associated variants cause a loss of potassium channel function by affecting a few different aspects of channel function. A few variants cause little to no change in channel function and are associated with a milder clinical symptoms (phenotype). KCNB1 encephalopathy is an autosomal dominant genetic condition meaning that only one non-working copy of the gene leads to disease. The non-working variant can either be inherited from either parent or be a new change (de novo) in the affected child. The risk of a patient passing the non-working gene to an offspring is 50% for each pregnancy. The risk of disease is the same for males and females.
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Causes of KCNB1 Encephalopathy. KCNB1 encephalopathy is caused by a change (variant/mutation) in one copy of the KCNB1 gene that prevents it from working properly. Genetic variation affecting the coding sequence of this gene in the general or unaffected population is extremely rare. KCNB1 is the gene that codes for KV2.1, an ion channel that helps potassium (K) flow out of the cell and has a role in the cell’s ability to make and transmit electrical signals. KCNB1 is a voltage gated potassium channel meaning that it opens based on the charge around it. Variants in a few other potassium channels are also associated with epilepsy and developmental delay (see Related Disorders section for KCNQ2). Two types of KCNB1 variants have been identified in patients with KCNB1 encephalopathy. The most common are point mutations, single base pair changes in the DNA sequence that result in a different amino acid in the KV2.1 protein. There are a few specific point mutations that have occurred in different, unrelated patients and the clinical features of these patients can be different. A few patients also have the same location of the point mutation but with a different substitution resulting in different proteins and different clinical features. Less commonly, there are truncating or frameshift variants that stop the protein product early and often cause a nonfunctional potassium channel. Most of the KCNB1 encephalopathy associated variants cause a loss of potassium channel function by affecting a few different aspects of channel function. A few variants cause little to no change in channel function and are associated with a milder clinical symptoms (phenotype). KCNB1 encephalopathy is an autosomal dominant genetic condition meaning that only one non-working copy of the gene leads to disease. The non-working variant can either be inherited from either parent or be a new change (de novo) in the affected child. The risk of a patient passing the non-working gene to an offspring is 50% for each pregnancy. The risk of disease is the same for males and females.
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Affects of KCNB1 Encephalopathy
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KCNB1 encephalopathy is a very rare disorder. About 35 patients have been described in the literature and about 65 cases are known worldwide. Patients are from families with various ethnic backgrounds in the USA and European countries. At this time, there does not appear to be a difference based on gender. Typically features of the disease present in infancy or childhood. Until recently, the KCNB1 gene was not screened in standard diagnostic sequencing. Now that KCNB1 is included on more epilepsy gene panels, more patients will likely be identified.
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Affects of KCNB1 Encephalopathy. KCNB1 encephalopathy is a very rare disorder. About 35 patients have been described in the literature and about 65 cases are known worldwide. Patients are from families with various ethnic backgrounds in the USA and European countries. At this time, there does not appear to be a difference based on gender. Typically features of the disease present in infancy or childhood. Until recently, the KCNB1 gene was not screened in standard diagnostic sequencing. Now that KCNB1 is included on more epilepsy gene panels, more patients will likely be identified.
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Related disorders of KCNB1 Encephalopathy
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Symptoms of the following disorders can be similar to those of KCNB1 encephalopathy. Comparisons may be useful for differential diagnosis.Early infantile epileptic encephalopathy (EIEE)/Developmental and epileptic encephalopathy (DEE) are a large group of disorders that result from changes in various genes (including KCNQ2, SCN1A, FOXG1, SLC6A1). These disorders have overlapping features of multiple seizure types and developmental impairment. Some patients with KCNB1 encephalopathy may also have a diagnosis of Lennox-Gastaut syndrome (LGS). This syndrome is diagnosed when patients have multiple types of seizures that are refractory to medications, cognitive impairment, and specific patterns on EEG. There are many causes of LGS and KCNB1 is now considered to be a cause of LGS in a few patients. (For more information on this disorder, choose “Lennox- Gastaut Syndrome” as your search term in the Rare Disease Database).Rett syndrome is a progressive neurodevelopmental disorder with loss of developmental skills, movement abnormalities, features of autism spectrum disorder, breathing abnormalities, and swallowing issues that predominantly affect females. Most cases of Rett syndrome are caused by variants in MECP2. At this time, KCNB1 is thought to cause variant or atypical Rett syndrome in some patients. (For more information on this disorder, choose “Rett Syndrome” as your search term in the Rare Disease Database).Landau-Kleffner syndrome is a rare childhood disease with loss of verbal expression and language comprehension with severely abnormal EEG during sleep. This disorder has a similar sleep EEG pattern to electrical status epilepticus of slow-wave sleep (ESES) and/or continuous spike wave of slow-wave sleep (CSWS) which has been diagnosed in a few patients with KCNB1 encephalopathy who do not have seizures. (For more information on this disorder, choose “Landau-Kleffner Syndrome” as your search term in the Rare Disease Database).The following disorders may be associated with KCNB1 encephalopathy as a secondary characteristic. It is not necessarily part of the differential diagnosis:Epilepsy is a chronic disease with recurrent, unprovoked seizures caused by abnormal electrical activity in the brain. There are many different causes of epilepsy and sometimes the types of seizures may help identify the cause. Epilepsy can also occur in patients with other neurodevelopmental disorders. Epilepsy can also be the result of other genetic disorders including Dravet syndrome, KCNQ2 encephalopathy, and Rett syndrome (For more information on these disorders, choose “Dravet Syndrome,” “KCNQ2”, or “Rett Syndrome” as your search term in the Rare Disease Database). The majority of patients with KCNB1 encephalopathy also have a diagnosis of epilepsy.Autism spectrum disorder is a neurodevelopmental disorder where patients have difficulty communicating and interacting with people and have repetitive behaviors or limited interests. Together these symptoms often make it difficult to function at home, school or work. About half of patients with KCNB1 encephalopathy may also have a diagnosis of autism spectrum disorder.
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Related disorders of KCNB1 Encephalopathy. Symptoms of the following disorders can be similar to those of KCNB1 encephalopathy. Comparisons may be useful for differential diagnosis.Early infantile epileptic encephalopathy (EIEE)/Developmental and epileptic encephalopathy (DEE) are a large group of disorders that result from changes in various genes (including KCNQ2, SCN1A, FOXG1, SLC6A1). These disorders have overlapping features of multiple seizure types and developmental impairment. Some patients with KCNB1 encephalopathy may also have a diagnosis of Lennox-Gastaut syndrome (LGS). This syndrome is diagnosed when patients have multiple types of seizures that are refractory to medications, cognitive impairment, and specific patterns on EEG. There are many causes of LGS and KCNB1 is now considered to be a cause of LGS in a few patients. (For more information on this disorder, choose “Lennox- Gastaut Syndrome” as your search term in the Rare Disease Database).Rett syndrome is a progressive neurodevelopmental disorder with loss of developmental skills, movement abnormalities, features of autism spectrum disorder, breathing abnormalities, and swallowing issues that predominantly affect females. Most cases of Rett syndrome are caused by variants in MECP2. At this time, KCNB1 is thought to cause variant or atypical Rett syndrome in some patients. (For more information on this disorder, choose “Rett Syndrome” as your search term in the Rare Disease Database).Landau-Kleffner syndrome is a rare childhood disease with loss of verbal expression and language comprehension with severely abnormal EEG during sleep. This disorder has a similar sleep EEG pattern to electrical status epilepticus of slow-wave sleep (ESES) and/or continuous spike wave of slow-wave sleep (CSWS) which has been diagnosed in a few patients with KCNB1 encephalopathy who do not have seizures. (For more information on this disorder, choose “Landau-Kleffner Syndrome” as your search term in the Rare Disease Database).The following disorders may be associated with KCNB1 encephalopathy as a secondary characteristic. It is not necessarily part of the differential diagnosis:Epilepsy is a chronic disease with recurrent, unprovoked seizures caused by abnormal electrical activity in the brain. There are many different causes of epilepsy and sometimes the types of seizures may help identify the cause. Epilepsy can also occur in patients with other neurodevelopmental disorders. Epilepsy can also be the result of other genetic disorders including Dravet syndrome, KCNQ2 encephalopathy, and Rett syndrome (For more information on these disorders, choose “Dravet Syndrome,” “KCNQ2”, or “Rett Syndrome” as your search term in the Rare Disease Database). The majority of patients with KCNB1 encephalopathy also have a diagnosis of epilepsy.Autism spectrum disorder is a neurodevelopmental disorder where patients have difficulty communicating and interacting with people and have repetitive behaviors or limited interests. Together these symptoms often make it difficult to function at home, school or work. About half of patients with KCNB1 encephalopathy may also have a diagnosis of autism spectrum disorder.
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Diagnosis of KCNB1 Encephalopathy
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The diagnosis of KCNB1 encephalopathy is made by molecular genetic testing. This is usually done with an epilepsy gene panel looking at a number of genes associated with epilepsy or by whole exome sequencing.Clinical Testing and Work-Up
Seizures are a clinical feature in the majority of patients. An EEG is highly recommended to help evaluate and guide treatment of seizures. Even in patients who do not have a diagnosis of seizures, an overnight EEG capturing non-REM sleep can be helpful to look for frequent epileptiform activity (as in continuous spike wave in slow-wave sleep and electrical status epilepticus in slow wave sleep).A few patients have borderline QT interval. Screening with an EKG or Holter monitor may be recommended.
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Diagnosis of KCNB1 Encephalopathy. The diagnosis of KCNB1 encephalopathy is made by molecular genetic testing. This is usually done with an epilepsy gene panel looking at a number of genes associated with epilepsy or by whole exome sequencing.Clinical Testing and Work-Up
Seizures are a clinical feature in the majority of patients. An EEG is highly recommended to help evaluate and guide treatment of seizures. Even in patients who do not have a diagnosis of seizures, an overnight EEG capturing non-REM sleep can be helpful to look for frequent epileptiform activity (as in continuous spike wave in slow-wave sleep and electrical status epilepticus in slow wave sleep).A few patients have borderline QT interval. Screening with an EKG or Holter monitor may be recommended.
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Therapies of KCNB1 Encephalopathy
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Treatment
Treatment often requires a team of specialists including pediatricians, child neurologists or pediatric epileptologists, developmental pediatricians, and/or other healthcare professionals. For children with seizures/epilepsy, anticonvulsant medications may be helpful in decreasing seizure frequency. There is no clear anticonvulsant medication that has been shown to be most helpful in patients with KCNB1 encephalopathy. In some patients, if seizures are not controlled with medication, other treatments including diet therapy (ketogenic diet, modified Atkins diet), surgically implanted devices, or epilepsy surgery may be considered. In some patients without discrete seizures but who have abnormal EEG activity during sleep, anticonvulsant medications may be recommended.For children with features of autism spectrum disorder, developmental pediatricians may be involved in the diagnosis and may recommend Applied Behavioral Analysis (ABA) or other therapies.
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Therapies of KCNB1 Encephalopathy. Treatment
Treatment often requires a team of specialists including pediatricians, child neurologists or pediatric epileptologists, developmental pediatricians, and/or other healthcare professionals. For children with seizures/epilepsy, anticonvulsant medications may be helpful in decreasing seizure frequency. There is no clear anticonvulsant medication that has been shown to be most helpful in patients with KCNB1 encephalopathy. In some patients, if seizures are not controlled with medication, other treatments including diet therapy (ketogenic diet, modified Atkins diet), surgically implanted devices, or epilepsy surgery may be considered. In some patients without discrete seizures but who have abnormal EEG activity during sleep, anticonvulsant medications may be recommended.For children with features of autism spectrum disorder, developmental pediatricians may be involved in the diagnosis and may recommend Applied Behavioral Analysis (ABA) or other therapies.
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Overview of KCNK9 Imprinting Syndrome
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SummaryKCNK9 imprinting syndrome is an extremely rare genetic disorder characterized by a variety of symptoms including distinctive facial features, varying degrees of the intellectual disability, and low muscle tone at birth (hypotonia). The specific symptoms and severity of the disorder can vary from one person to another. Because so few people with this disorder have been reported in the medical literature, researchers do not yet have a complete understanding of the symptoms potentially associated with the disorder. The KCNK9 imprinting syndrome is caused by an alteration in the maternal copy of the KCNK9 gene. An alteration in the paternal copy of the KCNK9 gene is not believed to be associated with disease.
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Overview of KCNK9 Imprinting Syndrome. SummaryKCNK9 imprinting syndrome is an extremely rare genetic disorder characterized by a variety of symptoms including distinctive facial features, varying degrees of the intellectual disability, and low muscle tone at birth (hypotonia). The specific symptoms and severity of the disorder can vary from one person to another. Because so few people with this disorder have been reported in the medical literature, researchers do not yet have a complete understanding of the symptoms potentially associated with the disorder. The KCNK9 imprinting syndrome is caused by an alteration in the maternal copy of the KCNK9 gene. An alteration in the paternal copy of the KCNK9 gene is not believed to be associated with disease.
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Symptoms of KCNK9 Imprinting Syndrome
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Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and other factors prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below or may have symptoms that are not discussed. Every case is unique and the disorder can be different in one child when compared to another.Affected children may have a head that is longer than would be expected (dolichocephaly). As infants and children age, distinctive facial features may become noticeable including an elongated face with a narrow bitemporal diameter, which means that the distance between the two temporal sutures (on the sides of the skull) is more narrow than normal. Additional facial features include full eyebrows that are arched and flared upward, a short groove or depression that runs from the nose to the upper lip (short philtrum), a tented upper lip, abnormalities of the roof of the mouth (cleft palate in 42% of known cases), and a small lower jaw (micrognathia) that is set back or recessed farther than normal (retrognathia) so that the upper and lower jaws don’t meet when the mouth is closed. The bridge of the nose may be narrow and high and the tip of the nose may be broad.Severe generalized low muscle tone (hypotonia) may be present at birth (congenital). These children may be described as being ‘floppy.’ Infants may have low blood sugar after birth that eventually goes away on its own (transient neonatal hypoglycemia). Some infants experience severe difficulties with feeding because of a poor ability to suck. Children may have difficulty swallowing (dysphagia) liquids, and some children may require the placement of a gastrostomy tube to aid with feeding. They may also have difficulty speaking (dysphonia) and a muffled-sounding voice into early adulthood.Older children have exhibited intellectual disability that has ranged from moderate to severe, delays in reaching developmental milestones, weakness of the muscles closest to the body (proximal muscles) such as those of the upper legs or upper arms, and reduced facial movements. Muscle weakness and hypotonia may eventually progress to cause contractures, which is when a joint becomes fixed, and this may be alleviated by physical therapy. Some children will develop seizures.
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Symptoms of KCNK9 Imprinting Syndrome. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and other factors prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below or may have symptoms that are not discussed. Every case is unique and the disorder can be different in one child when compared to another.Affected children may have a head that is longer than would be expected (dolichocephaly). As infants and children age, distinctive facial features may become noticeable including an elongated face with a narrow bitemporal diameter, which means that the distance between the two temporal sutures (on the sides of the skull) is more narrow than normal. Additional facial features include full eyebrows that are arched and flared upward, a short groove or depression that runs from the nose to the upper lip (short philtrum), a tented upper lip, abnormalities of the roof of the mouth (cleft palate in 42% of known cases), and a small lower jaw (micrognathia) that is set back or recessed farther than normal (retrognathia) so that the upper and lower jaws don’t meet when the mouth is closed. The bridge of the nose may be narrow and high and the tip of the nose may be broad.Severe generalized low muscle tone (hypotonia) may be present at birth (congenital). These children may be described as being ‘floppy.’ Infants may have low blood sugar after birth that eventually goes away on its own (transient neonatal hypoglycemia). Some infants experience severe difficulties with feeding because of a poor ability to suck. Children may have difficulty swallowing (dysphagia) liquids, and some children may require the placement of a gastrostomy tube to aid with feeding. They may also have difficulty speaking (dysphonia) and a muffled-sounding voice into early adulthood.Older children have exhibited intellectual disability that has ranged from moderate to severe, delays in reaching developmental milestones, weakness of the muscles closest to the body (proximal muscles) such as those of the upper legs or upper arms, and reduced facial movements. Muscle weakness and hypotonia may eventually progress to cause contractures, which is when a joint becomes fixed, and this may be alleviated by physical therapy. Some children will develop seizures.
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Causes of KCNK9 Imprinting Syndrome
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KCNK9 imprinting syndrome is caused by an alteration in the maternal copy of the KCNK9 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.To date, a specific amino acid change (p.G236R) has been detected in the KCNK9 gene most likely as a recurrent de novo event in families. Recently, a single patient with a p.Ala237Asp alteration has also been described. The alteration in the KCNK9 gene that causes the disorder is a de novo alteration in the maternal copy of the gene. This means that the change in the gene occurred randomly and was not passed on from a parent. The likelihood of another child in the family having the disorder is extremely low. This disorder involves a normal process called genetic imprinting. Everyone has two copies of every gene – one received from the father and one received from the mother. In most cases, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several disorders. With the KCNK9 gene, the copy received from the father is turned off or silenced. An alteration in this gene from the father is not associated with any consequences to the child, but it can be passed to his daughters, who would then be at risk to have affected children. The copy received from the mother is normally turned on. An alteration to the maternal copy of this gene leads to KCNK9 imprinting syndrome. The KCNK9 gene contains instructions for producing (encoding) a specialized protein. This protein is important for the proper health and function of the TASK3 ion channel. Ion channels are pores in cell membranes that regulate the movement of electrically-charged particles called ions (e.g. potassium and sodium ions) into various cells including nerve cells (neurons). These ions carry electrical impulses necessary for the normal function of the cells involved. TASK3 ion channels are found throughout the body, particularly in the brain. Alterations in maternal copy of the KCNK9 gene result in abnormal functioning (i.e. lack of activity) of this ion channel and, in turn, affect the proper function and development of nerve cells (neurons).
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Causes of KCNK9 Imprinting Syndrome. KCNK9 imprinting syndrome is caused by an alteration in the maternal copy of the KCNK9 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.To date, a specific amino acid change (p.G236R) has been detected in the KCNK9 gene most likely as a recurrent de novo event in families. Recently, a single patient with a p.Ala237Asp alteration has also been described. The alteration in the KCNK9 gene that causes the disorder is a de novo alteration in the maternal copy of the gene. This means that the change in the gene occurred randomly and was not passed on from a parent. The likelihood of another child in the family having the disorder is extremely low. This disorder involves a normal process called genetic imprinting. Everyone has two copies of every gene – one received from the father and one received from the mother. In most cases, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several disorders. With the KCNK9 gene, the copy received from the father is turned off or silenced. An alteration in this gene from the father is not associated with any consequences to the child, but it can be passed to his daughters, who would then be at risk to have affected children. The copy received from the mother is normally turned on. An alteration to the maternal copy of this gene leads to KCNK9 imprinting syndrome. The KCNK9 gene contains instructions for producing (encoding) a specialized protein. This protein is important for the proper health and function of the TASK3 ion channel. Ion channels are pores in cell membranes that regulate the movement of electrically-charged particles called ions (e.g. potassium and sodium ions) into various cells including nerve cells (neurons). These ions carry electrical impulses necessary for the normal function of the cells involved. TASK3 ion channels are found throughout the body, particularly in the brain. Alterations in maternal copy of the KCNK9 gene result in abnormal functioning (i.e. lack of activity) of this ion channel and, in turn, affect the proper function and development of nerve cells (neurons).
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Affects of KCNK9 Imprinting Syndrome
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KCNK9 imprinting syndrome is an extremely rare disorder that has been described in only several families worldwide. The incidence and prevalence of the disorder is unknown. It is likely that people with this disorder go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of KCNK9 imprinting syndrome in the general population.
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Affects of KCNK9 Imprinting Syndrome. KCNK9 imprinting syndrome is an extremely rare disorder that has been described in only several families worldwide. The incidence and prevalence of the disorder is unknown. It is likely that people with this disorder go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of KCNK9 imprinting syndrome in the general population.
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Related disorders of KCNK9 Imprinting Syndrome
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Related disorders of KCNK9 Imprinting Syndrome.
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Diagnosis of KCNK9 Imprinting Syndrome
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A diagnosis of KCNK9 imprinting syndrome is almost always made through molecular testing and confirmed by identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation with specialized tests to rule out other causes of congenital hypotonia. Molecular genetic testing looks for changes (mutations) in the KCNK9 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Most cases are diagnosed by whole exome sequencing, when a specific amino acid change (p.G236R) is detected in the KCNK9 gene.Whole exome sequencing is a test that looks for genetic changes (mutations) in a small portion of the human genome called the exome. The human genome is a person’s complete set of DNA, including all of his or her genes. The exome is the part of the genome that contains the coding portions of the genes (exons) that code for the various amino acids that make up individual proteins. These proteins have wide and varied responsibilities in the body. Up to 84% of genetic disorders occur because of a change or alteration in these coding exons of the gene. Whole exome sequencing can identify a diagnosis of KCNK9 imprinting syndrome by detecting a specific mutation (p.G236R) in the KCNK9 gene that is known to cause this disorder.
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Diagnosis of KCNK9 Imprinting Syndrome. A diagnosis of KCNK9 imprinting syndrome is almost always made through molecular testing and confirmed by identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation with specialized tests to rule out other causes of congenital hypotonia. Molecular genetic testing looks for changes (mutations) in the KCNK9 gene known to cause the disorder, but is available only as a diagnostic service at specialized laboratories. Most cases are diagnosed by whole exome sequencing, when a specific amino acid change (p.G236R) is detected in the KCNK9 gene.Whole exome sequencing is a test that looks for genetic changes (mutations) in a small portion of the human genome called the exome. The human genome is a person’s complete set of DNA, including all of his or her genes. The exome is the part of the genome that contains the coding portions of the genes (exons) that code for the various amino acids that make up individual proteins. These proteins have wide and varied responsibilities in the body. Up to 84% of genetic disorders occur because of a change or alteration in these coding exons of the gene. Whole exome sequencing can identify a diagnosis of KCNK9 imprinting syndrome by detecting a specific mutation (p.G236R) in the KCNK9 gene that is known to cause this disorder.
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Therapies of KCNK9 Imprinting Syndrome
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Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the KCNK9 imprinting syndrome, there are no treatment trials that have been tested on a large group of patients. Based on research in mouse models, specific nonsteroidal inflammatory drugs (flufenamic acid and mefenamic acid) have been used to treat children with KCNK9 imprinting syndrome due to the G236R variant. There are anecdotal reports that a few children have shown a favorable response to these drugs with no adverse effects.In general, treatment of KCNK9 imprinting syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, speech pathologists, specialists who diagnose and treat disorders of the stomach and intestines (gastroenterologists), psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Seizures may be treated with drugs that work to stop or reduce seizures (anticonvulsants). Children may benefit from occupational, physical and speech therapy. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well. Additional therapies for KCNK9 imprinting syndrome depend upon the specific abnormalities present.
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Therapies of KCNK9 Imprinting Syndrome. Treatment
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the KCNK9 imprinting syndrome, there are no treatment trials that have been tested on a large group of patients. Based on research in mouse models, specific nonsteroidal inflammatory drugs (flufenamic acid and mefenamic acid) have been used to treat children with KCNK9 imprinting syndrome due to the G236R variant. There are anecdotal reports that a few children have shown a favorable response to these drugs with no adverse effects.In general, treatment of KCNK9 imprinting syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, speech pathologists, specialists who diagnose and treat disorders of the stomach and intestines (gastroenterologists), psychiatrists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Seizures may be treated with drugs that work to stop or reduce seizures (anticonvulsants). Children may benefit from occupational, physical and speech therapy. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well. Additional therapies for KCNK9 imprinting syndrome depend upon the specific abnormalities present.
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Overview of KCNQ2 Developmental and Epileptic Encephalopathy
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SummaryChildren with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) typically present with seizures in the first week of life. Seizures appear as stiffening of the body (tonic) often associated with jerking and changes in breathing or heart rate. The seizures are usually quite frequent (many per day) and often difficult to treat. Typically, the seizures are associated with abnormal brain wave patterns on EEG during this time. The seizures often resolve within months to years, but children have some degree of developmental impairment involving one or more domains (motor, social, language, cognition). This can range from mild to severe depending on several different factors. Some children may also have autism or other neurobehavioral issues. Other, less common presentations have also been reported including later onset seizures, intellectual disability without seizures, infantile spasms and sudden twitching (myoclonus).
The story of KCNQ2-DEE begins with the identification and characterization of another related disorder, benign familial neonatal seizures (BFNS) now called SLFNE (self-limited familial neonatal epilepsy). This condition was initially described as a syndrome in 1964 by Rett and Teubel. They reported a family with eight affected individuals over 3 generations. The youngest infant had the onset of seizures at three days of age described as tonic-clonic events occurring multiple times per day. The EEG was normal in between seizures and the children developed appropriately after the seizures stopped later in infancy. Over the next twenty years, additional families with similar stories were described. In a few instances, seizures persisted into later life, but outcomes were otherwise favorable. The pattern of inheritance was determined to be autosomal dominant (see the Affected Populations section for further explanation) and genetic testing linked the disorder to the long arm of chromosome 20 (see the Causes section for further definition). In 1998, researchers identified a gene in the region that appeared similar in structure to a potassium channel within the heart. This new gene was named, according to convention, KCNQ2. Subsequently, several families were identified in which the outcome was not benign having either persistent seizures that did not respond to medication, developmental impairment or both. This prompted a group of researchers to screen patients with severe neonatal epilepsy syndromes for changes (variants or mutations) in KCNQ2. Eight children were identified from the group of 80 patients and the children shared many characteristics. Since that initial paper in 2012, many more individuals have been diagnosed and the syndrome has been defined further. Approximately 200 individuals with KCNQ2-DEE have been reported in the medical literature.
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Overview of KCNQ2 Developmental and Epileptic Encephalopathy. SummaryChildren with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) typically present with seizures in the first week of life. Seizures appear as stiffening of the body (tonic) often associated with jerking and changes in breathing or heart rate. The seizures are usually quite frequent (many per day) and often difficult to treat. Typically, the seizures are associated with abnormal brain wave patterns on EEG during this time. The seizures often resolve within months to years, but children have some degree of developmental impairment involving one or more domains (motor, social, language, cognition). This can range from mild to severe depending on several different factors. Some children may also have autism or other neurobehavioral issues. Other, less common presentations have also been reported including later onset seizures, intellectual disability without seizures, infantile spasms and sudden twitching (myoclonus).
The story of KCNQ2-DEE begins with the identification and characterization of another related disorder, benign familial neonatal seizures (BFNS) now called SLFNE (self-limited familial neonatal epilepsy). This condition was initially described as a syndrome in 1964 by Rett and Teubel. They reported a family with eight affected individuals over 3 generations. The youngest infant had the onset of seizures at three days of age described as tonic-clonic events occurring multiple times per day. The EEG was normal in between seizures and the children developed appropriately after the seizures stopped later in infancy. Over the next twenty years, additional families with similar stories were described. In a few instances, seizures persisted into later life, but outcomes were otherwise favorable. The pattern of inheritance was determined to be autosomal dominant (see the Affected Populations section for further explanation) and genetic testing linked the disorder to the long arm of chromosome 20 (see the Causes section for further definition). In 1998, researchers identified a gene in the region that appeared similar in structure to a potassium channel within the heart. This new gene was named, according to convention, KCNQ2. Subsequently, several families were identified in which the outcome was not benign having either persistent seizures that did not respond to medication, developmental impairment or both. This prompted a group of researchers to screen patients with severe neonatal epilepsy syndromes for changes (variants or mutations) in KCNQ2. Eight children were identified from the group of 80 patients and the children shared many characteristics. Since that initial paper in 2012, many more individuals have been diagnosed and the syndrome has been defined further. Approximately 200 individuals with KCNQ2-DEE have been reported in the medical literature.
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Symptoms of KCNQ2 Developmental and Epileptic Encephalopathy
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Symptoms of KCNQ2 Developmental and Epileptic Encephalopathy.
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Causes of KCNQ2 Developmental and Epileptic Encephalopathy
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The gene that is altered in patients with KCNQ2-DEE is the gene for a potassium channel within the brain.KCNQ2 belongs to a family of other ion channel genes and is sometimes abbreviated Kv7.2 to reflect that it is the 7th out of 12 different subgroups containing more than 40 genes. Ion channels are pores in the cell membrane that allow charged atoms (ions) to flow into and out of cells and play a key role in a cell’s ability to generate and transmit electrical signals. Electrical signals are one of the main mechanisms of neuronal communication but also control heartbeat and muscular contractions. These ion channel genes share important properties and are named to reflect them. “K” is the chemical symbol for potassium which is a positively charged atom. CN is an abbreviation for channel. This gene is the 2nd member of the Q subfamily which indicates that the channel is voltage gated. This means that the channel opens according to the charge in its cellular environment. Variants in the KCNQ2 gene cause a spectrum of disease that ranges from self-limited seizures in infancy to epileptic encephalopathy likely based on the degree of dysfunction in this channel and whether variants cause it to work poorly (loss of function) or be overactive (gain of function). Those that cause encephalopathy are typically located in several areas including the pore and voltage sensor; however, recent literature suggests that distinguishing presentations based on location may be more complex than initially thought. Much research is being done to determine how to accurately classify a gene variant as causative of disease (pathogenicity) and predict whether it causes a severe or milder presentation. Current testing and analysis allow for accurate pathogenicity assessments in about 90% of patients but are not yet able to reliably determine severity.
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Causes of KCNQ2 Developmental and Epileptic Encephalopathy. The gene that is altered in patients with KCNQ2-DEE is the gene for a potassium channel within the brain.KCNQ2 belongs to a family of other ion channel genes and is sometimes abbreviated Kv7.2 to reflect that it is the 7th out of 12 different subgroups containing more than 40 genes. Ion channels are pores in the cell membrane that allow charged atoms (ions) to flow into and out of cells and play a key role in a cell’s ability to generate and transmit electrical signals. Electrical signals are one of the main mechanisms of neuronal communication but also control heartbeat and muscular contractions. These ion channel genes share important properties and are named to reflect them. “K” is the chemical symbol for potassium which is a positively charged atom. CN is an abbreviation for channel. This gene is the 2nd member of the Q subfamily which indicates that the channel is voltage gated. This means that the channel opens according to the charge in its cellular environment. Variants in the KCNQ2 gene cause a spectrum of disease that ranges from self-limited seizures in infancy to epileptic encephalopathy likely based on the degree of dysfunction in this channel and whether variants cause it to work poorly (loss of function) or be overactive (gain of function). Those that cause encephalopathy are typically located in several areas including the pore and voltage sensor; however, recent literature suggests that distinguishing presentations based on location may be more complex than initially thought. Much research is being done to determine how to accurately classify a gene variant as causative of disease (pathogenicity) and predict whether it causes a severe or milder presentation. Current testing and analysis allow for accurate pathogenicity assessments in about 90% of patients but are not yet able to reliably determine severity.
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Affects of KCNQ2 Developmental and Epileptic Encephalopathy
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Epilepsy is estimated to affect 1 in 26 people during their lifetime with an incidence of approximately 44/100,000 people. The incidence is highest in young children and older adults with children often having the most severe types of epilepsies. The incidence of epilepsy in children under 2 years of age is estimated to be 70.1 per 100,000 based on a recent population-based study conducted in North London. In this research, severe epilepsies associated with abnormal development and EEG (epileptic encephalopathies) were identified in 22 (39%) of 57 infants and were associated with several genetic causes.KCNQ2-DEE affects males and females in equal numbers. Estimates of incidence are difficult for rare diseases but two recent studies using population data and novel genetic methodologies suggest KCNQ2-DEE occurs in 1/17,000 births or ~6/100,000. Patients can go undiagnosed or misdiagnosed, often due to the accessibility of genetic testing, making it difficult to determine the disorder’s true frequency in the general population. KCNQ2-DEE is considered an autosomal dominant disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new gene change in the affected individual (de novo). Most children with KCNQ2-DEE have a de novo gene variant in contrast to SLFNE which frequently runs in families. A small number of patients with KCNQ2-DEE have a gene variant inherited from an unaffected or mildly affected parent in a pattern called mosaicism. This means that only some cells in the parent’s body contain a copy of the altered gene and they may have mild or no symptoms. Sometimes, the gene variant is found only in egg or sperm cells which is called germline mosaicism. In such situations, the risk of having another affected child is estimated at 1-2%.
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Affects of KCNQ2 Developmental and Epileptic Encephalopathy. Epilepsy is estimated to affect 1 in 26 people during their lifetime with an incidence of approximately 44/100,000 people. The incidence is highest in young children and older adults with children often having the most severe types of epilepsies. The incidence of epilepsy in children under 2 years of age is estimated to be 70.1 per 100,000 based on a recent population-based study conducted in North London. In this research, severe epilepsies associated with abnormal development and EEG (epileptic encephalopathies) were identified in 22 (39%) of 57 infants and were associated with several genetic causes.KCNQ2-DEE affects males and females in equal numbers. Estimates of incidence are difficult for rare diseases but two recent studies using population data and novel genetic methodologies suggest KCNQ2-DEE occurs in 1/17,000 births or ~6/100,000. Patients can go undiagnosed or misdiagnosed, often due to the accessibility of genetic testing, making it difficult to determine the disorder’s true frequency in the general population. KCNQ2-DEE is considered an autosomal dominant disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new gene change in the affected individual (de novo). Most children with KCNQ2-DEE have a de novo gene variant in contrast to SLFNE which frequently runs in families. A small number of patients with KCNQ2-DEE have a gene variant inherited from an unaffected or mildly affected parent in a pattern called mosaicism. This means that only some cells in the parent’s body contain a copy of the altered gene and they may have mild or no symptoms. Sometimes, the gene variant is found only in egg or sperm cells which is called germline mosaicism. In such situations, the risk of having another affected child is estimated at 1-2%.
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Related disorders of KCNQ2 Developmental and Epileptic Encephalopathy
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Symptoms of the following disorders can be similar to those of KCNQ2E. Comparisons may be useful for a differential diagnosis:Epilepsy is a group of neurological disorders characterized by abnormal electrical discharges in the brain. It is characterized by loss of consciousness, convulsions, spasms, sensory confusion and disturbances in the autonomic nervous system. There are many different types of epilepsy and seizures, and the exact cause is frequently unknown. Epilepsy can also occur as part of larger genetic syndromes. Types of epilepsy or disorders associated with epilepsy include Rett syndrome, Angleman syndrome, Dravet syndrome and West syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Ohtahara syndrome (OS), sometimes referred to as early infantile epileptic encephalopathy (EIEE) is a rare type of epilepsy that typically becomes apparent during the first 1-3 months of life. It is characterized by frequent tonic seizures that are difficult to treat. Tonic seizures appear as stiffening of a limb or the body. The disorder is also characterized by a severely abnormal electroencephalogram (EEG) called “burst suppression” in which short periods of abnormal brain activity are separated by several seconds of quiet. Otahara syndrome is considered an epileptic encephalopathy because this abnormal brain activity is thought to contribute to the cognitive and behavioral impairments associated with the disorder. Most children will go on to develop additional seizure types such as infantile spasms or Lennox-Gastaut syndrome as they grow older. There are many causes of this epilepsy syndrome including metabolic disorders, genetic conditions and structural brain malformations or injuries.Lennox-Gastaut syndrome (LGS) is a rare type of epilepsy that typically becomes apparent during infancy or early childhood. The disorder is characterized by frequent episodes of uncontrolled electrical disturbances in the brain (seizures) and, in many children, delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor delay). Individuals with the disorder may experience several different types of seizures including drop attacks, tonic seizures, absence and convulsions. Lennox-Gastaut syndrome may be due to, or occur in association with, several different underlying disorders or conditions. (For more information on this disorder, choose “Lennox-Gastaut” as your search term in the Rare Disease Database.)
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Related disorders of KCNQ2 Developmental and Epileptic Encephalopathy. Symptoms of the following disorders can be similar to those of KCNQ2E. Comparisons may be useful for a differential diagnosis:Epilepsy is a group of neurological disorders characterized by abnormal electrical discharges in the brain. It is characterized by loss of consciousness, convulsions, spasms, sensory confusion and disturbances in the autonomic nervous system. There are many different types of epilepsy and seizures, and the exact cause is frequently unknown. Epilepsy can also occur as part of larger genetic syndromes. Types of epilepsy or disorders associated with epilepsy include Rett syndrome, Angleman syndrome, Dravet syndrome and West syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)Ohtahara syndrome (OS), sometimes referred to as early infantile epileptic encephalopathy (EIEE) is a rare type of epilepsy that typically becomes apparent during the first 1-3 months of life. It is characterized by frequent tonic seizures that are difficult to treat. Tonic seizures appear as stiffening of a limb or the body. The disorder is also characterized by a severely abnormal electroencephalogram (EEG) called “burst suppression” in which short periods of abnormal brain activity are separated by several seconds of quiet. Otahara syndrome is considered an epileptic encephalopathy because this abnormal brain activity is thought to contribute to the cognitive and behavioral impairments associated with the disorder. Most children will go on to develop additional seizure types such as infantile spasms or Lennox-Gastaut syndrome as they grow older. There are many causes of this epilepsy syndrome including metabolic disorders, genetic conditions and structural brain malformations or injuries.Lennox-Gastaut syndrome (LGS) is a rare type of epilepsy that typically becomes apparent during infancy or early childhood. The disorder is characterized by frequent episodes of uncontrolled electrical disturbances in the brain (seizures) and, in many children, delays in the acquisition of skills that require the coordination of mental and muscular activity (psychomotor delay). Individuals with the disorder may experience several different types of seizures including drop attacks, tonic seizures, absence and convulsions. Lennox-Gastaut syndrome may be due to, or occur in association with, several different underlying disorders or conditions. (For more information on this disorder, choose “Lennox-Gastaut” as your search term in the Rare Disease Database.)
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KCNQ2 Developmental and Epileptic Encephalopathy
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Diagnosis of KCNQ2 Developmental and Epileptic Encephalopathy
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The diagnosis of KCNQ2-DEE is made by molecular genetic testing. This can be done by examining only the potassium channel gene or by testing that looks for changes in several genes associated with epilepsy in infancy or childhood. Most children with KCNQ2-DEE have a single letter misspelling in the gene but some have a deletion of some or part of the gene (10%). Clinical Testing and Work-up
One of the first steps in the evaluation of new onset seizures in an infant is to characterize the patterns of brain activity associated with the seizures. This is done by performing an electroencephalogram or EEG. This is a painless and non-invasive means of recording the patterns of electrical activity of the brain. Electrodes placed on the scalp pick up and record the electrical waves during periods of activity, sleep and during seizures. KCNQ2-DEE is often associated with a burst-suppression pattern on EEG but may have other epileptiform abnormalities and is typically not normal between seizures, in contrast to SLFNE.When seizures are present in infancy, there are several potential causes that may need to be excluded before genetic testing is pursued. This often depends on the presentation and other clinical factors. Tests that may be performed include evaluations for infection, electrolyte disturbances, metabolic disorders and structural problems in the brain. Magnetic resonance imaging (MRI) is a radiological technique that produces detailed images of cross-sections or slices of the brain by using a magnetic field. The images can provide information concerning any malformation of the brain structures or other types of lesions commonly seen in epilepsy.
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Diagnosis of KCNQ2 Developmental and Epileptic Encephalopathy. The diagnosis of KCNQ2-DEE is made by molecular genetic testing. This can be done by examining only the potassium channel gene or by testing that looks for changes in several genes associated with epilepsy in infancy or childhood. Most children with KCNQ2-DEE have a single letter misspelling in the gene but some have a deletion of some or part of the gene (10%). Clinical Testing and Work-up
One of the first steps in the evaluation of new onset seizures in an infant is to characterize the patterns of brain activity associated with the seizures. This is done by performing an electroencephalogram or EEG. This is a painless and non-invasive means of recording the patterns of electrical activity of the brain. Electrodes placed on the scalp pick up and record the electrical waves during periods of activity, sleep and during seizures. KCNQ2-DEE is often associated with a burst-suppression pattern on EEG but may have other epileptiform abnormalities and is typically not normal between seizures, in contrast to SLFNE.When seizures are present in infancy, there are several potential causes that may need to be excluded before genetic testing is pursued. This often depends on the presentation and other clinical factors. Tests that may be performed include evaluations for infection, electrolyte disturbances, metabolic disorders and structural problems in the brain. Magnetic resonance imaging (MRI) is a radiological technique that produces detailed images of cross-sections or slices of the brain by using a magnetic field. The images can provide information concerning any malformation of the brain structures or other types of lesions commonly seen in epilepsy.
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KCNQ2 Developmental and Epileptic Encephalopathy
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Therapies of KCNQ2 Developmental and Epileptic Encephalopathy
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Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, developmental pediatricians and/or other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.
In some children, it is possible that treatment with anticonvulsant drugs may help reduce or control various types of seizure activity associated with KCNQ2-DEE. Anticonvulsant medications have many different mechanisms of action, and it is not entirely clear which medications are best for patients with KCNQ2-DEE. Some reports suggest that children respond best to medications which affect how sodium or potassium flow into nerve cells; however, the number of children reported may be too small to draw these conclusions. If seizures fail to respond to medication, other treatments including specialized diets, devices and surgeries may be considered.
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Therapies of KCNQ2 Developmental and Epileptic Encephalopathy. Treatment
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, developmental pediatricians and/or other health care professionals may need to plan an affected child’s treatment systematically and comprehensively.
In some children, it is possible that treatment with anticonvulsant drugs may help reduce or control various types of seizure activity associated with KCNQ2-DEE. Anticonvulsant medications have many different mechanisms of action, and it is not entirely clear which medications are best for patients with KCNQ2-DEE. Some reports suggest that children respond best to medications which affect how sodium or potassium flow into nerve cells; however, the number of children reported may be too small to draw these conclusions. If seizures fail to respond to medication, other treatments including specialized diets, devices and surgeries may be considered.
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KCNQ2 Developmental and Epileptic Encephalopathy
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Overview of Kearns Sayre Syndrome
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Kearns-Sayre syndrome (KSS) is a rare multisystemic disorder. An important clinical symptomatic feature is the presence of droopy eyelids (ptosis) in one or both eyes. This disease is mostly characterized by three primary findings: progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), or pigmentary retinopathy, leading to poor night vision and progressive vision loss; and heart disease such as cardiomyopathy and/or progressive arrhythmia leading to complete heart block. Other findings may include muscle weakness, short stature, sensorineural hearing loss, endocrine issues such as diabetes mellitus and hypoparathyroidism (which can cause hypocalcemia) and/or the loss of ability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). In some patients, KSS may be associated with other disorders and/or conditions.KSS belongs (in part) to a group of rare disorders known as mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in genetic material (DNA) arises from a part of the cell structure (mitochondria), that produces energy (in the form of adenosine triphosphate, or ATP) causing the brain and muscles to function improperly due to lack of energy (encephalomyopathies). In these disorders, abnormally high numbers of defective mitochondria are present. In approximately 80 percent of affected individuals with KSS, tests will reveal missing genetic material (deletion) involving the unique DNA in mitochondria (mtDNA).
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Overview of Kearns Sayre Syndrome. Kearns-Sayre syndrome (KSS) is a rare multisystemic disorder. An important clinical symptomatic feature is the presence of droopy eyelids (ptosis) in one or both eyes. This disease is mostly characterized by three primary findings: progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), or pigmentary retinopathy, leading to poor night vision and progressive vision loss; and heart disease such as cardiomyopathy and/or progressive arrhythmia leading to complete heart block. Other findings may include muscle weakness, short stature, sensorineural hearing loss, endocrine issues such as diabetes mellitus and hypoparathyroidism (which can cause hypocalcemia) and/or the loss of ability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). In some patients, KSS may be associated with other disorders and/or conditions.KSS belongs (in part) to a group of rare disorders known as mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in genetic material (DNA) arises from a part of the cell structure (mitochondria), that produces energy (in the form of adenosine triphosphate, or ATP) causing the brain and muscles to function improperly due to lack of energy (encephalomyopathies). In these disorders, abnormally high numbers of defective mitochondria are present. In approximately 80 percent of affected individuals with KSS, tests will reveal missing genetic material (deletion) involving the unique DNA in mitochondria (mtDNA).
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Kearns Sayre Syndrome
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Symptoms of Kearns Sayre Syndrome
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The three primary findings in KSS are progressive paralysis of certain eye muscles including the eyelid (ptosis) leading to chronic progressive external ophthalmoplegia (CPEO), pigmentary retinopathy, and heart disease such as an arrhythmia leading to complete heart block or cardiomyopathy. Symptoms of this disorder are usually apparent before the age of 20 years.In most patients, the first physical characteristic of this disorder is short stature and/or failure to thrive. In addition, drooping of the upper eyelid (ptosis) due to weakness of one of the muscles of the eyelid (levator palpebrae superioris) is also seen during childhood or adolescence. Other muscles involved in coordinating eye movements may be affected next, growing progressively weaker and eventually resulting in paralysis of certain eye movements (CPEO). Eventually, muscle weakness may extend to other portions of the face, throat (pharynx), neck, and/or shoulders. Muscle weakness in such areas may hinder talking and/or swallowing (dysphagia). As the disease progresses, the upper arms and legs may be affected, resulting in progressive weakness in addition to impairment of coordinated movement and balance disorder (ataxia). Most individuals with KSS will also have visual difficulties due to the abnormal accumulation of colored (pigmented) material on the delicate membrane that lines the eyes (atypical retinitis pigmentosa) and progressive degeneration of certain portions of the eye (pigmentary degeneration of the retina). This degenerative process may eventually affect the optic nerve (optic atrophy), the layers of membranes behind the retina (choroid), and/or the tough, white outer covering of the eyeball (sclera). Some affected individuals may also experience night blindness; rapid, involuntary eye movements (nystagmus); and a decrease in the sharpness of vision (visual acuity).Rarely, abnormal clouding of the front portion of the eyeball (cornea) may also contribute to nystagmus and decreased visual acuity. About 40 percent of people with KSS experience profound visual problems.The third primary finding in people with KSS is an interference with the transfer of nerve impulses (conduction) that control the activity of heart muscles (heart block). The severity of such conduction abnormalities may vary among affected individuals.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. In the mild form of heart block, the two upper chambers of the heart (atria) beat normally, but the contractions of the two lower chambers (ventricles) slightly lag behind. In the more severe forms, only a half to a quarter of the atrial beats are conducted to the ventricles. In complete heart block, the atria and ventricles beat separately. In some cases, heart block may lead to blackouts (syncope), breathlessness, and/or irregular heartbeats (arrhythmias). Bundle-branch block may be seen on electrocardiogram (EKG) and indicates that the arrhythmia is present; this may progress unpredictable and quickly to complete heart block and a prophylactic pacemaker is indicated to prevent a sudden cardiac event.Individuals with KSS may also exhibit a variety of other physical characteristics and symptoms. The number and severity of these symptoms may vary greatly from patient to patient; in some people, individuals may exhibit a partial or incomplete form of the disorder. The additional physical characteristics and symptoms associated with KSS may include developmental delays; short stature ; diminished muscle tone (hypotonia); hearing loss, eventually leading to deafness; cognitive impairment; progressive memory loss and deterioration of intellectual abilities (dementia), and/or abnormalities affecting various of parts of the brain (e.g., white and gray matter, brain stem, and/or cerebellum).In some affected individuals, KSS may also be associated with several disorders involving the function of structures and organs that secrete hormones into the blood system (multiple endocrine dysfunction). The most common of these disorders occurring in association with KSS include hypoparathyroidism, diabetes mellitus, and/or primary failure of the ovaries or testes (gonads). These disorders may result in short stature, a delay in reaching puberty, excessive fatigue, and/or muscle cramps. The relationship between KSS and endocrine abnormalities is not fully understood. KSS may also be associated with other disorders or conditions including absence of certain reflexes (peripheral neuropathy), and progressive kidney (renal) abnormalities including chronic renal failure. Peripheral neuropathy is a disorder that may affect one or several nerves of the body, causing pain and weakness. Peripheral neuropathy may affect sensory, motor, reflex, or blood vessel function.
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Symptoms of Kearns Sayre Syndrome. The three primary findings in KSS are progressive paralysis of certain eye muscles including the eyelid (ptosis) leading to chronic progressive external ophthalmoplegia (CPEO), pigmentary retinopathy, and heart disease such as an arrhythmia leading to complete heart block or cardiomyopathy. Symptoms of this disorder are usually apparent before the age of 20 years.In most patients, the first physical characteristic of this disorder is short stature and/or failure to thrive. In addition, drooping of the upper eyelid (ptosis) due to weakness of one of the muscles of the eyelid (levator palpebrae superioris) is also seen during childhood or adolescence. Other muscles involved in coordinating eye movements may be affected next, growing progressively weaker and eventually resulting in paralysis of certain eye movements (CPEO). Eventually, muscle weakness may extend to other portions of the face, throat (pharynx), neck, and/or shoulders. Muscle weakness in such areas may hinder talking and/or swallowing (dysphagia). As the disease progresses, the upper arms and legs may be affected, resulting in progressive weakness in addition to impairment of coordinated movement and balance disorder (ataxia). Most individuals with KSS will also have visual difficulties due to the abnormal accumulation of colored (pigmented) material on the delicate membrane that lines the eyes (atypical retinitis pigmentosa) and progressive degeneration of certain portions of the eye (pigmentary degeneration of the retina). This degenerative process may eventually affect the optic nerve (optic atrophy), the layers of membranes behind the retina (choroid), and/or the tough, white outer covering of the eyeball (sclera). Some affected individuals may also experience night blindness; rapid, involuntary eye movements (nystagmus); and a decrease in the sharpness of vision (visual acuity).Rarely, abnormal clouding of the front portion of the eyeball (cornea) may also contribute to nystagmus and decreased visual acuity. About 40 percent of people with KSS experience profound visual problems.The third primary finding in people with KSS is an interference with the transfer of nerve impulses (conduction) that control the activity of heart muscles (heart block). The severity of such conduction abnormalities may vary among affected individuals.The normal heart has four chambers. The two upper chambers, known as atria, are separated from each other by a fibrous partition known as the atrial septum. The two lower chambers are known as ventricles and are separated from each other by the ventricular septum. Valves connect the atria (left and right) to their respective ventricles. In the mild form of heart block, the two upper chambers of the heart (atria) beat normally, but the contractions of the two lower chambers (ventricles) slightly lag behind. In the more severe forms, only a half to a quarter of the atrial beats are conducted to the ventricles. In complete heart block, the atria and ventricles beat separately. In some cases, heart block may lead to blackouts (syncope), breathlessness, and/or irregular heartbeats (arrhythmias). Bundle-branch block may be seen on electrocardiogram (EKG) and indicates that the arrhythmia is present; this may progress unpredictable and quickly to complete heart block and a prophylactic pacemaker is indicated to prevent a sudden cardiac event.Individuals with KSS may also exhibit a variety of other physical characteristics and symptoms. The number and severity of these symptoms may vary greatly from patient to patient; in some people, individuals may exhibit a partial or incomplete form of the disorder. The additional physical characteristics and symptoms associated with KSS may include developmental delays; short stature ; diminished muscle tone (hypotonia); hearing loss, eventually leading to deafness; cognitive impairment; progressive memory loss and deterioration of intellectual abilities (dementia), and/or abnormalities affecting various of parts of the brain (e.g., white and gray matter, brain stem, and/or cerebellum).In some affected individuals, KSS may also be associated with several disorders involving the function of structures and organs that secrete hormones into the blood system (multiple endocrine dysfunction). The most common of these disorders occurring in association with KSS include hypoparathyroidism, diabetes mellitus, and/or primary failure of the ovaries or testes (gonads). These disorders may result in short stature, a delay in reaching puberty, excessive fatigue, and/or muscle cramps. The relationship between KSS and endocrine abnormalities is not fully understood. KSS may also be associated with other disorders or conditions including absence of certain reflexes (peripheral neuropathy), and progressive kidney (renal) abnormalities including chronic renal failure. Peripheral neuropathy is a disorder that may affect one or several nerves of the body, causing pain and weakness. Peripheral neuropathy may affect sensory, motor, reflex, or blood vessel function.
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Kearns Sayre Syndrome
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Causes of Kearns Sayre Syndrome
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The exact cause of KSS is established in most patients. Most cases appear to occur as the result of a new spontaneous (de novo) deletion of a large amount (typically ~25%) of genetic material found in the DNA of mitochondria (mtDNA). Mitochondria, which are found by the hundreds in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. As opposed to the genetic instructions of cellular chromosomes (nuclear DNA), which are found within the nucleus of each cell, multiple copies of mitochondrial DNA are found outside of the nucleus of the cell and within the mitochondria.In extremely rare cases, these deletions in mitochondrial genetic material may be inherited from the mother. The genetic instructions for mitochondria (mtDNA) found in sperm cells typically break off during fertilization. As a result, it is thought that human mtDNA comes from the mother. An affected mother may pass the mutation(s) on to all her children but only her daughters will pass the mutation(s) on to their children.Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of defective mitochondria may be out-numbered by the number of normal mitochondria. Symptoms of KSS may not appear in any given generation until the deletion affects a significant proportion of mitochondria. The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members. This can also mean that the mtDNA deletion might not be detected in some tissues, such as blood or cheek swab, and be found in other tissues such as muscle biopsy, in order to confirm the diagnosis.
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Causes of Kearns Sayre Syndrome. The exact cause of KSS is established in most patients. Most cases appear to occur as the result of a new spontaneous (de novo) deletion of a large amount (typically ~25%) of genetic material found in the DNA of mitochondria (mtDNA). Mitochondria, which are found by the hundreds in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. As opposed to the genetic instructions of cellular chromosomes (nuclear DNA), which are found within the nucleus of each cell, multiple copies of mitochondrial DNA are found outside of the nucleus of the cell and within the mitochondria.In extremely rare cases, these deletions in mitochondrial genetic material may be inherited from the mother. The genetic instructions for mitochondria (mtDNA) found in sperm cells typically break off during fertilization. As a result, it is thought that human mtDNA comes from the mother. An affected mother may pass the mutation(s) on to all her children but only her daughters will pass the mutation(s) on to their children.Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of defective mitochondria may be out-numbered by the number of normal mitochondria. Symptoms of KSS may not appear in any given generation until the deletion affects a significant proportion of mitochondria. The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members. This can also mean that the mtDNA deletion might not be detected in some tissues, such as blood or cheek swab, and be found in other tissues such as muscle biopsy, in order to confirm the diagnosis.
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Kearns Sayre Syndrome
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Affects of Kearns Sayre Syndrome
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KSS is a mitochondrial disorder that affects males and females in equal numbers. Onset is typically before the age of 20; however, symptoms may appear during infancy or adulthood. Eye abnormalities and developmental delays are often observed before the age of five.Some researchers believe that mitochondrial myopathies may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like KSS.
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Affects of Kearns Sayre Syndrome. KSS is a mitochondrial disorder that affects males and females in equal numbers. Onset is typically before the age of 20; however, symptoms may appear during infancy or adulthood. Eye abnormalities and developmental delays are often observed before the age of five.Some researchers believe that mitochondrial myopathies may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like KSS.
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Kearns Sayre Syndrome
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Related disorders of Kearns Sayre Syndrome
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Symptoms of the following disorders can be similar to those of KSS. Comparisons may be useful for a differential diagnosis:MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), is also in the family of disorders known as mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in the genetic material arises from a part of the cell structure that regulates energy production (mitochondria), causing the brain and muscles to function improperly (encephalomyopathies). The distinguishing feature in MELAS syndrome is the recurrence of stroke-like symptoms. Episodes of sudden headaches with vomiting and seizures may begin any time between the ages of five to 40 years. Muscular weakness on one side of the body (hemiparesis), blindness due to lesions in the area of the brain that regulates vision (cortical blindness), and/or impaired vision or blindness in one half of the visual field (hemianopsia) may also occur. In addition, individuals with MELAS syndrome may also exhibit an abnormal accumulation of lactic acid in the blood (lactic acidosis), progressive dementia, deafness, diabetes, and short stature. (For more information on this disorder, choose “MELAS” as your search term in the Rare Disease Database.)MERRF syndrome (myoclonus epilepsy associated with ragged red fibers) is a disorder also belonging to the group of mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in the genetic material arises from a part of the cell structure that releases energy (mitochondria), causing the brain and muscles to function improperly (encephalomyopathies). The distinguishing feature in MERRF syndrome is sudden, brief, jerking spasms that can affect the arms and legs (limbs) or the entire body (myoclonic seizures). In addition, individuals with MERRF syndrome may have an abnormal accumulation of lactic acid in the blood (lactic acidosis); impaired ability to coordinate movements (ataxia); muscle weakness; difficulty speaking (dysarthria); degeneration of the optic nerve (optic atrophy); and/or rapid, involuntary movements of the eyes (nystagmus). Short stature and hearing loss are also common symptoms. The symptoms of MERRF syndrome may begin in childhood or early adult life and progressively worsen. (For more information on this disorder, choose “MERRF” as your search term in the Rare Disease Database.)Leigh syndrome is a also a mitochondrial encephalomyopathy. It is characterized by the degeneration of the central nervous system (i.e., brain (basal ganglia and brainstem), spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. There appear to be more than 90 different genetic causes of Leigh syndrome. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh syndrome is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance have also been noted. (For more information on this disorder, choose “Leigh’s” as your search term in the Rare Disease Database.)The following disorder may precede the development of KSS. It may be helpful in identifying an underlying cause of some forms of this disorder:Pearson marrow-pancreas syndrome is an extremely rare disorder characterized by an impaired ability of red blood cells to carry oxygen (sideroblastic anemia) requiring transfusions, dysfunction of the exocrine pancreas (impaired fat absorption), low birth weight, failure to gain weight and grow at the expected rate (failure to thrive) and/or very rarely wasting away (atrophy) or absence of the spleen (asplenia). Other symptoms of this disorder may include the abnormal accumulation of connective tissue (fibrosis) in the pancreas, impaired absorption (malabsorption) of nutrients by the organs of the gastrointestinal tract, and/or an abnormal accumulation of lactic acid in the blood (lactic acidosis). Pearson marrow-pancreas syndrome may be caused by a change in the genetic material (mutation) found in the DNA of mitochondria (mtDNA) that is identical to the deletions found in KSS. Typically young children who have had Pearson marrow-pancreas syndrome later develop KSS in childhood or adolescence.
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Related disorders of Kearns Sayre Syndrome. Symptoms of the following disorders can be similar to those of KSS. Comparisons may be useful for a differential diagnosis:MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), is also in the family of disorders known as mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in the genetic material arises from a part of the cell structure that regulates energy production (mitochondria), causing the brain and muscles to function improperly (encephalomyopathies). The distinguishing feature in MELAS syndrome is the recurrence of stroke-like symptoms. Episodes of sudden headaches with vomiting and seizures may begin any time between the ages of five to 40 years. Muscular weakness on one side of the body (hemiparesis), blindness due to lesions in the area of the brain that regulates vision (cortical blindness), and/or impaired vision or blindness in one half of the visual field (hemianopsia) may also occur. In addition, individuals with MELAS syndrome may also exhibit an abnormal accumulation of lactic acid in the blood (lactic acidosis), progressive dementia, deafness, diabetes, and short stature. (For more information on this disorder, choose “MELAS” as your search term in the Rare Disease Database.)MERRF syndrome (myoclonus epilepsy associated with ragged red fibers) is a disorder also belonging to the group of mitochondrial encephalomyopathies. Mitochondrial encephalomyopathies are disorders in which a defect in the genetic material arises from a part of the cell structure that releases energy (mitochondria), causing the brain and muscles to function improperly (encephalomyopathies). The distinguishing feature in MERRF syndrome is sudden, brief, jerking spasms that can affect the arms and legs (limbs) or the entire body (myoclonic seizures). In addition, individuals with MERRF syndrome may have an abnormal accumulation of lactic acid in the blood (lactic acidosis); impaired ability to coordinate movements (ataxia); muscle weakness; difficulty speaking (dysarthria); degeneration of the optic nerve (optic atrophy); and/or rapid, involuntary movements of the eyes (nystagmus). Short stature and hearing loss are also common symptoms. The symptoms of MERRF syndrome may begin in childhood or early adult life and progressively worsen. (For more information on this disorder, choose “MERRF” as your search term in the Rare Disease Database.)Leigh syndrome is a also a mitochondrial encephalomyopathy. It is characterized by the degeneration of the central nervous system (i.e., brain (basal ganglia and brainstem), spinal cord, and optic nerve). The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh syndrome progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. There appear to be more than 90 different genetic causes of Leigh syndrome. Most individuals with Leigh syndrome have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh syndrome is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance have also been noted. (For more information on this disorder, choose “Leigh’s” as your search term in the Rare Disease Database.)The following disorder may precede the development of KSS. It may be helpful in identifying an underlying cause of some forms of this disorder:Pearson marrow-pancreas syndrome is an extremely rare disorder characterized by an impaired ability of red blood cells to carry oxygen (sideroblastic anemia) requiring transfusions, dysfunction of the exocrine pancreas (impaired fat absorption), low birth weight, failure to gain weight and grow at the expected rate (failure to thrive) and/or very rarely wasting away (atrophy) or absence of the spleen (asplenia). Other symptoms of this disorder may include the abnormal accumulation of connective tissue (fibrosis) in the pancreas, impaired absorption (malabsorption) of nutrients by the organs of the gastrointestinal tract, and/or an abnormal accumulation of lactic acid in the blood (lactic acidosis). Pearson marrow-pancreas syndrome may be caused by a change in the genetic material (mutation) found in the DNA of mitochondria (mtDNA) that is identical to the deletions found in KSS. Typically young children who have had Pearson marrow-pancreas syndrome later develop KSS in childhood or adolescence.
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Kearns Sayre Syndrome
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Diagnosis of Kearns Sayre Syndrome
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The diagnosis of KSS may be suspected when the three primary characteristics associated with this disorder occur in association with one another by the age of 20 years. These include paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]), abnormal coloration of the delicate membrane lining the eyes (atypical retinitis pigmentosa) and other changes in the structures of the eye (pigmentary degeneration of the retina), and disease affecting the heart (cardiomyopathy), especially conduction disorders (e.g., heart block). Diagnosis of KSS may be confirmed by a thorough clinical evaluation and a variety of specialized tests.Such specialized tests may include an electrocardiogram to detect the presence and evaluate the severity of heart block, blood and spinal fluid lactic acid levels, a muscle biopsy to demonstrate the presence of characteristic abnormalities in muscle tissue (ragged-red fibers), and/or a spinal tap to determine whether there are elevated levels of cerebrospinal fluid (CSF) protein (>100 mg/dL) or a deficiency of folate (cerebral folate deficiency). The muscle biopsy can determine the presence of deleted mtDNA, which may not be detected in the blood sample. In some cases of KSS, the levels of other substances (i.e., serum creatine kinase, blood lactate, gamma globulin, and/or pyruvate) may be elevated in the blood.Microscopic examination of biopsy tissue samples under an electron microscope may reveal large numbers of abnormal mitochondria in skeletal and eye muscle tissue. In some cases, a CT scan or tomography may be used to identify abnormal accumulation of calcium in and/or lesions affecting certain areas of the brain. MRI of the brain may also show white matter changes or changes similar to Leigh syndrome.
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Diagnosis of Kearns Sayre Syndrome. The diagnosis of KSS may be suspected when the three primary characteristics associated with this disorder occur in association with one another by the age of 20 years. These include paralysis of certain eye muscles (chronic progressive external ophthalmoplegia [CPEO]), abnormal coloration of the delicate membrane lining the eyes (atypical retinitis pigmentosa) and other changes in the structures of the eye (pigmentary degeneration of the retina), and disease affecting the heart (cardiomyopathy), especially conduction disorders (e.g., heart block). Diagnosis of KSS may be confirmed by a thorough clinical evaluation and a variety of specialized tests.Such specialized tests may include an electrocardiogram to detect the presence and evaluate the severity of heart block, blood and spinal fluid lactic acid levels, a muscle biopsy to demonstrate the presence of characteristic abnormalities in muscle tissue (ragged-red fibers), and/or a spinal tap to determine whether there are elevated levels of cerebrospinal fluid (CSF) protein (>100 mg/dL) or a deficiency of folate (cerebral folate deficiency). The muscle biopsy can determine the presence of deleted mtDNA, which may not be detected in the blood sample. In some cases of KSS, the levels of other substances (i.e., serum creatine kinase, blood lactate, gamma globulin, and/or pyruvate) may be elevated in the blood.Microscopic examination of biopsy tissue samples under an electron microscope may reveal large numbers of abnormal mitochondria in skeletal and eye muscle tissue. In some cases, a CT scan or tomography may be used to identify abnormal accumulation of calcium in and/or lesions affecting certain areas of the brain. MRI of the brain may also show white matter changes or changes similar to Leigh syndrome.
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Kearns Sayre Syndrome
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Therapies of Kearns Sayre Syndrome
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Treatment
Treatment of heart problems in KSS may require a prophylactic pacemaker for atrioventricular (AV) block to prevent complete heart black and asystole.Surgery may be used to correct visual problems; in some cases, whether or not surgery helps to improve vision often depends on how far the retinal changes have advanced. Various devices may help to improve impaired vision in affected individuals. The specific devices and/or surgical treatment techniques used will depend upon the severity and specific combination of visual abnormalities present. For example, many affected patients with KSS will have the ptosis repaired to lift the eyelid up.Separate treatment options for associated disorders (e.g., diabetes mellitus or hypoparathyroidism) may be necessary. In some cases, treatment may include hormone replacement therapies. Other treatments will depend on the specific conditions present. For example, folinic acid may be helpful to those that have reduced cerebral folate and/or neurological symptoms. A treatment team consisting of a geneticist/metabolic specialist, genetic counselors, neurologist, cardiologist, ophthalmologist (including retinal and oculoplastics specialists), Audiology/ENT, endocrinologist, gastroenterologist, etc familiar with mitochondrial disease is most beneficial. In the US, finding a center with specialized clinicians can be found through the Mitochondrial Care Network (https://www.mitonetwork.org/). Genetic counseling is recommended for affected individuals and their families. A team approach for those with this disorder may also be of benefit and may include special social support and other medical services including physical and occupational therapies. Other treatment is symptomatic and supportive. Patient support can be obtained from one of the mitochondrial support groups listed below.
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Therapies of Kearns Sayre Syndrome. Treatment
Treatment of heart problems in KSS may require a prophylactic pacemaker for atrioventricular (AV) block to prevent complete heart black and asystole.Surgery may be used to correct visual problems; in some cases, whether or not surgery helps to improve vision often depends on how far the retinal changes have advanced. Various devices may help to improve impaired vision in affected individuals. The specific devices and/or surgical treatment techniques used will depend upon the severity and specific combination of visual abnormalities present. For example, many affected patients with KSS will have the ptosis repaired to lift the eyelid up.Separate treatment options for associated disorders (e.g., diabetes mellitus or hypoparathyroidism) may be necessary. In some cases, treatment may include hormone replacement therapies. Other treatments will depend on the specific conditions present. For example, folinic acid may be helpful to those that have reduced cerebral folate and/or neurological symptoms. A treatment team consisting of a geneticist/metabolic specialist, genetic counselors, neurologist, cardiologist, ophthalmologist (including retinal and oculoplastics specialists), Audiology/ENT, endocrinologist, gastroenterologist, etc familiar with mitochondrial disease is most beneficial. In the US, finding a center with specialized clinicians can be found through the Mitochondrial Care Network (https://www.mitonetwork.org/). Genetic counseling is recommended for affected individuals and their families. A team approach for those with this disorder may also be of benefit and may include special social support and other medical services including physical and occupational therapies. Other treatment is symptomatic and supportive. Patient support can be obtained from one of the mitochondrial support groups listed below.
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Overview of Kennedy Disease
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Summary
Kennedy disease is a rare, X-linked slowly progressive neuromuscular disorder. Kennedy disease is typically an adult-onset disease, where symptoms present mainly between the ages of 20 and 50. The disease is characterized by symptoms such as muscle weakness and cramps in the arms, legs, and facial area, fasciculations of the tongue / face, enlarged breasts and sometimes difficulty with speaking and swallowing (dysphagia). Kennedy disease affects approximately 1/200,000 people worldwide and mostly occurs in males. Treatment is symptomatic and supportive and life expectancy is normal, though a small percentage of patients (~10%) succumb to the disease in their 60’s or 70’s due to swallowing complications (aspiration pneumonia, asphyxiation) resulting from the bulbar weakness. Introduction
Kennedy disease is named after William R. Kennedy, MD, who described this condition in an abstract in 1966 and a full report in 1968, although the disease was recognized in Japan previously, where the frequency is much more common.
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Overview of Kennedy Disease. Summary
Kennedy disease is a rare, X-linked slowly progressive neuromuscular disorder. Kennedy disease is typically an adult-onset disease, where symptoms present mainly between the ages of 20 and 50. The disease is characterized by symptoms such as muscle weakness and cramps in the arms, legs, and facial area, fasciculations of the tongue / face, enlarged breasts and sometimes difficulty with speaking and swallowing (dysphagia). Kennedy disease affects approximately 1/200,000 people worldwide and mostly occurs in males. Treatment is symptomatic and supportive and life expectancy is normal, though a small percentage of patients (~10%) succumb to the disease in their 60’s or 70’s due to swallowing complications (aspiration pneumonia, asphyxiation) resulting from the bulbar weakness. Introduction
Kennedy disease is named after William R. Kennedy, MD, who described this condition in an abstract in 1966 and a full report in 1968, although the disease was recognized in Japan previously, where the frequency is much more common.
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Kennedy Disease
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Symptoms of Kennedy Disease
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Affected individuals begin to develop neurological symptoms between 20 to 50 years of age. These early symptoms include:· Weakness/cramps in arm and leg muscles (proximal > distal)
· Face, mouth and tongue muscle weakness
· Difficulty with speaking and swallowing (dysphagia)
· Twitching (fasciculations)
· Tremors and trembling in certain positions
· Enlarged breasts (gynecomastia)
· Numbness
· Reduced fertility
· Testicular atrophyThe disease affects the lower motor neurons that are responsible for the movement of many muscles in the legs, arms, mouth and throat. Affected individuals show signs of twitching, often in the tongue, face and/or hand, followed by muscle weakness and problems with facial muscles. These neurons, which connect the spinal cord to the muscles, become defective and die, so the muscles cannot contract. The destruction of these nerves is the main reason for numbness, muscle weakness and inability to control muscle contraction. With lack of normal neuromuscular function, a patient may experience hypertrophied calves in which the calf muscles thicken due to muscle cramps. Some patients may have one side of the body more affected than the other side.The disease also affects nerves that control the bulbar muscles, which are important for breathing, speaking and swallowing. Androgen insensitivity can also occur, sometimes beginning in adolescence and continuing through adulthood, characterized by enlarged breasts, decreased masculine appearance and infertility. Patients may experience problems such as low sperm count and erectile dysfunction.
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Symptoms of Kennedy Disease. Affected individuals begin to develop neurological symptoms between 20 to 50 years of age. These early symptoms include:· Weakness/cramps in arm and leg muscles (proximal > distal)
· Face, mouth and tongue muscle weakness
· Difficulty with speaking and swallowing (dysphagia)
· Twitching (fasciculations)
· Tremors and trembling in certain positions
· Enlarged breasts (gynecomastia)
· Numbness
· Reduced fertility
· Testicular atrophyThe disease affects the lower motor neurons that are responsible for the movement of many muscles in the legs, arms, mouth and throat. Affected individuals show signs of twitching, often in the tongue, face and/or hand, followed by muscle weakness and problems with facial muscles. These neurons, which connect the spinal cord to the muscles, become defective and die, so the muscles cannot contract. The destruction of these nerves is the main reason for numbness, muscle weakness and inability to control muscle contraction. With lack of normal neuromuscular function, a patient may experience hypertrophied calves in which the calf muscles thicken due to muscle cramps. Some patients may have one side of the body more affected than the other side.The disease also affects nerves that control the bulbar muscles, which are important for breathing, speaking and swallowing. Androgen insensitivity can also occur, sometimes beginning in adolescence and continuing through adulthood, characterized by enlarged breasts, decreased masculine appearance and infertility. Patients may experience problems such as low sperm count and erectile dysfunction.
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Kennedy Disease
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Causes of Kennedy Disease
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Kennedy disease is caused by a change (variant or mutation) in the AR gene that encodes for a protein known as the androgen receptor on the X chromosome. The instructions within every gene consist of different arrangements of four basic chemicals (nucleotide bases) called adenine (A), cytosine (C), guanine (G), and thymine (T). Individuals with the disease have an abnormal section in the AR gene, which is due to an excessive number of CAG trinucleotide repetitions in the DNA sequence. An unaffected individual has 10-35 CAG repeats in the AR gene while a person with Kennedy disease has more than 36 CAG repeats in the gene.The androgen receptor is in the cytoplasm of a cell where it responds to signals from male sex hormones (androgens). These receptors are abundant in many body tissues such as the skin, kidney, prostate, skeletal muscle and the central nervous system motor neurons in the spinal cord and brainstem. In an unaffected person, the androgen hormone will bind to the receptor and then the hormone-receptor complex will translocate into the nucleus, where it will signal genes to increase protein production for various functions. The exact mechanism for neuronal impairment is unknown, but it has to do with an altered functioning of the abnormal androgen receptor.Kennedy disease is an X-linked genetic disorder that occurs primarily in males. Very rarely, female carriers of the altered AR gene may show symptoms. Normal females have two X chromosomes, in which one is an activated chromosome and the other is inactivated. Female carriers for Kennedy disease typically do not show symptoms because the androgen receptor must bind to its ligand, testosterone, to translocate to the nucleus and perform its functions. As females have low circulating levels of testosterone, Kennedy disease female carriers do not activate their mutant androgen receptors, thus rendering the mutant state of the androgen receptor protein harmless. Males have only one X chromosome and will develop Kennedy disease if they inherit the X chromosome containing the disease gene. Affected males with X-linked disorders will always pass the gene to their daughters but will only pass their normal Y chromosome to their sons. Therefore, all the daughters of an affected male will be carriers for the disease, while sons of an affected male will not have the disease. Sons of female carriers have a 50 percent chance of inheriting the disease, while daughters have a 50 percent chance of becoming carriers.
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Causes of Kennedy Disease. Kennedy disease is caused by a change (variant or mutation) in the AR gene that encodes for a protein known as the androgen receptor on the X chromosome. The instructions within every gene consist of different arrangements of four basic chemicals (nucleotide bases) called adenine (A), cytosine (C), guanine (G), and thymine (T). Individuals with the disease have an abnormal section in the AR gene, which is due to an excessive number of CAG trinucleotide repetitions in the DNA sequence. An unaffected individual has 10-35 CAG repeats in the AR gene while a person with Kennedy disease has more than 36 CAG repeats in the gene.The androgen receptor is in the cytoplasm of a cell where it responds to signals from male sex hormones (androgens). These receptors are abundant in many body tissues such as the skin, kidney, prostate, skeletal muscle and the central nervous system motor neurons in the spinal cord and brainstem. In an unaffected person, the androgen hormone will bind to the receptor and then the hormone-receptor complex will translocate into the nucleus, where it will signal genes to increase protein production for various functions. The exact mechanism for neuronal impairment is unknown, but it has to do with an altered functioning of the abnormal androgen receptor.Kennedy disease is an X-linked genetic disorder that occurs primarily in males. Very rarely, female carriers of the altered AR gene may show symptoms. Normal females have two X chromosomes, in which one is an activated chromosome and the other is inactivated. Female carriers for Kennedy disease typically do not show symptoms because the androgen receptor must bind to its ligand, testosterone, to translocate to the nucleus and perform its functions. As females have low circulating levels of testosterone, Kennedy disease female carriers do not activate their mutant androgen receptors, thus rendering the mutant state of the androgen receptor protein harmless. Males have only one X chromosome and will develop Kennedy disease if they inherit the X chromosome containing the disease gene. Affected males with X-linked disorders will always pass the gene to their daughters but will only pass their normal Y chromosome to their sons. Therefore, all the daughters of an affected male will be carriers for the disease, while sons of an affected male will not have the disease. Sons of female carriers have a 50 percent chance of inheriting the disease, while daughters have a 50 percent chance of becoming carriers.
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Kennedy Disease
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Affects of Kennedy Disease
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Kennedy disease affects approximately 1/200,000 people worldwide and is very rare in females. Kennedy disease has been diagnosed in the USA, Europe, Asia, South America and Australia. The Japanese population appears to have a very high prevalence of Kennedy Disease because of a founder effect.
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Affects of Kennedy Disease. Kennedy disease affects approximately 1/200,000 people worldwide and is very rare in females. Kennedy disease has been diagnosed in the USA, Europe, Asia, South America and Australia. The Japanese population appears to have a very high prevalence of Kennedy Disease because of a founder effect.
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Kennedy Disease
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Related disorders of Kennedy Disease
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Symptoms of the following disorders can be similar to those of Kennedy disease. Comparisons may be useful for a differential diagnosis:Adrenoleukodystrophy (ALD) is one of many different leukodystrophies. The adolescent or adult-onset form of the disorder is called adrenomyeloneuropathy (AMN), and symptoms of this form of ALD may be similar to those of Kennedy disease. Symptoms typically appear between the ages of 21 and 35. They may include progressive leg stiffness, spastic partial paralysis of the lower extremities and ataxia (clumsiness in walking). Decreased function of the sex glands may be present. Adult-onset ALD progresses slowly; however, it can ultimately result in deterioration of brain function. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database.)Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) send messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig’s disease. As many as 10% of Kennedy disease patients may be misdiagnosed with ALS prior to determining that they really have Kennedy disease. (For more information on this disorder, choose “amyotrophic lateral sclerosis” as your search term in the Rare Disease Database.) Spinal muscular atrophy type 3 (SMA type 3) is inherited in an autosomal recessive pattern. Major symptoms may include wasting and weakness in the muscles of the arms and legs, twitching, clumsiness in walking and eventually loss of reflexes. SMA type 3 is not apparent at birth but typically appears during the first ten to twenty years of life. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.)Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia gravis) or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired articulation of speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). About 10 percent of affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body’s natural immune defenses (i.e., antibodies) inappropriately attack and gradually destroy certain receptors at the neuromuscular junction that receive nerve impulses (antibody-mediated autoimmune response). (For more information on this disorder, choose “myasthenia gravis” as your search term in the Rare Disease Database.)Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic muscle disorder with onset during adulthood, most often between 40 and 60 years of age. OPMD is characterized by slowly progressive muscle disease (myopathy) affecting the muscles of the upper eyelids and the throat. Affected individuals may develop drooping of the eyelids (ptosis), double vision (diplopia) and/or difficulty swallowing (dysphagia). Eventually, additional muscles may become involved including those of the upper legs and arms (proximal limb weakness). In some patients, muscle weakness of the legs may eventually cause difficulty walking. OPMD is typically inherited in an autosomal dominant pattern. (For more information on this disorder, choose “oculopharyngeal muscular dystrophy” as your search term in the Rare Disease Database.)Charcot-Marie-Tooth (CMT) disease is a group of disorders in which the motor and/or sensory peripheral nerves are affected, resulting in muscle weakness and atrophy as well as sensory loss. Symptoms occur first in the distal legs and later in the hands. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. In CMT specific gene mutations are responsible for the abnormal function of the peripheral nerves. In many forms of CMT these genes are known and in others, while the condition is known to be inherited, the specific gene has not yet been identified. (For more information on this disorder, choose “CMT” as your search term in the Rare Disease Database.)
Polymyositis is a systemic connective tissue disorder characterized by inflammatory and degenerative changes in the muscles, leading to symmetric weakness and some degree of muscle atrophy. The areas principally affected are the hip, shoulders, arms, pharynx and neck. (For more information on this disorder, choose “polymyositis” as your search term in the Rare Disease Database.)
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Related disorders of Kennedy Disease. Symptoms of the following disorders can be similar to those of Kennedy disease. Comparisons may be useful for a differential diagnosis:Adrenoleukodystrophy (ALD) is one of many different leukodystrophies. The adolescent or adult-onset form of the disorder is called adrenomyeloneuropathy (AMN), and symptoms of this form of ALD may be similar to those of Kennedy disease. Symptoms typically appear between the ages of 21 and 35. They may include progressive leg stiffness, spastic partial paralysis of the lower extremities and ataxia (clumsiness in walking). Decreased function of the sex glands may be present. Adult-onset ALD progresses slowly; however, it can ultimately result in deterioration of brain function. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database.)Amyotrophic lateral sclerosis (ALS) is one of a group of disorders known as motor neuron diseases. It is characterized by the progressive degeneration and eventual death of nerve cells (motor neurons) in the brain, brainstem and spinal cord that facilitate communication between the nervous system and voluntary muscles of the body. Ordinarily, motor neurons in the brain (upper motor neurons) send messages to motor neurons in the spinal cord (lower motor neurons) and then to various muscles. ALS affects both the upper and lower motor neurons, so that the transmission of messages is interrupted, and muscles gradually weaken and waste away. As a result, the ability to initiate and control voluntary movement is lost. Ultimately, ALS leads to respiratory failure because affected individuals lose the ability to control muscles in the chest and diaphragm. ALS is often called Lou Gehrig’s disease. As many as 10% of Kennedy disease patients may be misdiagnosed with ALS prior to determining that they really have Kennedy disease. (For more information on this disorder, choose “amyotrophic lateral sclerosis” as your search term in the Rare Disease Database.) Spinal muscular atrophy type 3 (SMA type 3) is inherited in an autosomal recessive pattern. Major symptoms may include wasting and weakness in the muscles of the arms and legs, twitching, clumsiness in walking and eventually loss of reflexes. SMA type 3 is not apparent at birth but typically appears during the first ten to twenty years of life. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.)Myasthenia gravis is a neuromuscular disorder primarily characterized by muscle weakness and muscle fatigue. Although the disorder usually becomes apparent during adulthood, symptom onset may occur at any age. The condition may be restricted to certain muscle groups, particularly those of the eyes (ocular myasthenia gravis) or may become more generalized (generalized myasthenia gravis), involving multiple muscle groups. Most individuals with myasthenia gravis develop weakness and drooping of the eyelids (ptosis); weakness of eye muscles, resulting in double vision (diplopia); and excessive muscle fatigue following activity. Additional features commonly include weakness of facial muscles; impaired articulation of speech (dysarthria); difficulties chewing and swallowing (dysphagia); and weakness of the upper arms and legs (proximal limb weakness). About 10 percent of affected individuals may develop potentially life-threatening complications due to severe involvement of muscles used during breathing (myasthenic crisis). Myasthenia gravis results from an abnormal immune reaction in which the body’s natural immune defenses (i.e., antibodies) inappropriately attack and gradually destroy certain receptors at the neuromuscular junction that receive nerve impulses (antibody-mediated autoimmune response). (For more information on this disorder, choose “myasthenia gravis” as your search term in the Rare Disease Database.)Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic muscle disorder with onset during adulthood, most often between 40 and 60 years of age. OPMD is characterized by slowly progressive muscle disease (myopathy) affecting the muscles of the upper eyelids and the throat. Affected individuals may develop drooping of the eyelids (ptosis), double vision (diplopia) and/or difficulty swallowing (dysphagia). Eventually, additional muscles may become involved including those of the upper legs and arms (proximal limb weakness). In some patients, muscle weakness of the legs may eventually cause difficulty walking. OPMD is typically inherited in an autosomal dominant pattern. (For more information on this disorder, choose “oculopharyngeal muscular dystrophy” as your search term in the Rare Disease Database.)Charcot-Marie-Tooth (CMT) disease is a group of disorders in which the motor and/or sensory peripheral nerves are affected, resulting in muscle weakness and atrophy as well as sensory loss. Symptoms occur first in the distal legs and later in the hands. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. In CMT specific gene mutations are responsible for the abnormal function of the peripheral nerves. In many forms of CMT these genes are known and in others, while the condition is known to be inherited, the specific gene has not yet been identified. (For more information on this disorder, choose “CMT” as your search term in the Rare Disease Database.)
Polymyositis is a systemic connective tissue disorder characterized by inflammatory and degenerative changes in the muscles, leading to symmetric weakness and some degree of muscle atrophy. The areas principally affected are the hip, shoulders, arms, pharynx and neck. (For more information on this disorder, choose “polymyositis” as your search term in the Rare Disease Database.)
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Kennedy Disease
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Diagnosis of Kennedy Disease
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A diagnosis of Kennedy disease is suspected based on physical signs and symptoms, and sometimes family history. Diagnosis can be confirmed by molecular genetic testing on a blood sample for CAG trinucleotide repeat expansion in the AR gene. Individuals with greater than 36 CAG trinucleotide repeats in the AR gene are diagnosed with the condition.Clinical Testing and Work-Up
Annual examinations to assess muscle strength may be appropriate. It has recently been noted that Kennedy disease patients are at increased risk of developing heart disease and liver disease due to hyperlipidemia and insulin resistance. Some patients develop arrhythmias or occasionally hypertrophic cardiomyopathy, and hyperlipidemia and insulin resistance may predispose to coronary artery disease. Some patients display significant metabolic changes consistent with non-alcoholic fatty liver disease. Hence, Kennedy’s disease patients should receive an ECG and annual lipid, cholesterol and blood sugar testing.
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Diagnosis of Kennedy Disease. A diagnosis of Kennedy disease is suspected based on physical signs and symptoms, and sometimes family history. Diagnosis can be confirmed by molecular genetic testing on a blood sample for CAG trinucleotide repeat expansion in the AR gene. Individuals with greater than 36 CAG trinucleotide repeats in the AR gene are diagnosed with the condition.Clinical Testing and Work-Up
Annual examinations to assess muscle strength may be appropriate. It has recently been noted that Kennedy disease patients are at increased risk of developing heart disease and liver disease due to hyperlipidemia and insulin resistance. Some patients develop arrhythmias or occasionally hypertrophic cardiomyopathy, and hyperlipidemia and insulin resistance may predispose to coronary artery disease. Some patients display significant metabolic changes consistent with non-alcoholic fatty liver disease. Hence, Kennedy’s disease patients should receive an ECG and annual lipid, cholesterol and blood sugar testing.
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Kennedy Disease
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Therapies of Kennedy Disease
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Treatment
Currently, there is no known treatment or cure for Kennedy disease. Physical therapy, occupational therapy and speech therapy are commonly used to help patients adapt to progressing disease and maintain skills. Braces, walkers, and wheelchairs are used for ambulation. Breast reduction surgery is sometimes used as needed in patients with gynecomastia. Testosterone is not an appropriate treatment, as it can make the disease worse.
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Therapies of Kennedy Disease. Treatment
Currently, there is no known treatment or cure for Kennedy disease. Physical therapy, occupational therapy and speech therapy are commonly used to help patients adapt to progressing disease and maintain skills. Braces, walkers, and wheelchairs are used for ambulation. Breast reduction surgery is sometimes used as needed in patients with gynecomastia. Testosterone is not an appropriate treatment, as it can make the disease worse.
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Kennedy Disease
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Overview of Kenny-Caffey Syndrome
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Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare hereditary skeletal disorder characterized by thickening of the long bones, thin marrow cavities in the bones (medullary stenosis), and abnormalities affecting the head and eyes. Most cases are obvious at birth (congenital). The primary outcome of KCS2 is short stature. Intelligence is usually normal. Individuals with KCS may also have recurrent episodes of low levels of calcium in the blood stream (hypocalcemia) that is caused by insufficient production of parathyroid hormones (hypoparathyroidism). In most cases, KCS2 is an autosomal dominant genetic disorder.
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Overview of Kenny-Caffey Syndrome. Kenny-Caffey syndrome type 2 (KCS2) is an extremely rare hereditary skeletal disorder characterized by thickening of the long bones, thin marrow cavities in the bones (medullary stenosis), and abnormalities affecting the head and eyes. Most cases are obvious at birth (congenital). The primary outcome of KCS2 is short stature. Intelligence is usually normal. Individuals with KCS may also have recurrent episodes of low levels of calcium in the blood stream (hypocalcemia) that is caused by insufficient production of parathyroid hormones (hypoparathyroidism). In most cases, KCS2 is an autosomal dominant genetic disorder.
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Kenny-Caffey Syndrome
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Symptoms of Kenny-Caffey Syndrome
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KSC2 is present at birth (congenital) and low birth weight may be one of the first symptoms. This extremely rare genetic disorder is characterized by abnormalities affecting the skeleton, the head, and the eyes. Recurrent episodes of unusually low levels of calcium (hypocalcemia) in the blood are common. Most affected individuals, exhibit short stature of adult height ranging from 48 to 59 inches. Intelligence is usually normal. KCS2 usually affects several bones of the body. Affected individuals may have thickened outer layers (cortexes) of various long bones, and abnormally thin marrow cavities (medullary stenosis). Some individuals may also have abnormal hardening of some bones (osteosclerosis). KCS2 also affects the head and face. The anterior fontanel is a soft, membrane-covered area between the bones of an infant's skull that usually closes about 18 months after birth. However, in KCS2, the anterior fontanel is abnormally large, closes late, and a fibrous joint between the bones in the forehead (metopic suture) is spaced wider than usual. As a result, affected infants have an abnormally large head circumference (macrocephaly) with a prominent forehead. Several abnormalities of the eyes are also associated with KCS2. Affected individuals may have unusually small eyes (microphthalmia), leakage of cerebrospinal fluid into the optic disk of the eye may cause swelling of the disk (papilledema), and/or farsightedness (hyperopia). In some cases of this disorder, nearsightedness (myopia) has been observed. One case reported in the medical literature noted retinal and corneal calcification. Another case had bilateral optic atrophy. Episodes of abnormally low levels of calcium in the blood (hypocalcemia) are prevalent in individuals, especially infants, affected by KCS2. Onset of hypocalcemia is usually within two to three months after birth. Other episodes may occur in relation to stress or may follow surgery or illness in an adult. Hypocalcemia is not permanent (transient) and may be caused by insufficient production of parathyroid hormones (hypoparathyroidism). These hormones, along with vitamin D and the hormone calcitonin, regulate the levels of calcium in the blood. The lack of the parathyroid hormones may be due to improper function or absence of the parathyroid glands in people with KCS2. Symptoms of hypoparathyroidism include weakness, muscle cramps; excessive nervousness; loss of memory; headaches, and abnormal sensations such as tingling, burning, and numbness of the hands. (For more information about “Hypoparathyroidism,” please see the Related Disorders section of this report.) Low levels of calcium in the blood may also cause a condition called tetany, which is characterized by muscle cramps and periods of high-pitched respiration (stridor). Individuals with KCS2 may also exhibit abnormally low levels of phosphates in the blood (hypophosphatemia), low levels of a hormone that acts to reduce the blood level of calcium (calcitonin), low levels of circulating red blood cells (anemia), and seizures. People affected by the recessive form of KCS2 have most of the above-mentioned abnormalities and symptoms. They may also exhibit liver disease during the first month of life (neonatal period), abnormally low levels of a certain type of white blood cell (neutropenia), improper function of another type of white blood cell (T-cells), and/or underdeveloped (hypoplastic), malformed nails.
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Symptoms of Kenny-Caffey Syndrome. KSC2 is present at birth (congenital) and low birth weight may be one of the first symptoms. This extremely rare genetic disorder is characterized by abnormalities affecting the skeleton, the head, and the eyes. Recurrent episodes of unusually low levels of calcium (hypocalcemia) in the blood are common. Most affected individuals, exhibit short stature of adult height ranging from 48 to 59 inches. Intelligence is usually normal. KCS2 usually affects several bones of the body. Affected individuals may have thickened outer layers (cortexes) of various long bones, and abnormally thin marrow cavities (medullary stenosis). Some individuals may also have abnormal hardening of some bones (osteosclerosis). KCS2 also affects the head and face. The anterior fontanel is a soft, membrane-covered area between the bones of an infant's skull that usually closes about 18 months after birth. However, in KCS2, the anterior fontanel is abnormally large, closes late, and a fibrous joint between the bones in the forehead (metopic suture) is spaced wider than usual. As a result, affected infants have an abnormally large head circumference (macrocephaly) with a prominent forehead. Several abnormalities of the eyes are also associated with KCS2. Affected individuals may have unusually small eyes (microphthalmia), leakage of cerebrospinal fluid into the optic disk of the eye may cause swelling of the disk (papilledema), and/or farsightedness (hyperopia). In some cases of this disorder, nearsightedness (myopia) has been observed. One case reported in the medical literature noted retinal and corneal calcification. Another case had bilateral optic atrophy. Episodes of abnormally low levels of calcium in the blood (hypocalcemia) are prevalent in individuals, especially infants, affected by KCS2. Onset of hypocalcemia is usually within two to three months after birth. Other episodes may occur in relation to stress or may follow surgery or illness in an adult. Hypocalcemia is not permanent (transient) and may be caused by insufficient production of parathyroid hormones (hypoparathyroidism). These hormones, along with vitamin D and the hormone calcitonin, regulate the levels of calcium in the blood. The lack of the parathyroid hormones may be due to improper function or absence of the parathyroid glands in people with KCS2. Symptoms of hypoparathyroidism include weakness, muscle cramps; excessive nervousness; loss of memory; headaches, and abnormal sensations such as tingling, burning, and numbness of the hands. (For more information about “Hypoparathyroidism,” please see the Related Disorders section of this report.) Low levels of calcium in the blood may also cause a condition called tetany, which is characterized by muscle cramps and periods of high-pitched respiration (stridor). Individuals with KCS2 may also exhibit abnormally low levels of phosphates in the blood (hypophosphatemia), low levels of a hormone that acts to reduce the blood level of calcium (calcitonin), low levels of circulating red blood cells (anemia), and seizures. People affected by the recessive form of KCS2 have most of the above-mentioned abnormalities and symptoms. They may also exhibit liver disease during the first month of life (neonatal period), abnormally low levels of a certain type of white blood cell (neutropenia), improper function of another type of white blood cell (T-cells), and/or underdeveloped (hypoplastic), malformed nails.
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Kenny-Caffey Syndrome
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Causes of Kenny-Caffey Syndrome
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In most cases, KCS2 is an autosomal dominant genetic disorder. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the gender of the resulting child. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son. Investigators have determined that the recessive form of Kenny-Caffey syndrome is the same disorder as Hypoparathyroidism-retardation-dysmophic (HRD) syndrome, which is also known as Sanjad-Sakati syndrome. HRD is an extremely rare disorder characterized by hypoparathyroidism that is present at birth (congenital); growth retardation, mental retardation; and characteristic facial abnormalities. Such facial features may include deep-set eyes, abnormally thin upper lip, abnormally small jaw (micrognathia), and a depressed bridge of the nose. Affected individuals may also have skeletal defects, abnormally thin marrow cavities (medullary stenosis), and abnormally low levels of calcium in the blood (hypocalcemia). HRD syndrome is inherited as an autosomal recessive trait. HRD syndrome is caused by disruption or changes (mutations) of the tubulin-specific chaperone E (TBCE) gene located on the long arm (q) of chromosome 1 (1q42-q43). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q42” refers to band 42 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Some cases of autosomal recessive Kenny-Caffey syndrome/HRD syndrome have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Causes of Kenny-Caffey Syndrome. In most cases, KCS2 is an autosomal dominant genetic disorder. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the gender of the resulting child. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% to have a son affected with the disease, and a 25% chance to have an unaffected son. Investigators have determined that the recessive form of Kenny-Caffey syndrome is the same disorder as Hypoparathyroidism-retardation-dysmophic (HRD) syndrome, which is also known as Sanjad-Sakati syndrome. HRD is an extremely rare disorder characterized by hypoparathyroidism that is present at birth (congenital); growth retardation, mental retardation; and characteristic facial abnormalities. Such facial features may include deep-set eyes, abnormally thin upper lip, abnormally small jaw (micrognathia), and a depressed bridge of the nose. Affected individuals may also have skeletal defects, abnormally thin marrow cavities (medullary stenosis), and abnormally low levels of calcium in the blood (hypocalcemia). HRD syndrome is inherited as an autosomal recessive trait. HRD syndrome is caused by disruption or changes (mutations) of the tubulin-specific chaperone E (TBCE) gene located on the long arm (q) of chromosome 1 (1q42-q43). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q42” refers to band 42 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Some cases of autosomal recessive Kenny-Caffey syndrome/HRD syndrome have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
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Kenny-Caffey Syndrome
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Affects of Kenny-Caffey Syndrome
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KCS2 is an extremely rare skeletal disorder that affects males and females in equal numbers. Fewer than 60 cases have been reported in the medical literature. Onset of hypocalcemia is usually within two to three months of life; the hypocalcemia is not permanent (transient). In an adult, episodes of hypocalcemia may be due to stress or follow surgery or illness. KCS2 was first described in the medical literature in 1966.
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Affects of Kenny-Caffey Syndrome. KCS2 is an extremely rare skeletal disorder that affects males and females in equal numbers. Fewer than 60 cases have been reported in the medical literature. Onset of hypocalcemia is usually within two to three months of life; the hypocalcemia is not permanent (transient). In an adult, episodes of hypocalcemia may be due to stress or follow surgery or illness. KCS2 was first described in the medical literature in 1966.
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Kenny-Caffey Syndrome
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Related disorders of Kenny-Caffey Syndrome
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Symptoms of the following disorders can be similar to those of Kenny-Caffey syndrome type 2. Comparisons may be useful for a differential diagnosis: Kenny-Caffey syndrome type 1 is the recessive form of KCS, and is also called hypoparathyroidism-retardation-dysmophic (HRD) syndrome or Sanjad-Sakati syndrome. HRD is an extremely rare disorder characterized by hypoparathyroidism that is present at birth (congenital); growth retardation,intellectual disability ; and characteristic facial abnormalities. Such facial features may include deep-set eyes, abnormally thin upper lip, abnormally small jaw (micrognathia), and a depressed bridge of the nose. Affected individuals may also have skeletal defects, abnormally thin marrow cavities (medullary stenosis), and abnormally low levels of calcium in the blood (hypocalcemia). HRD is caused by disruption or changes (mutations) of the tubulin-specific chaperone E (TBCE) gene. Osteopetrosis is a rare genetic skeletal disorder characterized by the abnormal hardening of bones. Symptoms may include thickening of the bones, increased density of the bone marrow, delayed closure of a soft spot of an infant's skull (anterior fontanel), and anemia. The basic defect in bone growth involves insufficient production of intercellular bone tissue by cells called osteoblasts. These osteoblasts aid in the production of bone by maintaining a balance between formation and loss of calcium in the bone. Osteopetrosis can be inherited as either an autosomal dominant or recessive trait. (For more information on this disorder, choose “Osteopetrosis” as your search term in the Rare Disease Database.) Pycnodysostosis is a rare disorder characterized by short stature and increased density of the bones. Individuals with this disorder typically have short arms and legs with broad hands and feet. Delayed closure of the space between the bones of the skull (fontanels) typically occurs. Additional features may include an unusually large head (macrocephaly) with a small face, a receding chin with a small jaw, brittle finger and toe nails, a bluish discoloration of the whites of the eyes (blue sclerae), dental abnormalities, and/or an underdeveloped collarbone. Pycnodysostosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Pycnodysostosis” as your search term in the Rare Disease Database.) A large anterior fontanel that closes late is also seen in cleidocranial dysplasia and congenital hypoparathyroidism. (For more information on these disorders, choose “Cleidocranial Dysplasia” and “Hypoparathyroidism” as your search terms in the Rare Disease Database.) The following disorder may be associated with KCS2 as a secondary characteristic. It is not necessary for a differential diagnosis: Hypoparathyroidism is a rare endocrine disorder characterized by low levels of calcium in the blood. It is caused by insufficient production of parathyroid hormones. These hormones, along with vitamin D and the hormone calcitonin, regulate the levels of calcium in the blood. The lack of production of parathyroid hormones may be due to improper function or absence of the parathyroid glands. Symptoms of hypoparathyroidism include weakness; muscle cramps; excessive nervousness; loss of memory; headaches; and abnormal sensations such as tingling, burning, and numbness of the hands. The exact cause of hypoparathyroidism is not fully understood. (For more information on this disorder, choose “Hypoparathyroidism” as your search term in the Rare Disease Database.)
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Related disorders of Kenny-Caffey Syndrome. Symptoms of the following disorders can be similar to those of Kenny-Caffey syndrome type 2. Comparisons may be useful for a differential diagnosis: Kenny-Caffey syndrome type 1 is the recessive form of KCS, and is also called hypoparathyroidism-retardation-dysmophic (HRD) syndrome or Sanjad-Sakati syndrome. HRD is an extremely rare disorder characterized by hypoparathyroidism that is present at birth (congenital); growth retardation,intellectual disability ; and characteristic facial abnormalities. Such facial features may include deep-set eyes, abnormally thin upper lip, abnormally small jaw (micrognathia), and a depressed bridge of the nose. Affected individuals may also have skeletal defects, abnormally thin marrow cavities (medullary stenosis), and abnormally low levels of calcium in the blood (hypocalcemia). HRD is caused by disruption or changes (mutations) of the tubulin-specific chaperone E (TBCE) gene. Osteopetrosis is a rare genetic skeletal disorder characterized by the abnormal hardening of bones. Symptoms may include thickening of the bones, increased density of the bone marrow, delayed closure of a soft spot of an infant's skull (anterior fontanel), and anemia. The basic defect in bone growth involves insufficient production of intercellular bone tissue by cells called osteoblasts. These osteoblasts aid in the production of bone by maintaining a balance between formation and loss of calcium in the bone. Osteopetrosis can be inherited as either an autosomal dominant or recessive trait. (For more information on this disorder, choose “Osteopetrosis” as your search term in the Rare Disease Database.) Pycnodysostosis is a rare disorder characterized by short stature and increased density of the bones. Individuals with this disorder typically have short arms and legs with broad hands and feet. Delayed closure of the space between the bones of the skull (fontanels) typically occurs. Additional features may include an unusually large head (macrocephaly) with a small face, a receding chin with a small jaw, brittle finger and toe nails, a bluish discoloration of the whites of the eyes (blue sclerae), dental abnormalities, and/or an underdeveloped collarbone. Pycnodysostosis is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Pycnodysostosis” as your search term in the Rare Disease Database.) A large anterior fontanel that closes late is also seen in cleidocranial dysplasia and congenital hypoparathyroidism. (For more information on these disorders, choose “Cleidocranial Dysplasia” and “Hypoparathyroidism” as your search terms in the Rare Disease Database.) The following disorder may be associated with KCS2 as a secondary characteristic. It is not necessary for a differential diagnosis: Hypoparathyroidism is a rare endocrine disorder characterized by low levels of calcium in the blood. It is caused by insufficient production of parathyroid hormones. These hormones, along with vitamin D and the hormone calcitonin, regulate the levels of calcium in the blood. The lack of production of parathyroid hormones may be due to improper function or absence of the parathyroid glands. Symptoms of hypoparathyroidism include weakness; muscle cramps; excessive nervousness; loss of memory; headaches; and abnormal sensations such as tingling, burning, and numbness of the hands. The exact cause of hypoparathyroidism is not fully understood. (For more information on this disorder, choose “Hypoparathyroidism” as your search term in the Rare Disease Database.)
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Kenny-Caffey Syndrome
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Diagnosis of Kenny-Caffey Syndrome
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The diagnosis of KCS2 may be confirmed by x-ray studies of the skeleton that reveal distinctive thickening of the outer layers (cortexes) of long bones along with unusually thin marrow cavities. Blood tests can detect episodes of low levels of calcium in the blood (hypocalcemia).
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Diagnosis of Kenny-Caffey Syndrome. The diagnosis of KCS2 may be confirmed by x-ray studies of the skeleton that reveal distinctive thickening of the outer layers (cortexes) of long bones along with unusually thin marrow cavities. Blood tests can detect episodes of low levels of calcium in the blood (hypocalcemia).
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Kenny-Caffey Syndrome
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Therapies of Kenny-Caffey Syndrome
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TreatmentThe treatment of KCS2 is directed toward the specific symptoms that are apparent in each individual. Vitamin D and calcium have been prescribed for and proven effective in treating hypocalcemia. If anemia occurs, iron supplements may be prescribed. People with KCS2 should be monitored regularly by an eye doctor (ophthalmologist) who is familiar with the eye abnormalities associated with this syndrome.Genetic counseling is recommended for affected individuals and their families. A supportive team approach for children with KCS2 may be of benefit. Such a team approach may include physical therapy and other medical, social, or vocational services. Other treatment is symptomatic and supportive.
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Therapies of Kenny-Caffey Syndrome. TreatmentThe treatment of KCS2 is directed toward the specific symptoms that are apparent in each individual. Vitamin D and calcium have been prescribed for and proven effective in treating hypocalcemia. If anemia occurs, iron supplements may be prescribed. People with KCS2 should be monitored regularly by an eye doctor (ophthalmologist) who is familiar with the eye abnormalities associated with this syndrome.Genetic counseling is recommended for affected individuals and their families. A supportive team approach for children with KCS2 may be of benefit. Such a team approach may include physical therapy and other medical, social, or vocational services. Other treatment is symptomatic and supportive.
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Kenny-Caffey Syndrome
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Overview of Keratitis Ichthyosis Deafness Syndrome
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Keratitis ichthyosis deafness (KID) syndrome is a rare, genetic, multi-system disorder. It is characterized by defects of the surface of the corneas (keratitis), red, rough thickened plaques of skin (erythrokeratoderma) and sensorineural deafness or severe hearing impairment. The skin on the palms of the hands and soles of the feet and the nails may be affected. KID syndrome belongs to a group of skin disorders marked by dry, scaly skin known as the ichthyoses. KID syndrome is inherited as an autosomal dominant trait.
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Overview of Keratitis Ichthyosis Deafness Syndrome. Keratitis ichthyosis deafness (KID) syndrome is a rare, genetic, multi-system disorder. It is characterized by defects of the surface of the corneas (keratitis), red, rough thickened plaques of skin (erythrokeratoderma) and sensorineural deafness or severe hearing impairment. The skin on the palms of the hands and soles of the feet and the nails may be affected. KID syndrome belongs to a group of skin disorders marked by dry, scaly skin known as the ichthyoses. KID syndrome is inherited as an autosomal dominant trait.
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Keratitis Ichthyosis Deafness Syndrome
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Symptoms of Keratitis Ichthyosis Deafness Syndrome
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KID syndrome is present at birth. Nearly all cases have skin involvement, which includes red, rough, thickened plaques that are sometimes scaling, as well as sensorineural deafness or severe hearing impairment.Most patients develop eye findings, predominantly keratitis (superficial defects of the cornea), which may result in the eyes being very sensitive to light (photophobia), small blood vessels growing from the iris over the cornea (neovascularization), and progressive decline of vision. A small percentage of patients may have recurrent or chronic inflammation of the mucous membrane of the eye (conjunctivitis). Sparse hair or areas of baldness (alopecia) are relatively common, while a complete lack of hair is rare. The palms of the hands and soles of the feet have thickened hardened skin in most patients, while a smaller percentage may have absent or abnormal nails.There is a whole spectrum of other associated symptoms, including recurrent infections, abnormal teeth, reduced sweating, and an increased risk for developing squamous cell carcinoma of the skin or mucous membranes, which may occur in some but not many patients. A very small percentage of patients encounter life-threatening infections during the neonatal period.
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Symptoms of Keratitis Ichthyosis Deafness Syndrome. KID syndrome is present at birth. Nearly all cases have skin involvement, which includes red, rough, thickened plaques that are sometimes scaling, as well as sensorineural deafness or severe hearing impairment.Most patients develop eye findings, predominantly keratitis (superficial defects of the cornea), which may result in the eyes being very sensitive to light (photophobia), small blood vessels growing from the iris over the cornea (neovascularization), and progressive decline of vision. A small percentage of patients may have recurrent or chronic inflammation of the mucous membrane of the eye (conjunctivitis). Sparse hair or areas of baldness (alopecia) are relatively common, while a complete lack of hair is rare. The palms of the hands and soles of the feet have thickened hardened skin in most patients, while a smaller percentage may have absent or abnormal nails.There is a whole spectrum of other associated symptoms, including recurrent infections, abnormal teeth, reduced sweating, and an increased risk for developing squamous cell carcinoma of the skin or mucous membranes, which may occur in some but not many patients. A very small percentage of patients encounter life-threatening infections during the neonatal period.
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Keratitis Ichthyosis Deafness Syndrome
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Causes of Keratitis Ichthyosis Deafness Syndrome
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KID syndrome is a genetic disorder and can be transmitted from a parent to a child in an autosomal dominant fashion. That means that each individual affected with the disease will have one abnormal gene for the disease and one normal gene. When, by chance, the abnormal gene copy is passed on to the offspring, the child will be affected. When the normal gene copy is transmitted, the child will be unaffected. The risk for an adult with KID syndrome to have an affected child is 50% for each pregnancy. Nevertheless, approximately nine out of ten patients carry a new, spontaneously occurring mutation that is not present in either parent.The gene whose mutation causes KID syndrome is called gap junction protein beta 2 (GJB2) and is located on the long arm of human chromosome 13 (13q11-q12). This gene encodes the structural protein “connexin-26” (Cx26), which forms gap junction channels that connect neighboring cells and permit the exchange of small molecules and ions. The impairment of this connection and exchange may affect direct cell-to-cell communication in the skin and other tissues, such as the cornea and inner ear. Very rarely, KID syndrome with congenital absence of hair, may be caused by mutations in the gene GJB6 encoding the gap junction protein beta 6, also known as “connexin-30,” which fulfills similar functions as connexin-26.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 13q11-q12” refers to bands 11-12 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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Causes of Keratitis Ichthyosis Deafness Syndrome. KID syndrome is a genetic disorder and can be transmitted from a parent to a child in an autosomal dominant fashion. That means that each individual affected with the disease will have one abnormal gene for the disease and one normal gene. When, by chance, the abnormal gene copy is passed on to the offspring, the child will be affected. When the normal gene copy is transmitted, the child will be unaffected. The risk for an adult with KID syndrome to have an affected child is 50% for each pregnancy. Nevertheless, approximately nine out of ten patients carry a new, spontaneously occurring mutation that is not present in either parent.The gene whose mutation causes KID syndrome is called gap junction protein beta 2 (GJB2) and is located on the long arm of human chromosome 13 (13q11-q12). This gene encodes the structural protein “connexin-26” (Cx26), which forms gap junction channels that connect neighboring cells and permit the exchange of small molecules and ions. The impairment of this connection and exchange may affect direct cell-to-cell communication in the skin and other tissues, such as the cornea and inner ear. Very rarely, KID syndrome with congenital absence of hair, may be caused by mutations in the gene GJB6 encoding the gap junction protein beta 6, also known as “connexin-30,” which fulfills similar functions as connexin-26.Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 13q11-q12” refers to bands 11-12 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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Keratitis Ichthyosis Deafness Syndrome
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Affects of Keratitis Ichthyosis Deafness Syndrome
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KID syndrome appears to affect females slightly more often than males. The disorder is very rare with fewer than 100 cases reported in the medical literature. Collectively, the ichthyoses affect more than 1,000,000 people in the United States.
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Affects of Keratitis Ichthyosis Deafness Syndrome. KID syndrome appears to affect females slightly more often than males. The disorder is very rare with fewer than 100 cases reported in the medical literature. Collectively, the ichthyoses affect more than 1,000,000 people in the United States.
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Keratitis Ichthyosis Deafness Syndrome
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Related disorders of Keratitis Ichthyosis Deafness Syndrome
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Symptoms of the following disorders can be similar to those of KID syndrome. Comparisons may be useful for a differential diagnosis:Ichthyoses or “disorders of cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or the fat-rich matrix around these cells. These cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Palmoplantar keratodermas (PPK) are a large group of skin disorders with thickening of the skin of the palms and soles. There are many different variants of PPK, which have many different causes. In one form of PPK, called “Vohwinkel syndrome,” the skin findings are associated with sensorineural hearing loss similar to KID syndrome. However there is no eye disease. (For more information, choose “Palmoplantar Keratoderma” in the Rare Disease Database.)Ectodermal dysplasias are also a very large group of disorders with diverse clinical features including two or more different tissues of common origin, such as skin, nails, teeth, mucous membranes, eyes, hearing, and sweat glands. (For more informatiom, choose “Ectodermal Dyslplasia” in the Rare Disease Database.)
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Related disorders of Keratitis Ichthyosis Deafness Syndrome. Symptoms of the following disorders can be similar to those of KID syndrome. Comparisons may be useful for a differential diagnosis:Ichthyoses or “disorders of cornification” are general terms describing a group of scaly skin disorders. They are characterized by an abnormal accumulation of large amounts of dead skin cells (squames) in the top layer of the skin. The conversion of an abnormally large number of epidermal cells into squamous cells is thought to be caused by a defect in the metabolism of the skin cells known as “corneocytes” or the fat-rich matrix around these cells. These cells can be thought of as bricks, while the matrix would be the mortar holding these cells together. (See “Ichthyosis” in the Rare Disease Database.)Palmoplantar keratodermas (PPK) are a large group of skin disorders with thickening of the skin of the palms and soles. There are many different variants of PPK, which have many different causes. In one form of PPK, called “Vohwinkel syndrome,” the skin findings are associated with sensorineural hearing loss similar to KID syndrome. However there is no eye disease. (For more information, choose “Palmoplantar Keratoderma” in the Rare Disease Database.)Ectodermal dysplasias are also a very large group of disorders with diverse clinical features including two or more different tissues of common origin, such as skin, nails, teeth, mucous membranes, eyes, hearing, and sweat glands. (For more informatiom, choose “Ectodermal Dyslplasia” in the Rare Disease Database.)
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Keratitis Ichthyosis Deafness Syndrome
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Diagnosis of Keratitis Ichthyosis Deafness Syndrome
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Diagnosis of Keratitis Ichthyosis Deafness Syndrome.
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Keratitis Ichthyosis Deafness Syndrome
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Therapies of Keratitis Ichthyosis Deafness Syndrome
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Individuals with KID syndrome usually require multidisciplinary treatment due to the involvement of several organ systems and the potential impairment of hearing, speech, and sight.The skin symptoms of KID syndrome can be treated by applying skin softening emollients. This can be particularly effective after bathing while the skin is still moist. Lotions containing alpha-hydroxy acids can be an effective treatment for scaling skin. Cholesterol or ceramide containing emollients may also improve the scaling.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Keratitis Ichthyosis Deafness Syndrome. Individuals with KID syndrome usually require multidisciplinary treatment due to the involvement of several organ systems and the potential impairment of hearing, speech, and sight.The skin symptoms of KID syndrome can be treated by applying skin softening emollients. This can be particularly effective after bathing while the skin is still moist. Lotions containing alpha-hydroxy acids can be an effective treatment for scaling skin. Cholesterol or ceramide containing emollients may also improve the scaling.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Keratitis Ichthyosis Deafness Syndrome
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Overview of Keratoconus
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Keratoconus is an eye (ocular) disorder characterized by progressive thinning and changes in the shape of the cornea. The cornea is the thin, clear outer layer of the eye and is normally dome-shaped. Slowly progressive thinning of the cornea causes a cone-shaped bulge to develop towards the center of the cornea in the areas of greatest thinning. Affected individuals develop blurry or distorted vision, sensitivity to light (photophobia) and additional vision problems. Keratoconus often begins at puberty and most often is seen in teenagers or young adults. The specific underlying cause is not fully understood and most likely the condition results from the interaction of multiple factors including genetic and environmental ones. One factor known to contribute to progression of keratoconus is eye rubbing. In some cases, keratoconus may occur as part of a larger disorder. Keratoconus is treated with glasses or contact lenses early in the condition. A small number of individuals may require surgery.
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Overview of Keratoconus. Keratoconus is an eye (ocular) disorder characterized by progressive thinning and changes in the shape of the cornea. The cornea is the thin, clear outer layer of the eye and is normally dome-shaped. Slowly progressive thinning of the cornea causes a cone-shaped bulge to develop towards the center of the cornea in the areas of greatest thinning. Affected individuals develop blurry or distorted vision, sensitivity to light (photophobia) and additional vision problems. Keratoconus often begins at puberty and most often is seen in teenagers or young adults. The specific underlying cause is not fully understood and most likely the condition results from the interaction of multiple factors including genetic and environmental ones. One factor known to contribute to progression of keratoconus is eye rubbing. In some cases, keratoconus may occur as part of a larger disorder. Keratoconus is treated with glasses or contact lenses early in the condition. A small number of individuals may require surgery.
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Keratoconus
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Symptoms of Keratoconus
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The corneas in both eyes are usually affected (bilateral), although the progression and severity of the condition in each eye may differ (asymmetric development), which means one eye may be notably worse than the other. Symptoms usually become apparent during adolescence or young adulthood (i.e., late teens through early 20s). Keratoconus may become progressively worse for 10 to 20 years before slowing. Older adults typically do not have worsening of keratoconus. Because of the progressive nature of the disorder, affected individuals may have to change glasses frequently.The cornea’s primary function is acting as the eye’s most powerful lens, bending incoming light onto the lower-powered internal lens, where the light is then directed to the retina (a membranous layer of light-sensing cells in the back of the eye). The retina converts light to specific nerve signals, which are then transmitted to the brain to form images. The cornea must remain clear (transparent) and the proper shape to be able to transmit and focus incoming light.The abnormal cone-shape that characterizes keratoconus leads to changes in the ability of the cornea to help focus light appropriately on the retina (i.e., refractive abnormalities). Keratoconus may initially cause slight blurring of vision, abnormally increased sensitivity to glare or bright light and difficulty seeing at night (poor night vision). Some individuals may experience double vision (diplopia) or see a partial, incomplete image around what they are looking at (‘ghost’ images). In some people, there may be a loss of clarity of vision (visual acuity). With progressive corneal changes, affected individuals experience increased difficulty in seeing far away (nearsightedness or myopia) and further decreased clarity of vision. Overall vision changes can vary from one person to another, and the severity can range from mild vision loss to more severe vision loss that causes a decreased ability to see clearly even with corrective lenses. Some affected individuals may develop an irregular astigmatism, in which there is an irregular curvature of the eye.Rarely, affected individuals may develop a corneal blister that causes swelling of the cornea due to fluid accumulation (acute corneal hydrops) in specific layers of the cornea. This condition can be painful and cause redness of the eye. Scarring of the cornea can occur.
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Symptoms of Keratoconus. The corneas in both eyes are usually affected (bilateral), although the progression and severity of the condition in each eye may differ (asymmetric development), which means one eye may be notably worse than the other. Symptoms usually become apparent during adolescence or young adulthood (i.e., late teens through early 20s). Keratoconus may become progressively worse for 10 to 20 years before slowing. Older adults typically do not have worsening of keratoconus. Because of the progressive nature of the disorder, affected individuals may have to change glasses frequently.The cornea’s primary function is acting as the eye’s most powerful lens, bending incoming light onto the lower-powered internal lens, where the light is then directed to the retina (a membranous layer of light-sensing cells in the back of the eye). The retina converts light to specific nerve signals, which are then transmitted to the brain to form images. The cornea must remain clear (transparent) and the proper shape to be able to transmit and focus incoming light.The abnormal cone-shape that characterizes keratoconus leads to changes in the ability of the cornea to help focus light appropriately on the retina (i.e., refractive abnormalities). Keratoconus may initially cause slight blurring of vision, abnormally increased sensitivity to glare or bright light and difficulty seeing at night (poor night vision). Some individuals may experience double vision (diplopia) or see a partial, incomplete image around what they are looking at (‘ghost’ images). In some people, there may be a loss of clarity of vision (visual acuity). With progressive corneal changes, affected individuals experience increased difficulty in seeing far away (nearsightedness or myopia) and further decreased clarity of vision. Overall vision changes can vary from one person to another, and the severity can range from mild vision loss to more severe vision loss that causes a decreased ability to see clearly even with corrective lenses. Some affected individuals may develop an irregular astigmatism, in which there is an irregular curvature of the eye.Rarely, affected individuals may develop a corneal blister that causes swelling of the cornea due to fluid accumulation (acute corneal hydrops) in specific layers of the cornea. This condition can be painful and cause redness of the eye. Scarring of the cornea can occur.
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Keratoconus
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nord_670_2
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Causes of Keratoconus
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The specific underlying mechanism(s) responsible for keratoconus are not fully understood. Most cases appear to occur randomly for unknown reasons (sporadically). However, a positive family history of keratoconus has been established in some cases. Most researchers believe that multiple, complex factors are required for the development of keratoconus including both genetic and environmental factors.Researchers believe that some individuals who develop keratoconus have a genetic predisposition to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disorder, but the condition may not be expressed unless it is triggered or “activated” under certain circumstances such as due to environmental factors. Research is underway to identify specific genes associated with keratoconus.Environmental risk factors that may play a role in the development of keratoconus include contact lens use, repeated eye-rubbing or atopy, a general term for conditions that involve hypersensitivity reactions such as hay fever (allergic rhinitis), eczema (atopic dermatitis), sleep apnea or allergic asthma. However, studies have proven an association with any of these potential risk factors and the development of keratoconus.Traditionally, keratoconus has been considered a non-inflammatory disorder. Inflammation is a normal process that occurs in the body in response to injury or infection. In inflammatory disorders there is an abnormal immune (inflammatory) response, which can lead to symptoms or specific disorders. Although keratoconus has been defined as a non-inflammatory disorder, recent evidence, including abnormally high levels of proteolytic enzymes, an association with free radicals and oxidative stress, or the presence of cytokines, specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. More research is necessary to determine the complex, underlying causes of keratoconus.Keratoconus may also sometimes occur in association with certain underlying disorders, such as Down syndrome, sleep apnea, asthma, Leber congenital amaurosis and various connective tissue disorders including Ehlers-Danlos syndrome, Marfan syndrome or brittle cornea syndrome. A direct cause-and-effect relationship between these disorders and keratoconus has not been established. (For additional information on these disorders, please choose the appropriate name as your search term in the Rare Disease Database or see the “Related Disorders” section of this report below.)
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Causes of Keratoconus. The specific underlying mechanism(s) responsible for keratoconus are not fully understood. Most cases appear to occur randomly for unknown reasons (sporadically). However, a positive family history of keratoconus has been established in some cases. Most researchers believe that multiple, complex factors are required for the development of keratoconus including both genetic and environmental factors.Researchers believe that some individuals who develop keratoconus have a genetic predisposition to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disorder, but the condition may not be expressed unless it is triggered or “activated” under certain circumstances such as due to environmental factors. Research is underway to identify specific genes associated with keratoconus.Environmental risk factors that may play a role in the development of keratoconus include contact lens use, repeated eye-rubbing or atopy, a general term for conditions that involve hypersensitivity reactions such as hay fever (allergic rhinitis), eczema (atopic dermatitis), sleep apnea or allergic asthma. However, studies have proven an association with any of these potential risk factors and the development of keratoconus.Traditionally, keratoconus has been considered a non-inflammatory disorder. Inflammation is a normal process that occurs in the body in response to injury or infection. In inflammatory disorders there is an abnormal immune (inflammatory) response, which can lead to symptoms or specific disorders. Although keratoconus has been defined as a non-inflammatory disorder, recent evidence, including abnormally high levels of proteolytic enzymes, an association with free radicals and oxidative stress, or the presence of cytokines, specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells. More research is necessary to determine the complex, underlying causes of keratoconus.Keratoconus may also sometimes occur in association with certain underlying disorders, such as Down syndrome, sleep apnea, asthma, Leber congenital amaurosis and various connective tissue disorders including Ehlers-Danlos syndrome, Marfan syndrome or brittle cornea syndrome. A direct cause-and-effect relationship between these disorders and keratoconus has not been established. (For additional information on these disorders, please choose the appropriate name as your search term in the Rare Disease Database or see the “Related Disorders” section of this report below.)
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Keratoconus
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nord_670_3
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Affects of Keratoconus
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Keratoconus affects both men and women and all ethnic groups worldwide. The disorder tends to develop most often among adolescents at or around puberty or during the late teen-age years. Males, African Americans and Latinos have a greater risk of development keratoconus, while females, Asian-Americans, and people with diabetes appear to have a lower risk.The incidence and prevalence rates reported in the medical literature for keratoconus tend to vary widely. One long-term study in the United States indicated a prevalence of 54.5 diagnosed individuals per 100,000 individuals in the general population, or approximately 1 in 2,000 individuals. However, some estimates suggest that the incidence may be as high as 1 in 400 individuals. Individuals with a family history of keratoconus are at a greater risk of developing the condition than people the general population.
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Affects of Keratoconus. Keratoconus affects both men and women and all ethnic groups worldwide. The disorder tends to develop most often among adolescents at or around puberty or during the late teen-age years. Males, African Americans and Latinos have a greater risk of development keratoconus, while females, Asian-Americans, and people with diabetes appear to have a lower risk.The incidence and prevalence rates reported in the medical literature for keratoconus tend to vary widely. One long-term study in the United States indicated a prevalence of 54.5 diagnosed individuals per 100,000 individuals in the general population, or approximately 1 in 2,000 individuals. However, some estimates suggest that the incidence may be as high as 1 in 400 individuals. Individuals with a family history of keratoconus are at a greater risk of developing the condition than people the general population.
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Keratoconus
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nord_670_4
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Related disorders of Keratoconus
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Symptoms of the following disorders can be similar to those of keratoconus. Comparisons may be useful for a differential diagnosis:There are a variety of conditions that can resemble keratoconus including abnormal thinning and steepening of the outer (peripheral) edges of the cornea (pellucid marginal degeneration); thinning of the cornea and an abnormal globe-shaped (globular) or spherical form to the cornea (keratoglobus); chronic non-ulcerative infiltration in the deep layers of the cornea of the eye (interstitial keratitis); and the corneal dystrophies, a group of genetic, often progressive, eye disorders in which abnormal material often accumulates in the cornea.
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Related disorders of Keratoconus. Symptoms of the following disorders can be similar to those of keratoconus. Comparisons may be useful for a differential diagnosis:There are a variety of conditions that can resemble keratoconus including abnormal thinning and steepening of the outer (peripheral) edges of the cornea (pellucid marginal degeneration); thinning of the cornea and an abnormal globe-shaped (globular) or spherical form to the cornea (keratoglobus); chronic non-ulcerative infiltration in the deep layers of the cornea of the eye (interstitial keratitis); and the corneal dystrophies, a group of genetic, often progressive, eye disorders in which abnormal material often accumulates in the cornea.
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Keratoconus
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nord_670_5
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Diagnosis of Keratoconus
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Keratoconus may be diagnosed based upon a complete patient and family history and thorough eye examination. Such an examination may include evaluation of the external appearance of the eyes, visual acuity, eye movements, and visual fields; the use of a special, illuminated microscope that allows physicians to view the eye through high magnification (slit-lamp examination) and/or additional tests or procedures.A specific imaging test known as corneal topography is used to aid in a diagnosis of keratoconus, in part by detecting very early keratoconus where the corneal changes are not visible by a doctor looking at the eye (subclinical). This is sometimes referred to as “forme fruste” keratoconus. Corneal topography is an imaging study that typically uses an instrument to project a series of light rings onto the surface of the cornea. These rings of light are reflected back to the instrument and recorded. These recordings can show changes in the shape and integrity of the cornea. Corneal topography is useful for determining the severity of keratoconus and monitoring the progression of the disorder.
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Diagnosis of Keratoconus. Keratoconus may be diagnosed based upon a complete patient and family history and thorough eye examination. Such an examination may include evaluation of the external appearance of the eyes, visual acuity, eye movements, and visual fields; the use of a special, illuminated microscope that allows physicians to view the eye through high magnification (slit-lamp examination) and/or additional tests or procedures.A specific imaging test known as corneal topography is used to aid in a diagnosis of keratoconus, in part by detecting very early keratoconus where the corneal changes are not visible by a doctor looking at the eye (subclinical). This is sometimes referred to as “forme fruste” keratoconus. Corneal topography is an imaging study that typically uses an instrument to project a series of light rings onto the surface of the cornea. These rings of light are reflected back to the instrument and recorded. These recordings can show changes in the shape and integrity of the cornea. Corneal topography is useful for determining the severity of keratoconus and monitoring the progression of the disorder.
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Keratoconus
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nord_670_6
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Therapies of Keratoconus
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Treatment
The treatment of keratoconus is based upon the severity of the condition in the individual and the rate of progression of the disorder. In some individuals with mild symptoms, vision may be improved with the use of appropriate eyeglasses or soft contact lenses. However, progressive changes in vision often necessitate frequent prescription changes.In many individuals, rigid gas permeable contact lenses (a modern version of ‘hard’ contact lenses) may be required. These lenses can reshape the corneal surface to hide or mask the underlying cone-shaped defect of the cornea. In some individuals, these contact lenses may become uncomfortable and are not tolerated well. In such cases, individuals can use ‘piggyback’ contacts lenses in which hard contact lenses are placed over soft lenses. The underlying soft lenses provide comfort and support, while the hard lenses improve vision. Other types of contact lenses that may be used include hybrid lenses, which have a rigid center and soft ring on the outside, or scleral lenses, which are larger traditional contact lenses and which rest atop the sclera (the whites of the eyes) and mount above the cornea.However, some severely affected individuals may not be able to wear contact lenses due to progressively severe corneal thinning, corneal scarring and/or contact intolerance. In cases of severe visual deterioration in which contact lenses cannot sufficiently correct vision or are not tolerated, surgery may be required such as intracorneal ring segments or a corneal transplant (keratoplasty).In 2004, the U.S. Food and Drug Administration approved intracorneal ring segments for the treatment of individuals with keratoconus. During this procedure, two tiny crescent-shaped plastic pieces are inserted into the cornea. These inserts can help to flatten, strengthen and support the cornea and improve vision. Typically, eyeglasses or contact lenses are still required for proper vision.In 2016, the U.S. Food and Drug Administration granted the first approval of a corneal cross-linking device to treat progressive keratoconus. This device, KXL, uses UV light and riboflavin formulations to strengthen the cornea. This procedure in the US currently requires removal of the outermost layer of the cornea (the epithelium). This is also referred to as ‘epi-off’ crosslinking. Studies are currently underway to evaluate protocols that do not involve removal of the epithelium, referred to as ‘epi-off’ protocols. A corneal transplant is a surgical procedure in which abnormal corneal tissue is removed and replaced with healthy donor corneal tissue. This surgery is generally reserved for individuals with severe disease (e.g., the cornea is extremely thin and/or vision is significantly compromised) or who cannot tolerate or did not respond to more conservative treatments. A corneal transplant may also be indicated after an episode of corneal swelling (corneal hydrops) that does not respond to other treatment options. There are several different corneal transplant procedures that may be used. Corneal transplants are generally effective for treating individuals with keratoconus, but do carry a small risk of complications, including rejection of the donated tissue by the body (graft rejection). Of note, individuals who have a corneal transplant typically still need hard contact lenses after the transplant because the cornea, while flatter, still does not have a perfect shape.Preventative Therapies
A procedure known as corneal cross-linking (CXL) has been used to successfully treat individuals with keratoconus. This procedure uses ultraviolet A (UVA) light and riboflavin, a type of B vitamin, to slow or halt the progression of keratoconus. During the procedure, riboflavin is placed on the cornea via eye drops. Riboflavin acts as a photosensitizer, which allows corneal tissue to absorb ultraviolet light. Basically, this procedure creates new chemical bonds in the collagen of the cornea, strengthening the cornea and halting progression. In some cases, the cornea obtains a flatter shape after CXL, but it does not return to ‘normal’ entirely.A procedure known as topography-guided photorefractive keratectomy has been combined with collagen cross-linking to treat some individuals with mild to moderate keratoconus. Photorefractive keratectomy is a type of laser eye surgery that is most often used to treat individuals with mild or moderate nearsightedness, farsightedness or astigmatism. Generally, laser surgery is not recommended (contraindicated) for individuals with keratoconus. During this procedure a laser is used to reshape the affected cornea(s). More research is necessary to determine the long-term safety and effectiveness of this potential procedure for specific individuals with keratoconus.
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Therapies of Keratoconus. Treatment
The treatment of keratoconus is based upon the severity of the condition in the individual and the rate of progression of the disorder. In some individuals with mild symptoms, vision may be improved with the use of appropriate eyeglasses or soft contact lenses. However, progressive changes in vision often necessitate frequent prescription changes.In many individuals, rigid gas permeable contact lenses (a modern version of ‘hard’ contact lenses) may be required. These lenses can reshape the corneal surface to hide or mask the underlying cone-shaped defect of the cornea. In some individuals, these contact lenses may become uncomfortable and are not tolerated well. In such cases, individuals can use ‘piggyback’ contacts lenses in which hard contact lenses are placed over soft lenses. The underlying soft lenses provide comfort and support, while the hard lenses improve vision. Other types of contact lenses that may be used include hybrid lenses, which have a rigid center and soft ring on the outside, or scleral lenses, which are larger traditional contact lenses and which rest atop the sclera (the whites of the eyes) and mount above the cornea.However, some severely affected individuals may not be able to wear contact lenses due to progressively severe corneal thinning, corneal scarring and/or contact intolerance. In cases of severe visual deterioration in which contact lenses cannot sufficiently correct vision or are not tolerated, surgery may be required such as intracorneal ring segments or a corneal transplant (keratoplasty).In 2004, the U.S. Food and Drug Administration approved intracorneal ring segments for the treatment of individuals with keratoconus. During this procedure, two tiny crescent-shaped plastic pieces are inserted into the cornea. These inserts can help to flatten, strengthen and support the cornea and improve vision. Typically, eyeglasses or contact lenses are still required for proper vision.In 2016, the U.S. Food and Drug Administration granted the first approval of a corneal cross-linking device to treat progressive keratoconus. This device, KXL, uses UV light and riboflavin formulations to strengthen the cornea. This procedure in the US currently requires removal of the outermost layer of the cornea (the epithelium). This is also referred to as ‘epi-off’ crosslinking. Studies are currently underway to evaluate protocols that do not involve removal of the epithelium, referred to as ‘epi-off’ protocols. A corneal transplant is a surgical procedure in which abnormal corneal tissue is removed and replaced with healthy donor corneal tissue. This surgery is generally reserved for individuals with severe disease (e.g., the cornea is extremely thin and/or vision is significantly compromised) or who cannot tolerate or did not respond to more conservative treatments. A corneal transplant may also be indicated after an episode of corneal swelling (corneal hydrops) that does not respond to other treatment options. There are several different corneal transplant procedures that may be used. Corneal transplants are generally effective for treating individuals with keratoconus, but do carry a small risk of complications, including rejection of the donated tissue by the body (graft rejection). Of note, individuals who have a corneal transplant typically still need hard contact lenses after the transplant because the cornea, while flatter, still does not have a perfect shape.Preventative Therapies
A procedure known as corneal cross-linking (CXL) has been used to successfully treat individuals with keratoconus. This procedure uses ultraviolet A (UVA) light and riboflavin, a type of B vitamin, to slow or halt the progression of keratoconus. During the procedure, riboflavin is placed on the cornea via eye drops. Riboflavin acts as a photosensitizer, which allows corneal tissue to absorb ultraviolet light. Basically, this procedure creates new chemical bonds in the collagen of the cornea, strengthening the cornea and halting progression. In some cases, the cornea obtains a flatter shape after CXL, but it does not return to ‘normal’ entirely.A procedure known as topography-guided photorefractive keratectomy has been combined with collagen cross-linking to treat some individuals with mild to moderate keratoconus. Photorefractive keratectomy is a type of laser eye surgery that is most often used to treat individuals with mild or moderate nearsightedness, farsightedness or astigmatism. Generally, laser surgery is not recommended (contraindicated) for individuals with keratoconus. During this procedure a laser is used to reshape the affected cornea(s). More research is necessary to determine the long-term safety and effectiveness of this potential procedure for specific individuals with keratoconus.
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Keratoconus
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nord_671_0
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Overview of Keratolytic Winter Erythema
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SummaryKeratolytic winter erythema (KWE) is an extremely rare form of skin shedding that was first described in South Africa but has subsequently been identified in other countries. In such cases, a link to South Africa has NOT been determined. The disorder is characterized by periodic episodes of palmoplantar skin shedding preceded by redness and the appearance of dry superficial blisters. The peel is substantial and may be easily gripped. The peeling is enhanced by exposure to water. Symptoms may improve during pregnancy and with age. The disorder may worsen with cold weather and improve in the summer.IntroductionKWE was first described in 1977 by Findlay et al. Many of the Afrikaner families seen could trace their family back to a town in the Western Cape Province of South Africa, called Oudtshoorn, hence the name Oudtshoorn skin or Oudtshoorn disease. In a genealogical study, the condition was traced to Francois Renier Duminy (born 1747 in Lorient, France), a ship captain who settled in South Africa in the late 1700s.
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Overview of Keratolytic Winter Erythema. SummaryKeratolytic winter erythema (KWE) is an extremely rare form of skin shedding that was first described in South Africa but has subsequently been identified in other countries. In such cases, a link to South Africa has NOT been determined. The disorder is characterized by periodic episodes of palmoplantar skin shedding preceded by redness and the appearance of dry superficial blisters. The peel is substantial and may be easily gripped. The peeling is enhanced by exposure to water. Symptoms may improve during pregnancy and with age. The disorder may worsen with cold weather and improve in the summer.IntroductionKWE was first described in 1977 by Findlay et al. Many of the Afrikaner families seen could trace their family back to a town in the Western Cape Province of South Africa, called Oudtshoorn, hence the name Oudtshoorn skin or Oudtshoorn disease. In a genealogical study, the condition was traced to Francois Renier Duminy (born 1747 in Lorient, France), a ship captain who settled in South Africa in the late 1700s.
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Keratolytic Winter Erythema
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nord_671_1
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Symptoms of Keratolytic Winter Erythema
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KWE is characterized by the cyclical patchy redness and thickening of the skin of the palms and soles, followed by the appearance dry blisters which subsequently peel in an expanding pattern. The shedding skin has a thickish peel. The revealed surface skin appears glazed. These signs first appear during infancy or childhood and the disorder usually improves with age. The condition may be worsened by cold weather or episodes of fever. Secondary infection may complicate the condition. In some patients, slowly enlarging circular red patches may develop, usually on the extremities. These slowly expand and have a trailing edge of peeling. Other frequently encountered associated symptoms include itching, excessive sweating (hyperhidrosis or palmoplantar sweating) and a strong unpleasant odor.
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Symptoms of Keratolytic Winter Erythema. KWE is characterized by the cyclical patchy redness and thickening of the skin of the palms and soles, followed by the appearance dry blisters which subsequently peel in an expanding pattern. The shedding skin has a thickish peel. The revealed surface skin appears glazed. These signs first appear during infancy or childhood and the disorder usually improves with age. The condition may be worsened by cold weather or episodes of fever. Secondary infection may complicate the condition. In some patients, slowly enlarging circular red patches may develop, usually on the extremities. These slowly expand and have a trailing edge of peeling. Other frequently encountered associated symptoms include itching, excessive sweating (hyperhidrosis or palmoplantar sweating) and a strong unpleasant odor.
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Keratolytic Winter Erythema
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nord_671_2
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Causes of Keratolytic Winter Erythema
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KWE is inherited and follows an autosomal mode of inheritance with males and females equally affected. It has been found to be associated with a duplication of an area of a chromosome that included an element known as an enhancer. This ‘switches on’ a nearby gene or genes. One of these appears to be the gene CTSB which is has been shown to be overexpressed. The protein produced by this gene is cathepsin B. This is an enzyme that plays an important role in proteolysis (breakdown of proteins) causing a major disruption to the epidermal cell’s normal growth and development. These damaged cells fail to mature properly and are pushed outwards, still retaining their nuclei and this forms the peel.Furthermore, two different duplications have been discovered. The duplication found in the South African families is 7.67-kb in length while the duplication in Norwegian families is 15.93-kb. Both duplications overlap in the region of the enhancer. The genetic variation has not been determined for the families with KWE reported from Germany, Denmark or the USA.
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Causes of Keratolytic Winter Erythema. KWE is inherited and follows an autosomal mode of inheritance with males and females equally affected. It has been found to be associated with a duplication of an area of a chromosome that included an element known as an enhancer. This ‘switches on’ a nearby gene or genes. One of these appears to be the gene CTSB which is has been shown to be overexpressed. The protein produced by this gene is cathepsin B. This is an enzyme that plays an important role in proteolysis (breakdown of proteins) causing a major disruption to the epidermal cell’s normal growth and development. These damaged cells fail to mature properly and are pushed outwards, still retaining their nuclei and this forms the peel.Furthermore, two different duplications have been discovered. The duplication found in the South African families is 7.67-kb in length while the duplication in Norwegian families is 15.93-kb. Both duplications overlap in the region of the enhancer. The genetic variation has not been determined for the families with KWE reported from Germany, Denmark or the USA.
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Keratolytic Winter Erythema
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