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nord_1128_4
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Related disorders of Sjögren-Larsson Syndrome
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Symptoms of the following disorders can be similar to those of Sjögren-Larsson syndrome. Comparisons may be useful for a differential diagnosis.Ichthyosis is a general term for a family of rare genetic skin diseases characterized by dry, thickened, scaling skin.The various forms are distinguished from one another by: 1) extent of the scaling and how widely and where the scaling is scattered over the body; 2) the presence or absence and intensity of reddening of the skin (erythroderma); 3) the mode of inheritance; and 4) the character of associated abnormalities. For more information on this disorder, choose “Ichthyosis” as your search term in the Rare Disease Database.Refsum disease is one of a family of genetic disorders known as the leukodystrophies in which, due to problems breaking down fats, the protective insulation around the nerves of the brain (myelin sheath) fails to grow. It is inherited in an autosomal recessive pattern. It is characterized by progressive loss of vision (retinitis pigmentosa); degenerative nerve disease (peripheral neuropathy); failure of muscle coordination (ataxia); and dry, rough, scaly skin (ichthyosis). The disorder is caused by the accumulation of a particular fatty acid (phytanic acid) in blood plasma and tissues. This occurs because of a malfunction of the gene that makes the enzyme that breaks down (metabolizes) this acid. The essential enzyme is absent. For more information on this disorder, choose “Refsum disease” as your search term in the Rare Disease Database.Chanarin Dorfman syndrome is a rare hereditary disorder of fat (lipid) metabolism. It is characterized by scaly skin (ichthyosis), degeneration of the muscles (myopathy), and abnormal white blood cells with small spaces (vacuoles) filled with fat (lipids).
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Related disorders of Sjögren-Larsson Syndrome. Symptoms of the following disorders can be similar to those of Sjögren-Larsson syndrome. Comparisons may be useful for a differential diagnosis.Ichthyosis is a general term for a family of rare genetic skin diseases characterized by dry, thickened, scaling skin.The various forms are distinguished from one another by: 1) extent of the scaling and how widely and where the scaling is scattered over the body; 2) the presence or absence and intensity of reddening of the skin (erythroderma); 3) the mode of inheritance; and 4) the character of associated abnormalities. For more information on this disorder, choose “Ichthyosis” as your search term in the Rare Disease Database.Refsum disease is one of a family of genetic disorders known as the leukodystrophies in which, due to problems breaking down fats, the protective insulation around the nerves of the brain (myelin sheath) fails to grow. It is inherited in an autosomal recessive pattern. It is characterized by progressive loss of vision (retinitis pigmentosa); degenerative nerve disease (peripheral neuropathy); failure of muscle coordination (ataxia); and dry, rough, scaly skin (ichthyosis). The disorder is caused by the accumulation of a particular fatty acid (phytanic acid) in blood plasma and tissues. This occurs because of a malfunction of the gene that makes the enzyme that breaks down (metabolizes) this acid. The essential enzyme is absent. For more information on this disorder, choose “Refsum disease” as your search term in the Rare Disease Database.Chanarin Dorfman syndrome is a rare hereditary disorder of fat (lipid) metabolism. It is characterized by scaly skin (ichthyosis), degeneration of the muscles (myopathy), and abnormal white blood cells with small spaces (vacuoles) filled with fat (lipids).
| 1,128 |
Sjögren-Larsson Syndrome
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nord_1128_5
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Diagnosis of Sjögren-Larsson Syndrome
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A diagnosis of Sjögren-Larsson syndrome may be suspected at birth. A clinical diagnosis can be made by age 3 when the primary features of the disorder are usually apparent. The affected individual usually does not have a family history of this disease.Clinical Testing and Work-Up
Following a clinical suspicion of SLS, molecular genetic testing can be performed to look for mutations in the ALDH3A2 gene. 95% of patients have two mutations in this gene, leading to the symptoms seen in Sjögren-Larsson syndrome. Biochemical testing could also be ordered when suspecting SLS. However, it is very difficult to confirm a diagnosis of SLS at this level, and genetic testing is the more definitive means of making a diagnosis.
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Diagnosis of Sjögren-Larsson Syndrome. A diagnosis of Sjögren-Larsson syndrome may be suspected at birth. A clinical diagnosis can be made by age 3 when the primary features of the disorder are usually apparent. The affected individual usually does not have a family history of this disease.Clinical Testing and Work-Up
Following a clinical suspicion of SLS, molecular genetic testing can be performed to look for mutations in the ALDH3A2 gene. 95% of patients have two mutations in this gene, leading to the symptoms seen in Sjögren-Larsson syndrome. Biochemical testing could also be ordered when suspecting SLS. However, it is very difficult to confirm a diagnosis of SLS at this level, and genetic testing is the more definitive means of making a diagnosis.
| 1,128 |
Sjögren-Larsson Syndrome
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nord_1128_6
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Therapies of Sjögren-Larsson Syndrome
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Treatment
There is no cure for Sjögren-Larsson syndrome. Treatment focuses on treating symptoms as they appear and may require multiple different specialists to help address them. A comprehensive team to care for children with SLS might include specialists who help with problems of the brain and central nervous system (neurologists), specialists who assess and treat problems with the skin (dermatologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat problems of the skeleton and associated muscles and joints (orthopedists), and specialists who help with movement problems (physiotherapists).Diets low in long-chain fats, such as oils, fish, nuts, avocados, and meat, and supplemented with medium-chain fats (triglycerides), such as dairy products and coconut oil, have been associated with skin improvement for some patients. Other means of diminishing scaling of the skin includes applying keratolytic or urea-containing lotions or creams.While there is no cure for the muscle stiffness, physical therapy may help with movement. Other means in assisting movement might include bracing and support. Individuals with SLS will likely benefit from special education services in light of their intellectual disability. Speech and language therapy has shown some benefit in improving language performance and augmented communication skills. Genetic counseling is recommended for affected individuals and their family members.
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Therapies of Sjögren-Larsson Syndrome. Treatment
There is no cure for Sjögren-Larsson syndrome. Treatment focuses on treating symptoms as they appear and may require multiple different specialists to help address them. A comprehensive team to care for children with SLS might include specialists who help with problems of the brain and central nervous system (neurologists), specialists who assess and treat problems with the skin (dermatologists), specialists who assess and treat eye problems (ophthalmologists), specialists who assess and treat problems of the skeleton and associated muscles and joints (orthopedists), and specialists who help with movement problems (physiotherapists).Diets low in long-chain fats, such as oils, fish, nuts, avocados, and meat, and supplemented with medium-chain fats (triglycerides), such as dairy products and coconut oil, have been associated with skin improvement for some patients. Other means of diminishing scaling of the skin includes applying keratolytic or urea-containing lotions or creams.While there is no cure for the muscle stiffness, physical therapy may help with movement. Other means in assisting movement might include bracing and support. Individuals with SLS will likely benefit from special education services in light of their intellectual disability. Speech and language therapy has shown some benefit in improving language performance and augmented communication skills. Genetic counseling is recommended for affected individuals and their family members.
| 1,128 |
Sjögren-Larsson Syndrome
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nord_1129_0
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Overview of SLC13A5 Citrate Transporter Disorder
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SummarySLC13A5 citrate transporter disorder is a recently identified autosomal recessive disorder. Patients with SLC13A5 citrate transporter disorder are initially identified by the multiple types of seizures that begin within the first week of life. This rare disease is due to changes (mutations) in SLC13A5 gene (solute carrier family 13, member 5). As we learn more about SLC13A5 citrate transporter disorder, the number of affected children described in the literature is increasing (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016; Schossig et al. 2017; Weeke et al. 2017; Yang et al. 2020; Matricardi et al. 2020). Additionally, as of June 2021, there is an ongoing natural history study collecting information to further characterize SLC13A5 citrate transporter disorder.Patients with SLC13A5 citrate transporter disorder express a wide variety of mostly neurologic symptoms (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016; Schossig et al. 2017; Weeke et al. 2017). Affected children present with seizures beginning within a few days of birth, which are often refractory to medications and most patients remain on anti-seizure medications throughout life (Yang et al. 2020; Matricardi et al. 2020). Additional symptoms include limited ability to speak, slow motor development including problems standing or walking independently, as well as abnormalities in tooth enamel. Problems with tone are also reported with chronic low tone but also periodic episodes of body stiffening and post stiffening weakness (Klotz et al. 2016; Thevenon et al. 2014; Matricardi et al. 2020; Yang et al. 2020).This disorder is caused by mutations in both copies of the SLC13A5 gene. The SLC13A5 gene codes for a sodium dependent citrate transporter (NaCT) that brings citrate, a key substrate involved in energy production, into the cell (Inoue et al. 2002; Birkenfeld et al. 2011). To date, all tested mutations lead to reduced amounts or mislocalization of the citrate transporter in the cells (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016). Consistent with this finding, SLC13A5 citrate transporter disorder patients have elevated citrate levels in the cerebrospinal fluid, blood and urine (Bainbridge et al. 2017).
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Overview of SLC13A5 Citrate Transporter Disorder. SummarySLC13A5 citrate transporter disorder is a recently identified autosomal recessive disorder. Patients with SLC13A5 citrate transporter disorder are initially identified by the multiple types of seizures that begin within the first week of life. This rare disease is due to changes (mutations) in SLC13A5 gene (solute carrier family 13, member 5). As we learn more about SLC13A5 citrate transporter disorder, the number of affected children described in the literature is increasing (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016; Schossig et al. 2017; Weeke et al. 2017; Yang et al. 2020; Matricardi et al. 2020). Additionally, as of June 2021, there is an ongoing natural history study collecting information to further characterize SLC13A5 citrate transporter disorder.Patients with SLC13A5 citrate transporter disorder express a wide variety of mostly neurologic symptoms (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016; Schossig et al. 2017; Weeke et al. 2017). Affected children present with seizures beginning within a few days of birth, which are often refractory to medications and most patients remain on anti-seizure medications throughout life (Yang et al. 2020; Matricardi et al. 2020). Additional symptoms include limited ability to speak, slow motor development including problems standing or walking independently, as well as abnormalities in tooth enamel. Problems with tone are also reported with chronic low tone but also periodic episodes of body stiffening and post stiffening weakness (Klotz et al. 2016; Thevenon et al. 2014; Matricardi et al. 2020; Yang et al. 2020).This disorder is caused by mutations in both copies of the SLC13A5 gene. The SLC13A5 gene codes for a sodium dependent citrate transporter (NaCT) that brings citrate, a key substrate involved in energy production, into the cell (Inoue et al. 2002; Birkenfeld et al. 2011). To date, all tested mutations lead to reduced amounts or mislocalization of the citrate transporter in the cells (Thevenon et al. 2014; Hardies et al. 2015; Klotz et al. 2016). Consistent with this finding, SLC13A5 citrate transporter disorder patients have elevated citrate levels in the cerebrospinal fluid, blood and urine (Bainbridge et al. 2017).
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SLC13A5 Citrate Transporter Disorder
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nord_1129_1
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Symptoms of SLC13A5 Citrate Transporter Disorder
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There are several symptoms that are common in the majority of children diagnosed with SLC13A5 citrate transporter disorder:Siblings with the same genetic mutation show differences in the severity of symptoms. Variations include the type and frequency of seizures as well as the time course of developmental milestones (Anselm et al. 2016; Matricardi et al. 2020; Yang et al. 2020).
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Symptoms of SLC13A5 Citrate Transporter Disorder. There are several symptoms that are common in the majority of children diagnosed with SLC13A5 citrate transporter disorder:Siblings with the same genetic mutation show differences in the severity of symptoms. Variations include the type and frequency of seizures as well as the time course of developmental milestones (Anselm et al. 2016; Matricardi et al. 2020; Yang et al. 2020).
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SLC13A5 Citrate Transporter Disorder
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Causes of SLC13A5 Citrate Transporter Disorder
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SLC13A5 citrate transporter disorder is caused by mutations in SLC13A5 gene. There are multiple SLC13A5 mutations that cause SLC13A5 citrate transporter disorder. Currently identified mutations result in reduced citrate transporter (NaCT) activity (Hardies et al. 2015; Klotz et al. 2016; Knauf et al. 2002; Selch et al. 2018). Since citrate is a key metabolite and is known to play an important role in the energy production in cells, disrupting citrate import into cells may prevent cells from functioning properly. SLC13A5 is most highly expressed in the liver, brain and reproductive organs and most extensively studied in liver cells (Inoue, Zhuang, and Ganapathy 2002; Gopal et al. 2007). However, the role of SLC13A5 in the human brain is not well understood, and researchers hope to better understand the molecular mechanism underlying the symptoms of this devastating disease.SLC13A5 citrate transporter disorder is inherited in an autosomal recessive pattern, meaning that the disorder occurs when a child inherits a harmful mutation in the SLC13A5 gene 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 mutated gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents is 25 percent. The risk is the same for males and females.
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Causes of SLC13A5 Citrate Transporter Disorder. SLC13A5 citrate transporter disorder is caused by mutations in SLC13A5 gene. There are multiple SLC13A5 mutations that cause SLC13A5 citrate transporter disorder. Currently identified mutations result in reduced citrate transporter (NaCT) activity (Hardies et al. 2015; Klotz et al. 2016; Knauf et al. 2002; Selch et al. 2018). Since citrate is a key metabolite and is known to play an important role in the energy production in cells, disrupting citrate import into cells may prevent cells from functioning properly. SLC13A5 is most highly expressed in the liver, brain and reproductive organs and most extensively studied in liver cells (Inoue, Zhuang, and Ganapathy 2002; Gopal et al. 2007). However, the role of SLC13A5 in the human brain is not well understood, and researchers hope to better understand the molecular mechanism underlying the symptoms of this devastating disease.SLC13A5 citrate transporter disorder is inherited in an autosomal recessive pattern, meaning that the disorder occurs when a child inherits a harmful mutation in the SLC13A5 gene 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 mutated gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents is 25 percent. The risk is the same for males and females.
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SLC13A5 Citrate Transporter Disorder
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Affects of SLC13A5 Citrate Transporter Disorder
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SLC13A5 citrate transporter disorder is a rare genetic disorder that affects both males and females equally. So far reports on about 120 patients have been reported in various databases and publications (Thevenon et al. 2014; Bainbridge et al. 2017; Klotz et al. 2016; Matricardi et al. 2020; Yang et al. 2020; Hardies et al. 2015; “TESS Research Foundation” 2021). Patients are from families with various ethnic backgrounds from the USA, European and South American countries (Thevenon et al. 2014; “TESS Research Foundation” 2021; Bainbridge et al. 2017).
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Affects of SLC13A5 Citrate Transporter Disorder. SLC13A5 citrate transporter disorder is a rare genetic disorder that affects both males and females equally. So far reports on about 120 patients have been reported in various databases and publications (Thevenon et al. 2014; Bainbridge et al. 2017; Klotz et al. 2016; Matricardi et al. 2020; Yang et al. 2020; Hardies et al. 2015; “TESS Research Foundation” 2021). Patients are from families with various ethnic backgrounds from the USA, European and South American countries (Thevenon et al. 2014; “TESS Research Foundation” 2021; Bainbridge et al. 2017).
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Related disorders of SLC13A5 Citrate Transporter Disorder
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Mutations in various genes (including KCNQ2, FOXG1, etc) cause a large number of early infantile epileptic encephalopathies. Epileptic encephalopathies show overlapping phenotypes with SLC13A5 citrate transporter disorder such as seizures presenting within the first three months of life (Gürsoy and Erçal 2016). Another disorder with some overlap with SLC13A5 citrate transporter disorder is Kohlschütter-Tönz syndrome (KTZS) an autosomal recessive disorder caused by mutations in the ROGDI gene (Akgün-Doğan et al. 2021). It is characterized by severe global developmental delay, early-onset intractable seizures, spasticity and a disorder of tooth development (amelogenesis imperfecta) affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth (Akgün-Doğan et al. 2021).
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Related disorders of SLC13A5 Citrate Transporter Disorder. Mutations in various genes (including KCNQ2, FOXG1, etc) cause a large number of early infantile epileptic encephalopathies. Epileptic encephalopathies show overlapping phenotypes with SLC13A5 citrate transporter disorder such as seizures presenting within the first three months of life (Gürsoy and Erçal 2016). Another disorder with some overlap with SLC13A5 citrate transporter disorder is Kohlschütter-Tönz syndrome (KTZS) an autosomal recessive disorder caused by mutations in the ROGDI gene (Akgün-Doğan et al. 2021). It is characterized by severe global developmental delay, early-onset intractable seizures, spasticity and a disorder of tooth development (amelogenesis imperfecta) affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth (Akgün-Doğan et al. 2021).
| 1,129 |
SLC13A5 Citrate Transporter Disorder
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Diagnosis of SLC13A5 Citrate Transporter Disorder
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Currently, SLC13A5 citrate transporter disorder is diagnosed by DNA sequencing of the SLC13A5 gene. If both copies of the patient’s SLC13A5 genes are mutated, it is considered to be disease causing. For diagnosis, either whole exome sequencing (WES) can be performed or targeted panel sequencing (SLC13A5 is included in many epilepsy panels) can be performed which is often less expensive and faster. Efforts are underway to find other methods of diagnosis with quick turn-around-time such as high throughput metabolomic profiling of a patient’s urine, blood plasma or CSF (cerebro-spinal fluid) (Bainbridge et al. 2017).
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Diagnosis of SLC13A5 Citrate Transporter Disorder. Currently, SLC13A5 citrate transporter disorder is diagnosed by DNA sequencing of the SLC13A5 gene. If both copies of the patient’s SLC13A5 genes are mutated, it is considered to be disease causing. For diagnosis, either whole exome sequencing (WES) can be performed or targeted panel sequencing (SLC13A5 is included in many epilepsy panels) can be performed which is often less expensive and faster. Efforts are underway to find other methods of diagnosis with quick turn-around-time such as high throughput metabolomic profiling of a patient’s urine, blood plasma or CSF (cerebro-spinal fluid) (Bainbridge et al. 2017).
| 1,129 |
SLC13A5 Citrate Transporter Disorder
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nord_1129_6
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Therapies of SLC13A5 Citrate Transporter Disorder
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Treatment
The first line of treatment in SLC13A5 citrate transporter disorder is anti-seizure medications. Although anti-seizure medications have been successful in controlling seizures in some affected children, patients have variable success with the available drugs.
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Therapies of SLC13A5 Citrate Transporter Disorder. Treatment
The first line of treatment in SLC13A5 citrate transporter disorder is anti-seizure medications. Although anti-seizure medications have been successful in controlling seizures in some affected children, patients have variable success with the available drugs.
| 1,129 |
SLC13A5 Citrate Transporter Disorder
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nord_1130_0
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Overview of SLC6A1 Epileptic Encephalopathy
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SummarySLC6A1 epileptic encephalopathy is an autosomal dominant genetic disorder characterized by the loss-of-function of one copy of the human SLC6A1 gene. Clinical manifestation of SLC6A1 epileptic encephalopathy is characterized by early onset seizures (mean onset 3.7 years) and mild to severe intellectual disability. Seizure types include absences, myoclonic and atonic seizures. Language impairment and behavioral problems have also been observed. Some patients have shown intellectual disability without seizures or associated with focal epilepsy.
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Overview of SLC6A1 Epileptic Encephalopathy. SummarySLC6A1 epileptic encephalopathy is an autosomal dominant genetic disorder characterized by the loss-of-function of one copy of the human SLC6A1 gene. Clinical manifestation of SLC6A1 epileptic encephalopathy is characterized by early onset seizures (mean onset 3.7 years) and mild to severe intellectual disability. Seizure types include absences, myoclonic and atonic seizures. Language impairment and behavioral problems have also been observed. Some patients have shown intellectual disability without seizures or associated with focal epilepsy.
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SLC6A1 Epileptic Encephalopathy
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Symptoms of SLC6A1 Epileptic Encephalopathy
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Given the limited number of patients available for characterization, the full extent of symptoms is yet to be described. The most common features observed include absence seizures, myoclonic-atonic epilepsy (onset from 7 months to 6 years, mean 3.7 years) and mild-to-moderate intellectual disability. Speech difficulties and behavioral problems have been described. The most common EEG pattern observed comprises irregular, high ample, and generalized spike-and-waves. To date, the most extensive patient collection was published by Johannesen et al5 and includes 34 patients. In this cohort, cognitive development was impaired in 33/34 (97%) subjects; 28/34 (82%) had mild to moderate intellectual disability, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 patients with a mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24). Two patients had speech delay only, and 1 had severe intellectual disability. After epilepsy onset, cognition declined in 46% (11 out of 24) of patients. The most common seizure types were absences, myoclonic, and atonic seizures. Sixteen patients (47%) fulfilled the diagnostic criteria for myoclonic-atonic epilepsy. Seven additional patients had different forms of generalized epilepsy, and two had focal epilepsy. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7 out of 34 patients (21%).
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Symptoms of SLC6A1 Epileptic Encephalopathy. Given the limited number of patients available for characterization, the full extent of symptoms is yet to be described. The most common features observed include absence seizures, myoclonic-atonic epilepsy (onset from 7 months to 6 years, mean 3.7 years) and mild-to-moderate intellectual disability. Speech difficulties and behavioral problems have been described. The most common EEG pattern observed comprises irregular, high ample, and generalized spike-and-waves. To date, the most extensive patient collection was published by Johannesen et al5 and includes 34 patients. In this cohort, cognitive development was impaired in 33/34 (97%) subjects; 28/34 (82%) had mild to moderate intellectual disability, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 patients with a mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24). Two patients had speech delay only, and 1 had severe intellectual disability. After epilepsy onset, cognition declined in 46% (11 out of 24) of patients. The most common seizure types were absences, myoclonic, and atonic seizures. Sixteen patients (47%) fulfilled the diagnostic criteria for myoclonic-atonic epilepsy. Seven additional patients had different forms of generalized epilepsy, and two had focal epilepsy. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7 out of 34 patients (21%).
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SLC6A1 Epileptic Encephalopathy
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nord_1130_2
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Causes of SLC6A1 Epileptic Encephalopathy
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SLC6A1 epileptic encephalopathy is caused by a change (mutation) in one copy of the SLC6A1 gene that prevents the gene from working properly. Two types of SLC6A1 gene variants have been observed in patients: 1) protein truncating variants that stop the protein production for one of the two SLC6A1 genes inherited from parents and 2) point mutations in critical regions of the protein such as GABA binding sites and transmembrane domains, which lead to loss-of-function of mutated proteins. Thus, the expected molecular pathomechanism of SLC6A1 disorders is haploinsufficiency; a single functional copy of the gene is not enough. The disease-mode is supported by experiments in GAT-1 knockout mice as well as mice administered with GAT-1 inhibitor. In these experiments, the mice show spontaneous spike-wave discharges typical of absence seizures, the predominant seizure type seen in individuals with SLC6A1 mutations. Recently, experimental evidence showed that SLC6A1 variants identified in epilepsy patients reduce GABA transport6 in vitro.The SLC6A1 gene encodes for the voltage-dependent c-aminobutyric acid (GABA) transporter 1 (GAT-1) protein, one of the major GABA transporters of the human central nervous system. SLC6A1 is primarily expressed in the brain, specifically, in GABAergic neurons and astrocytes. The primary function of SLC6A1 is the reuptake of the GABA neurotransmitter from the extracellular space in the synapsys1. The SLC6A1 gene is located in the short arm of chromosome 3 (GRCh38 genomic coordinates: 3:10,992,733-11,039,248), contains 15 exons and is approximately 25 kb long. Genetic variation affecting the coding sequence of the gene in the general population is extremely rare2. Thus, the SLC6A1 gene is highly intolerant to variation. Patient variants in SLC6A1 were first described by Carvill et al. in 20153 (Online Mendelian Inheritance in Man database (OMIM) 137165)4 and were associated with early onset myoclonic-atonic epilepsy and intellectual disability. Later, with the collection of more patients, the phenotypic spectrum of SLC6A1-related disorders was expanded to include several types of seizures and different degrees of developmental delay. Notably, almost all of the genetic variants reported to date were not present in the parents (they arose ‘de novo’) and have not been observed in the general population. SLC6A1 epileptic encephalopathy is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene 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 SLC6A1 Epileptic Encephalopathy. SLC6A1 epileptic encephalopathy is caused by a change (mutation) in one copy of the SLC6A1 gene that prevents the gene from working properly. Two types of SLC6A1 gene variants have been observed in patients: 1) protein truncating variants that stop the protein production for one of the two SLC6A1 genes inherited from parents and 2) point mutations in critical regions of the protein such as GABA binding sites and transmembrane domains, which lead to loss-of-function of mutated proteins. Thus, the expected molecular pathomechanism of SLC6A1 disorders is haploinsufficiency; a single functional copy of the gene is not enough. The disease-mode is supported by experiments in GAT-1 knockout mice as well as mice administered with GAT-1 inhibitor. In these experiments, the mice show spontaneous spike-wave discharges typical of absence seizures, the predominant seizure type seen in individuals with SLC6A1 mutations. Recently, experimental evidence showed that SLC6A1 variants identified in epilepsy patients reduce GABA transport6 in vitro.The SLC6A1 gene encodes for the voltage-dependent c-aminobutyric acid (GABA) transporter 1 (GAT-1) protein, one of the major GABA transporters of the human central nervous system. SLC6A1 is primarily expressed in the brain, specifically, in GABAergic neurons and astrocytes. The primary function of SLC6A1 is the reuptake of the GABA neurotransmitter from the extracellular space in the synapsys1. The SLC6A1 gene is located in the short arm of chromosome 3 (GRCh38 genomic coordinates: 3:10,992,733-11,039,248), contains 15 exons and is approximately 25 kb long. Genetic variation affecting the coding sequence of the gene in the general population is extremely rare2. Thus, the SLC6A1 gene is highly intolerant to variation. Patient variants in SLC6A1 were first described by Carvill et al. in 20153 (Online Mendelian Inheritance in Man database (OMIM) 137165)4 and were associated with early onset myoclonic-atonic epilepsy and intellectual disability. Later, with the collection of more patients, the phenotypic spectrum of SLC6A1-related disorders was expanded to include several types of seizures and different degrees of developmental delay. Notably, almost all of the genetic variants reported to date were not present in the parents (they arose ‘de novo’) and have not been observed in the general population. SLC6A1 epileptic encephalopathy is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene 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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SLC6A1 Epileptic Encephalopathy
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Affects of SLC6A1 Epileptic Encephalopathy
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This is an extremely rare disorder. To date, only 34 patients have been characterized in the literature5. Patients are from families with various ethnic backgrounds from the USA, Canada and European countries. The SLC6A1 gene was until recently not screened in diagnostic sequencing and it is likely that many more patients will be reported with inclusion of this gene on gene panels.
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Affects of SLC6A1 Epileptic Encephalopathy. This is an extremely rare disorder. To date, only 34 patients have been characterized in the literature5. Patients are from families with various ethnic backgrounds from the USA, Canada and European countries. The SLC6A1 gene was until recently not screened in diagnostic sequencing and it is likely that many more patients will be reported with inclusion of this gene on gene panels.
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SLC6A1 Epileptic Encephalopathy
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nord_1130_4
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Related disorders of SLC6A1 Epileptic Encephalopathy
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A large number of infantile epileptic encephalopathies are known which result from mutations in various genes (including KCNQ2, FOXG1, etc.) and show overlapping characteristics (phenotypes) with SLC6A1 deficiency. Specifically, GABA transporters are part of the large family of neurotransmitters known as sodium symporters and include 13 gene members that have highly conserved sequence and redundant functions. For five additional gene family members, disease-causing mutations have been described in public repositories7: SLC6A2, SLC6A3, SLC6A5, SLC6A8 and SLC6A9 which are associated with a broad spectrum of neurodevelopmental disorders including epilepsy and intellectual disability. Genetic variants in the genes SCN1A, SCN1B, GABRG2, and CHD2 can cause similar phenotypes including myoclonic atonic seizures and response to valproic acid.
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Related disorders of SLC6A1 Epileptic Encephalopathy. A large number of infantile epileptic encephalopathies are known which result from mutations in various genes (including KCNQ2, FOXG1, etc.) and show overlapping characteristics (phenotypes) with SLC6A1 deficiency. Specifically, GABA transporters are part of the large family of neurotransmitters known as sodium symporters and include 13 gene members that have highly conserved sequence and redundant functions. For five additional gene family members, disease-causing mutations have been described in public repositories7: SLC6A2, SLC6A3, SLC6A5, SLC6A8 and SLC6A9 which are associated with a broad spectrum of neurodevelopmental disorders including epilepsy and intellectual disability. Genetic variants in the genes SCN1A, SCN1B, GABRG2, and CHD2 can cause similar phenotypes including myoclonic atonic seizures and response to valproic acid.
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Diagnosis of SLC6A1 Epileptic Encephalopathy
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In order to diagnose a SLC6A1 epileptic encephalopathy, DNA sequencing is required. Depending on the available resources, whole genome and whole exome sequencing can be performed. However, targeted gene panel sequencing is often faster, less expensive and easier to reimburse by insurance. The SLC6A1 gene is included in a variety of current epilepsy-oriented gene panels. Independently of the sequencing method used, variants found in the SLC6A1 genes should be interpreted carefully. The American College of Medical Genetics (ACMG) guidelines should be followed to assign the variants found a disease-causing state8.
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Diagnosis of SLC6A1 Epileptic Encephalopathy. In order to diagnose a SLC6A1 epileptic encephalopathy, DNA sequencing is required. Depending on the available resources, whole genome and whole exome sequencing can be performed. However, targeted gene panel sequencing is often faster, less expensive and easier to reimburse by insurance. The SLC6A1 gene is included in a variety of current epilepsy-oriented gene panels. Independently of the sequencing method used, variants found in the SLC6A1 genes should be interpreted carefully. The American College of Medical Genetics (ACMG) guidelines should be followed to assign the variants found a disease-causing state8.
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Therapies of SLC6A1 Epileptic Encephalopathy
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Treatment
Currently, the number of patients and clinical data available is limited. Treatment may require interdisciplinary efforts including neurologists, developmental pediatricians, speech therapy and/or other health care professionals to systematically and comprehensively plan the treatment of an affected child. Data on drug treatment is not conclusive. However, valproic acid by itself or in combination with other antiepileptic drugs has shown positive results. Johannesen et al5 shows that ten out of 15 patients treated with valproic acid became seizure-free, and the remaining 5 showed a partial benefit. Valproic acid is thought to have a positive effect on the GABA system, possibly by increasing the GABA concentration in the human brain9. Overall, 20 out of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome.
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Therapies of SLC6A1 Epileptic Encephalopathy. Treatment
Currently, the number of patients and clinical data available is limited. Treatment may require interdisciplinary efforts including neurologists, developmental pediatricians, speech therapy and/or other health care professionals to systematically and comprehensively plan the treatment of an affected child. Data on drug treatment is not conclusive. However, valproic acid by itself or in combination with other antiepileptic drugs has shown positive results. Johannesen et al5 shows that ten out of 15 patients treated with valproic acid became seizure-free, and the remaining 5 showed a partial benefit. Valproic acid is thought to have a positive effect on the GABA system, possibly by increasing the GABA concentration in the human brain9. Overall, 20 out of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome.
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Overview of Small Cell Lung Cancer
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SummarySmall cell lung cancer (SCLC) is an aggressive form of lung cancer. It is characterized by rapid, uncontrolled growth of certain cells in the lungs. Eventually, a tumor forms and the cancer can spread (metastasize) to other areas of the body. The primary risk factor is tobacco use; almost all affected individuals smoke or have a history of smoking. Symptoms can vary from one person to another, and there are rarely any symptoms early in the course of the disease. Generally, SCLC is broken down into two main stages: limited stage disease, which is potentially curable in about 20%-25% of people, and extensive stage disease, which is more difficult to treat. Affected individuals are treated with chemotherapy and often radiation therapy. In a small group of people with very early stage cancer, surgery may be recommended. Although there has been only slight progress in treatment over the last couple of decades, there has been a renewed interest in SCLC over the past several years and multiple clinical trials are underway for newer, targeted therapies to treat the disorder.IntroductionSmall cell lung cancer is characterized as a neuroendocrine carcinoma because the cancer cells have features of nerve cells and endocrine (hormone-secreting) cells. Endocrine tissue is specialized tissue that contains hormone-secreting cells. These hormones have a variety of functions within the body.
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Overview of Small Cell Lung Cancer. SummarySmall cell lung cancer (SCLC) is an aggressive form of lung cancer. It is characterized by rapid, uncontrolled growth of certain cells in the lungs. Eventually, a tumor forms and the cancer can spread (metastasize) to other areas of the body. The primary risk factor is tobacco use; almost all affected individuals smoke or have a history of smoking. Symptoms can vary from one person to another, and there are rarely any symptoms early in the course of the disease. Generally, SCLC is broken down into two main stages: limited stage disease, which is potentially curable in about 20%-25% of people, and extensive stage disease, which is more difficult to treat. Affected individuals are treated with chemotherapy and often radiation therapy. In a small group of people with very early stage cancer, surgery may be recommended. Although there has been only slight progress in treatment over the last couple of decades, there has been a renewed interest in SCLC over the past several years and multiple clinical trials are underway for newer, targeted therapies to treat the disorder.IntroductionSmall cell lung cancer is characterized as a neuroendocrine carcinoma because the cancer cells have features of nerve cells and endocrine (hormone-secreting) cells. Endocrine tissue is specialized tissue that contains hormone-secreting cells. These hormones have a variety of functions within the body.
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Symptoms of Small Cell Lung Cancer
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The signs and symptoms of small cell lung cancer can vary from one person to another. Specific findings depend on numerous factors including the exact location and size of the tumor, the extent of invasion of the tumor into nearby tissue or organs, and whether the disease has remained localized or spread to other areas of the body (metastasized). Early in the course of the disease, there may be no symptoms (asymptomatic) or only a few, mild symptoms. As the tumor grows, more signs and symptoms develop. Common symptoms include a cough that doesn’t get better, chest pain that is worse when coughing, laughing or taking a deep breath, shortness of breath, coughing up of blood (hemoptysis), and hoarseness or wheezing. Some affected individuals can develop loss of appetite, unintended weight loss, fatigue, and recurrent episodes of lung infections such as pneumonia or bronchitis. When SCLC spreads (metastasizes) the most commonly affected areas are the lymph nodes, brain, liver, adrenal glands, bone, and bone marrow. The symptoms that develop will vary depending upon the specific area(s) affected and the extent of the disease. Symptoms can include bone pain from spread to bones; yellowing of the eyes, skin and mucous membranes (jaundice) from cancer spreading to the liver; headaches, dizziness, double vision, seizures, or a sensation of numbness or tingling in the hands and arms and feet and legs when cancer spreads to the brain; or small lumps or growths on the skin when cancer has spread to the skin or lymph nodes. Individuals with SCLC can also develop paraneoplastic syndromes. These syndromes are rare disorders that are caused by either abnormal production of hormones or an abnormal response of the immune system to a cancerous tumor. It is believed that white blood cells, which normally help to protect the body from bacteria, viruses and other foreign invaders, can mistakenly attack healthy tissue causing a variety of neurologic problems, such as weakness, loss of sensation, imbalance or confusion. A common paraneoplastic syndrome in SCLC is called the syndrome of inappropriate antidiuretic hormone secretion. This syndrome is characterized by excessive production of antidiuretic hormone, which causes people to retain water and lowers salt (sodium) levels in the body which can cause fatigue, lethargy, and confusion.
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Symptoms of Small Cell Lung Cancer. The signs and symptoms of small cell lung cancer can vary from one person to another. Specific findings depend on numerous factors including the exact location and size of the tumor, the extent of invasion of the tumor into nearby tissue or organs, and whether the disease has remained localized or spread to other areas of the body (metastasized). Early in the course of the disease, there may be no symptoms (asymptomatic) or only a few, mild symptoms. As the tumor grows, more signs and symptoms develop. Common symptoms include a cough that doesn’t get better, chest pain that is worse when coughing, laughing or taking a deep breath, shortness of breath, coughing up of blood (hemoptysis), and hoarseness or wheezing. Some affected individuals can develop loss of appetite, unintended weight loss, fatigue, and recurrent episodes of lung infections such as pneumonia or bronchitis. When SCLC spreads (metastasizes) the most commonly affected areas are the lymph nodes, brain, liver, adrenal glands, bone, and bone marrow. The symptoms that develop will vary depending upon the specific area(s) affected and the extent of the disease. Symptoms can include bone pain from spread to bones; yellowing of the eyes, skin and mucous membranes (jaundice) from cancer spreading to the liver; headaches, dizziness, double vision, seizures, or a sensation of numbness or tingling in the hands and arms and feet and legs when cancer spreads to the brain; or small lumps or growths on the skin when cancer has spread to the skin or lymph nodes. Individuals with SCLC can also develop paraneoplastic syndromes. These syndromes are rare disorders that are caused by either abnormal production of hormones or an abnormal response of the immune system to a cancerous tumor. It is believed that white blood cells, which normally help to protect the body from bacteria, viruses and other foreign invaders, can mistakenly attack healthy tissue causing a variety of neurologic problems, such as weakness, loss of sensation, imbalance or confusion. A common paraneoplastic syndrome in SCLC is called the syndrome of inappropriate antidiuretic hormone secretion. This syndrome is characterized by excessive production of antidiuretic hormone, which causes people to retain water and lowers salt (sodium) levels in the body which can cause fatigue, lethargy, and confusion.
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Causes of Small Cell Lung Cancer
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SCLC is primarily caused by cancer causing chemicals (carcinogens) that are found in tobacco smoke. These carcinogens cause damage to the DNA (deoxyribonucleic acid; genes) in cells which leads to cancer. However, the exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the development of SCLC in certain people. Current research suggests that abnormalities of DNA which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation.In SCLC, genetic changes can affect oncogenes or tumor suppressor genes. These gene changes are acquired during life; they are not inherited. They are acquired because of exposure to environmental factors like smoking or they occur randomly for no known reason (spontaneously). These gene changes are altered or incomplete versions of ordinary genes that normally regulate cell growth and division. An altered oncogene promotes out-of-control growth (cancer). Tumor suppressor genes normally limit or stop the growth of cells. When the tumor suppressor genes are altered (mutated), cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing. There are many different oncogenes or tumor suppressor genes that have been linked to SCLC. Two tumor suppressor genes that have been linked to many people with SCLC are the TP53 gene, which has been associated with many cancers, and the RB1 gene, which is associated with retinoblastoma and other cancers. The TP53 gene is altered in 75% of SCLCs and the RB1 gene is altered in 90% of SCLCs. There are several risk factors associated with SCLC. A risk factor is anything that increases a person’s risk of developing a condition. Having a risk factor does not mean a person will definitely develop that condition, and people who do not have any risk factors can still develop a condition. The main risk factor for SCLC is smoking with over 95% of affected individuals being current or former smokers. Heavy smokers are particularly at risk for SCLC. Chronic exposure to secondhand smoke also increases the risk of lung cancer. Other environmental risk factors are less common, but include exposure to chloromethyl esters, which are used in chemical manufacturing, asbestos, or radon. Radon is a colorless, odorless, radioactive gas. It occurs naturally in the environment when uranium breaks down in the soil or rock. Radon exposure in concentrated amounts, which can sometimes occur inside a home, usually in a basement, can increase the risk of lung cancer.
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Causes of Small Cell Lung Cancer. SCLC is primarily caused by cancer causing chemicals (carcinogens) that are found in tobacco smoke. These carcinogens cause damage to the DNA (deoxyribonucleic acid; genes) in cells which leads to cancer. However, the exact reason normal cells become cancerous is not known. Most likely, multiple factors including genetic and environmental ones play a role in the development of SCLC in certain people. Current research suggests that abnormalities of DNA which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation.In SCLC, genetic changes can affect oncogenes or tumor suppressor genes. These gene changes are acquired during life; they are not inherited. They are acquired because of exposure to environmental factors like smoking or they occur randomly for no known reason (spontaneously). These gene changes are altered or incomplete versions of ordinary genes that normally regulate cell growth and division. An altered oncogene promotes out-of-control growth (cancer). Tumor suppressor genes normally limit or stop the growth of cells. When the tumor suppressor genes are altered (mutated), cells can multiply (proliferate) wildly, causing cancer. When the normal gene is present, they appear to prevent cancer from developing. There are many different oncogenes or tumor suppressor genes that have been linked to SCLC. Two tumor suppressor genes that have been linked to many people with SCLC are the TP53 gene, which has been associated with many cancers, and the RB1 gene, which is associated with retinoblastoma and other cancers. The TP53 gene is altered in 75% of SCLCs and the RB1 gene is altered in 90% of SCLCs. There are several risk factors associated with SCLC. A risk factor is anything that increases a person’s risk of developing a condition. Having a risk factor does not mean a person will definitely develop that condition, and people who do not have any risk factors can still develop a condition. The main risk factor for SCLC is smoking with over 95% of affected individuals being current or former smokers. Heavy smokers are particularly at risk for SCLC. Chronic exposure to secondhand smoke also increases the risk of lung cancer. Other environmental risk factors are less common, but include exposure to chloromethyl esters, which are used in chemical manufacturing, asbestos, or radon. Radon is a colorless, odorless, radioactive gas. It occurs naturally in the environment when uranium breaks down in the soil or rock. Radon exposure in concentrated amounts, which can sometimes occur inside a home, usually in a basement, can increase the risk of lung cancer.
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Affects of Small Cell Lung Cancer
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The incidence of small cell lung cancer in the United States has been declining over the last two decades, which most researchers attribute to the decline in smoking in the country. Lung cancer, as a group, is the second most common form of cancer in the United States. SCLC accounts for about 10%-15% of people who have lung cancer. There are about 30,000 to 35,000 new people diagnosed with SCLC each year in the United States. Almost everyone who develops SCLC has a history of smoking. It is extremely rare in individuals who have never smoked.
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Affects of Small Cell Lung Cancer. The incidence of small cell lung cancer in the United States has been declining over the last two decades, which most researchers attribute to the decline in smoking in the country. Lung cancer, as a group, is the second most common form of cancer in the United States. SCLC accounts for about 10%-15% of people who have lung cancer. There are about 30,000 to 35,000 new people diagnosed with SCLC each year in the United States. Almost everyone who develops SCLC has a history of smoking. It is extremely rare in individuals who have never smoked.
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Related disorders of Small Cell Lung Cancer
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Related disorders of Small Cell Lung Cancer.
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Diagnosis of Small Cell Lung Cancer
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A diagnosis of small cell lung cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. SCLC is an aggressive cancer and in may affected individuals the cancer has already spread once a diagnosis is made. Clinical Testing and Workup
A plain x-ray (radiography) of the chest can show a tumor or mass in the lungs. If a mass is found, more specialized imaging techniques can be used to determine whether cancer is present, the extent of the disease, and whether the cancer has spread to other areas. Such imaging techniques may include computerized tomography (CT), positron emission tomography (PET) and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create cross-sectional images of the inside of the body. A CT scan of the chest can show smaller tumors that do not show up on conventional x-rays and can also show whether cancer has spread to nearby lymph nodes. A CT scan of other areas of the body can show whether cancer has spread (metastasized) to specific areas. Another advanced imaging technique known as positron emission tomography (PET scan) may also be used. During a PET scan, a radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. When the scan is taken, areas that take up the radioactive sugar, including SCLC, may show up as bright spots on the film. A PET scan is often used to help show whether SCLC has spread to other parts of the body. For example, a PET scan can determine whether cancer has spread to the bones. In the past, this required a bone scan, but when a PET scan is used, a bone scan is no longer necessary. Nowadays, PET scans are almost always done in conjunction with a CT scan (PET/CT). The PET/CT gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has while also mapping the adjacent body structures (CT).During a bone scan, a relatively harmless radioactive dye is injected into the blood and is taken up by abnormal areas of bone. A special camera that can detect the dye in the bones is used to create a picture of the skeleton to determine whether SCLC has spread to other areas of the body. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain may be ordered to determine whether cancer has spread to the brain. Obtaining a piece of the tumor (biopsy) from the lungs or another site of the body needs to be performed in order to determine the specific type of cancer. In order to obtain a tumor sample, physicians usually recommend a bronchoscopy or a needle biopsy. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down into the affected individual’s lungs to obtain a sample of tissue to be analyzed (biopsy). Fine needle aspiration is another type of biopsy. It involves a thinner, hollow needle, which is inserted into the tumor to remove tissue. The needle is attached to a syringe, which is used to draw out (aspirate) a sample of tissue and fluid from the mass or tumor. During video thoracoscopy, a thin tube with a built-in camera (thoracoscope) is inserted into the chest through a small surgical cut (incision) allowing a physician to view the lungs and obtain tissue samples. This is usually a formal operative procedure performed in an operating room or similar setting, and may require a general anesthetic with a temporary breathing tube.Sometimes, doctors may order a mediastinoscopy to evaluate whether the cancer has spread to the lymph nodes in the middle of the chest. This involves making a small cut near the top of the breastbone, which is the thin bone that runs down the center of the chest. A small thin tube called a mediastinoscope is passed behind the breastbone along the windpipe to allow doctors to view and take tissue samples from the mediastinum, which is the area between the lungs in the central region of the chest.Staging
The most commonly used staging system for SCLC is the Veterans Administration Lung Study Group (VALG) staging system. This system basically breaks the disorder into two categories – limited stage SCLC and extensive stage SCLC. Limited stage refers to when the cancer is confined to one side of the chest and can be treated within one radiation field or port. A radiation field or port is the area of the body where radiation is directed to kill cancer cells. If the cancer is contained to a small area, it can be treated within one radiation field or port. Extensive stage refers to when the cancer has spread beyond just one side of the chest. The primary goal of staging in SCLC is to determine whether the cancer has spread. The International Association of the Study of Lung Cancer has proposed that physicians should adopt a different staging system called the Tumor Node Metastasis (TNM) Staging System, which is a common staging system for cancer developed by the American Joint Committee on Cancer. This system is based on the extent of the tumor (T), whether and to what extent cancer has spread to the lymph nodes (N), and whether cancer has spread (metastasized) to other areas of the body (M). It is a more complex staging system. For more information on this staging system for SCLC, visit: https://emedicine.medscape.com/article/2006716-overview.
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Diagnosis of Small Cell Lung Cancer. A diagnosis of small cell lung cancer is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. SCLC is an aggressive cancer and in may affected individuals the cancer has already spread once a diagnosis is made. Clinical Testing and Workup
A plain x-ray (radiography) of the chest can show a tumor or mass in the lungs. If a mass is found, more specialized imaging techniques can be used to determine whether cancer is present, the extent of the disease, and whether the cancer has spread to other areas. Such imaging techniques may include computerized tomography (CT), positron emission tomography (PET) and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create cross-sectional images of the inside of the body. A CT scan of the chest can show smaller tumors that do not show up on conventional x-rays and can also show whether cancer has spread to nearby lymph nodes. A CT scan of other areas of the body can show whether cancer has spread (metastasized) to specific areas. Another advanced imaging technique known as positron emission tomography (PET scan) may also be used. During a PET scan, a radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading, and will soak up the radioactive sugar. When the scan is taken, areas that take up the radioactive sugar, including SCLC, may show up as bright spots on the film. A PET scan is often used to help show whether SCLC has spread to other parts of the body. For example, a PET scan can determine whether cancer has spread to the bones. In the past, this required a bone scan, but when a PET scan is used, a bone scan is no longer necessary. Nowadays, PET scans are almost always done in conjunction with a CT scan (PET/CT). The PET/CT gathers information about how much metabolic activity (glucose uptake, measured by PET) a cancer has while also mapping the adjacent body structures (CT).During a bone scan, a relatively harmless radioactive dye is injected into the blood and is taken up by abnormal areas of bone. A special camera that can detect the dye in the bones is used to create a picture of the skeleton to determine whether SCLC has spread to other areas of the body. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain may be ordered to determine whether cancer has spread to the brain. Obtaining a piece of the tumor (biopsy) from the lungs or another site of the body needs to be performed in order to determine the specific type of cancer. In order to obtain a tumor sample, physicians usually recommend a bronchoscopy or a needle biopsy. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down into the affected individual’s lungs to obtain a sample of tissue to be analyzed (biopsy). Fine needle aspiration is another type of biopsy. It involves a thinner, hollow needle, which is inserted into the tumor to remove tissue. The needle is attached to a syringe, which is used to draw out (aspirate) a sample of tissue and fluid from the mass or tumor. During video thoracoscopy, a thin tube with a built-in camera (thoracoscope) is inserted into the chest through a small surgical cut (incision) allowing a physician to view the lungs and obtain tissue samples. This is usually a formal operative procedure performed in an operating room or similar setting, and may require a general anesthetic with a temporary breathing tube.Sometimes, doctors may order a mediastinoscopy to evaluate whether the cancer has spread to the lymph nodes in the middle of the chest. This involves making a small cut near the top of the breastbone, which is the thin bone that runs down the center of the chest. A small thin tube called a mediastinoscope is passed behind the breastbone along the windpipe to allow doctors to view and take tissue samples from the mediastinum, which is the area between the lungs in the central region of the chest.Staging
The most commonly used staging system for SCLC is the Veterans Administration Lung Study Group (VALG) staging system. This system basically breaks the disorder into two categories – limited stage SCLC and extensive stage SCLC. Limited stage refers to when the cancer is confined to one side of the chest and can be treated within one radiation field or port. A radiation field or port is the area of the body where radiation is directed to kill cancer cells. If the cancer is contained to a small area, it can be treated within one radiation field or port. Extensive stage refers to when the cancer has spread beyond just one side of the chest. The primary goal of staging in SCLC is to determine whether the cancer has spread. The International Association of the Study of Lung Cancer has proposed that physicians should adopt a different staging system called the Tumor Node Metastasis (TNM) Staging System, which is a common staging system for cancer developed by the American Joint Committee on Cancer. This system is based on the extent of the tumor (T), whether and to what extent cancer has spread to the lymph nodes (N), and whether cancer has spread (metastasized) to other areas of the body (M). It is a more complex staging system. For more information on this staging system for SCLC, visit: https://emedicine.medscape.com/article/2006716-overview.
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Therapies of Small Cell Lung Cancer
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Treatment
The therapeutic management of individuals with small cell lung cancer may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and drug treatment of cancer (medical oncologists), physicians who specialize in the treatment of cancer with radiation (radiation oncologists), physicians who specialize in examining tissues and cells to find disease and determine what disease is present (pathologists), physicians who specialize in interpreting x-rays and advanced imaging scans (radiologists), surgeons who specialize in removing cancer by surgery (surgical oncologists), physicians who specialize in the diagnosis and treatment of lung disease (pulmonologists); nurses who specialize in the care and treatment of cancer (oncology nurses), psychiatrists, nutritionists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on lung cancer or lung disease. Individuals who have SCLC and who still smoke are strongly encouraged to quit smoking. The importance of quitting smoking cannot be overemphasized. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; whether the cancer has spread (metastasized) and to which organs it has spread; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her situation; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Limited Disease
In rare instances, individuals with limited stage SCLC who have a small tumor that has not spread to nearby lymph nodes (early stage or stage 1 SCLC) can sometimes be treated with surgical removal of the tumor. However, in most people, the tumor is not localized and because it is usually a fast-growing cancer, often has spread at least to nearby lymph nodes or other areas of the chest. Most affected individuals with limited stage SCLC are treated with a combination of chemotherapy and radiation therapy given at the same time. Chemotherapy is the use of certain medications to kill or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. The most common chemotherapeutic regimen used for SCLC is etoposide combined with cisplatin or carboplatin. This may be referred to as platinum-based chemotherapy because and carboplatin and cisplatin are platinum-containing compounds. Carboplatin is generally associated with fewer and less severe side effects than cisplatin. SCLC is highly responsive to chemotherapy and sometimes improvement can be rapid and dramatic. However, cancer often returns and may become resistant to the chemotherapy regimen that was successful in the past. Radiation therapy is usually used in combination with chemotherapy (chemoradiotherapy) to treat individuals with limited stage SCLC. Radiation therapy uses high-powered x-rays to directly destroy cancer cells. Radiation therapy is directed at the chest (thoracic radiotherapy) to the main lung tumor and the lymph nodes to which the cancer has spread. Individuals who are successfully treated with chemotherapy and radiation therapy to the chest may also receive preventive radiation therapy to the brain called prophylactic cranial irradiation (PCI). Because SCLC is an aggressive cancer and can spread to the brain, PCI is used to destroy any microscopic cancer cells that may have reached the brain. PCI is generally given to individuals who have a good response to initial therapy and are healthy enough to undergo the treatment. About 25% of individuals with limited stage SCLC can be cured with prompt treatment with chemotherapy and radiation therapy. Extensive Disease
The treatment for extensive stage SCLC is primarily platinum-based chemotherapy, similar to that which is used in limited stage disease. Sometimes, instead of using etoposide along with cisplatin or carboplatin, doctors may use a drug called irinotecan. The combination of irinotecan plus a platinum-drug appears to be more effective in Japanese people; in Caucasians, etoposide appears to be equally effective and is associated with less severe side effects. Recently, the addition of an immunotherapy drug called atezolizumab, that boosts the body’s immune system to fight the cancer, to the standard regimen of carboplatin plus etoposide was shown to improve the outcome of some patients with extensive stage SCLC. However, this combination of drugs has not been approved by the U.S. Food and Drug Administration (FDA). Although extensive stage disease is not curable, the majority of patients will have shrinkage of their cancer, improvement in symptoms and prolongation of life with chemotherapy. The goals of treatment are to improve symptoms, maintain quality of life and prolong life. In some situations, thoracic radiation will be recommended after chemotherapy in people with extensive stage SCLC. Because of the high risk of spread of SCLC to the brain, frequent MRI scans of the brain are usually recommended.Recurrence
Although SCLC is highly responsive to initial chemotherapy, the cancer often comes back (recurs). When the cancer returns, it is usually more resistant to the previously effective chemotherapy regimens. Different chemotherapy regimens can be tried, but are usually not as effective. When the cancer comes back, it can be extremely aggressive. The only second-line therapy approved for SCLC in the U.S. is a chemotherapeutic drug called topotecan. Several drugs other available drugs do have some ability to shrink or slow the cancer, but results are generally disappointing. Newer drugs are being studied in clinical trials for second-line therapy for individuals with SCLC. In 2017, the FDA approved the drug nivolumab (Opdivo®) for the treatment of individuals with SCLC cancer in whom the cancer has spread (metastasized) and who have been previously treated with two types of therapy including chemotherapy. Nivolumab is a form of immunotherapy. Immunotherapy is the most recent addition to therapy for cancer. It is designed to enlist the body’s immune system to act against cancer. Supportive Therapy
Affected individuals may require supportive therapies. Many individuals with SCLC have a significant decrease in lung function and may need therapies to assist with breathing. This can include drugs called bronchodilators, which widen the airways of the lungs, or supplemental oxygen therapy. Clinical Trials
Affected individuals are encouraged to explore participating in clinical trials. Participating in a clinical trial can give an affected individual access to new therapies. This decision should be made after close consultation with an individual’s oncologist and entire medical team.
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Therapies of Small Cell Lung Cancer. Treatment
The therapeutic management of individuals with small cell lung cancer may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and drug treatment of cancer (medical oncologists), physicians who specialize in the treatment of cancer with radiation (radiation oncologists), physicians who specialize in examining tissues and cells to find disease and determine what disease is present (pathologists), physicians who specialize in interpreting x-rays and advanced imaging scans (radiologists), surgeons who specialize in removing cancer by surgery (surgical oncologists), physicians who specialize in the diagnosis and treatment of lung disease (pulmonologists); nurses who specialize in the care and treatment of cancer (oncology nurses), psychiatrists, nutritionists, and other healthcare specialists. Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on lung cancer or lung disease. Individuals who have SCLC and who still smoke are strongly encouraged to quit smoking. The importance of quitting smoking cannot be overemphasized. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size; whether the cancer has spread (metastasized) and to which organs it has spread; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her situation; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Limited Disease
In rare instances, individuals with limited stage SCLC who have a small tumor that has not spread to nearby lymph nodes (early stage or stage 1 SCLC) can sometimes be treated with surgical removal of the tumor. However, in most people, the tumor is not localized and because it is usually a fast-growing cancer, often has spread at least to nearby lymph nodes or other areas of the chest. Most affected individuals with limited stage SCLC are treated with a combination of chemotherapy and radiation therapy given at the same time. Chemotherapy is the use of certain medications to kill or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. Different combinations of medications may be used; this is called a chemotherapy regimen. The most common chemotherapeutic regimen used for SCLC is etoposide combined with cisplatin or carboplatin. This may be referred to as platinum-based chemotherapy because and carboplatin and cisplatin are platinum-containing compounds. Carboplatin is generally associated with fewer and less severe side effects than cisplatin. SCLC is highly responsive to chemotherapy and sometimes improvement can be rapid and dramatic. However, cancer often returns and may become resistant to the chemotherapy regimen that was successful in the past. Radiation therapy is usually used in combination with chemotherapy (chemoradiotherapy) to treat individuals with limited stage SCLC. Radiation therapy uses high-powered x-rays to directly destroy cancer cells. Radiation therapy is directed at the chest (thoracic radiotherapy) to the main lung tumor and the lymph nodes to which the cancer has spread. Individuals who are successfully treated with chemotherapy and radiation therapy to the chest may also receive preventive radiation therapy to the brain called prophylactic cranial irradiation (PCI). Because SCLC is an aggressive cancer and can spread to the brain, PCI is used to destroy any microscopic cancer cells that may have reached the brain. PCI is generally given to individuals who have a good response to initial therapy and are healthy enough to undergo the treatment. About 25% of individuals with limited stage SCLC can be cured with prompt treatment with chemotherapy and radiation therapy. Extensive Disease
The treatment for extensive stage SCLC is primarily platinum-based chemotherapy, similar to that which is used in limited stage disease. Sometimes, instead of using etoposide along with cisplatin or carboplatin, doctors may use a drug called irinotecan. The combination of irinotecan plus a platinum-drug appears to be more effective in Japanese people; in Caucasians, etoposide appears to be equally effective and is associated with less severe side effects. Recently, the addition of an immunotherapy drug called atezolizumab, that boosts the body’s immune system to fight the cancer, to the standard regimen of carboplatin plus etoposide was shown to improve the outcome of some patients with extensive stage SCLC. However, this combination of drugs has not been approved by the U.S. Food and Drug Administration (FDA). Although extensive stage disease is not curable, the majority of patients will have shrinkage of their cancer, improvement in symptoms and prolongation of life with chemotherapy. The goals of treatment are to improve symptoms, maintain quality of life and prolong life. In some situations, thoracic radiation will be recommended after chemotherapy in people with extensive stage SCLC. Because of the high risk of spread of SCLC to the brain, frequent MRI scans of the brain are usually recommended.Recurrence
Although SCLC is highly responsive to initial chemotherapy, the cancer often comes back (recurs). When the cancer returns, it is usually more resistant to the previously effective chemotherapy regimens. Different chemotherapy regimens can be tried, but are usually not as effective. When the cancer comes back, it can be extremely aggressive. The only second-line therapy approved for SCLC in the U.S. is a chemotherapeutic drug called topotecan. Several drugs other available drugs do have some ability to shrink or slow the cancer, but results are generally disappointing. Newer drugs are being studied in clinical trials for second-line therapy for individuals with SCLC. In 2017, the FDA approved the drug nivolumab (Opdivo®) for the treatment of individuals with SCLC cancer in whom the cancer has spread (metastasized) and who have been previously treated with two types of therapy including chemotherapy. Nivolumab is a form of immunotherapy. Immunotherapy is the most recent addition to therapy for cancer. It is designed to enlist the body’s immune system to act against cancer. Supportive Therapy
Affected individuals may require supportive therapies. Many individuals with SCLC have a significant decrease in lung function and may need therapies to assist with breathing. This can include drugs called bronchodilators, which widen the airways of the lungs, or supplemental oxygen therapy. Clinical Trials
Affected individuals are encouraged to explore participating in clinical trials. Participating in a clinical trial can give an affected individual access to new therapies. This decision should be made after close consultation with an individual’s oncologist and entire medical team.
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Overview of Smallpox
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Smallpox is an infectious disease caused by the variola virus. It is characterized by fever, a general feeling of ill health (malaise), headaches and back pain. These initial symptoms are followed by a rash and small, raised bumps or lesions (pocks) within two or three days. Smallpox was a highly contagious disease, but was declared eradicated in 1980. However, recently smallpox has become of interest because of the possibility of its use as a weapon of warfare or of terrorism. There were two strains of smallpox, variola major and variola minor.
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Overview of Smallpox. Smallpox is an infectious disease caused by the variola virus. It is characterized by fever, a general feeling of ill health (malaise), headaches and back pain. These initial symptoms are followed by a rash and small, raised bumps or lesions (pocks) within two or three days. Smallpox was a highly contagious disease, but was declared eradicated in 1980. However, recently smallpox has become of interest because of the possibility of its use as a weapon of warfare or of terrorism. There were two strains of smallpox, variola major and variola minor.
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Symptoms of Smallpox
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Symptoms of smallpox appear after an incubation period of approximately 12 days (7-17 days). Initial symptoms are a high fever, a general feeling of ill health (malaise), headaches, and back pain often resulting in affected individuals becoming bedridden. In some cases, severe abdominal pain and delirium may also be present.Approximately two to three days after the onset of the disease, a characteristic rash forms on the mucous membranes (mucosa) of the mouth and throat (pharynx) as well as on the face and arms. The rash often spreads to affect the legs and trunk. Within one or two days, small, red bumps or lesions form (papules). These lesions become pus-filled (pustules) sometimes breaking open and resulting in bloody, oozing sores. Eventually, the pustules begin to crust and then scab. In three to four weeks, the scabs fall off, usually leaving scars or pox marks.There were two strains of smallpox. Variola major was more severe and had a fatality rate of approximately 30 percent; variola minor was less severe and had a fatality rate of less than 1 percent. Life-threatening complications that may be associated with smallpox include blood loss, the presence of toxins in the blood (toxcemia), cardiovascular problems, and/or secondary bacterial infections.
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Symptoms of Smallpox. Symptoms of smallpox appear after an incubation period of approximately 12 days (7-17 days). Initial symptoms are a high fever, a general feeling of ill health (malaise), headaches, and back pain often resulting in affected individuals becoming bedridden. In some cases, severe abdominal pain and delirium may also be present.Approximately two to three days after the onset of the disease, a characteristic rash forms on the mucous membranes (mucosa) of the mouth and throat (pharynx) as well as on the face and arms. The rash often spreads to affect the legs and trunk. Within one or two days, small, red bumps or lesions form (papules). These lesions become pus-filled (pustules) sometimes breaking open and resulting in bloody, oozing sores. Eventually, the pustules begin to crust and then scab. In three to four weeks, the scabs fall off, usually leaving scars or pox marks.There were two strains of smallpox. Variola major was more severe and had a fatality rate of approximately 30 percent; variola minor was less severe and had a fatality rate of less than 1 percent. Life-threatening complications that may be associated with smallpox include blood loss, the presence of toxins in the blood (toxcemia), cardiovascular problems, and/or secondary bacterial infections.
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Causes of Smallpox
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Smallpox is caused by infection with the variola virus. The disease is spread through person to person contact, most often from inhalation of droplet nuclei expelled through the back of the throat (oropharynx) of an infected person. Droplet nuclei are small particles containing virus-infected respiratory secretions that are pushed out into the air by coughing or sneezing. These airborne particles may then be inhaled by another person. Individuals with smallpox are most infectious during the first week of illness.Smallpox may also be spread through direct contact with an infected person or through contact with contaminated material such as clothing, blankets or bed linen.
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Causes of Smallpox. Smallpox is caused by infection with the variola virus. The disease is spread through person to person contact, most often from inhalation of droplet nuclei expelled through the back of the throat (oropharynx) of an infected person. Droplet nuclei are small particles containing virus-infected respiratory secretions that are pushed out into the air by coughing or sneezing. These airborne particles may then be inhaled by another person. Individuals with smallpox are most infectious during the first week of illness.Smallpox may also be spread through direct contact with an infected person or through contact with contaminated material such as clothing, blankets or bed linen.
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Affects of Smallpox
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Smallpox existed for thousands of years until the World Health Organization declared it extinct in May of 1980. The last known case of smallpox occurred in Somalia in 1977. The only known stores of the smallpox virus are in two locations: the Centers for Disease Control and Prevention (CDC) in Atlanta and Russian government laboratories near Moscow. However, government officials fear that secret stores may be maintained elsewhere and may be released deliberately as an act of warfare (bioterrorism). Individuals with weakened immune systems such as those with leukemia, lymphoma or AIDS would be more susceptible to smallpox infection if the disease was reintroduced into society.
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Affects of Smallpox. Smallpox existed for thousands of years until the World Health Organization declared it extinct in May of 1980. The last known case of smallpox occurred in Somalia in 1977. The only known stores of the smallpox virus are in two locations: the Centers for Disease Control and Prevention (CDC) in Atlanta and Russian government laboratories near Moscow. However, government officials fear that secret stores may be maintained elsewhere and may be released deliberately as an act of warfare (bioterrorism). Individuals with weakened immune systems such as those with leukemia, lymphoma or AIDS would be more susceptible to smallpox infection if the disease was reintroduced into society.
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Related disorders of Smallpox
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Symptoms of the following disorders can be similar to those of smallpox. Comparisons may be useful for a differential diagnosis: Monkeypox is a rare infectious disease caused by a virus that is related to the virus that causes smallpox. Individuals with monkeypox develop a rash that is similar to one associated with smallpox. Most cases of monkeypox occur in remote villages in Africa where there is close contact with infected animals. The vaccine developed to treat smallpox also protects against monkeypox. Varicella-zoster is an infectious disease caused by a common virus known as herpes virus. During childhood, infection with the varicella virus causes chickenpox . The varicella virus remains viable in body nerve cells for the rest of that individual's life. From time to time, the latent virus leaves its nerve cell home and travels down nerve rootlets to the skin, where it produces the typical rash and pain of the syndrome known as shingles. First infection with the varicella virus always causes chickenpox, even in adults who never had the infection as children. Chickenpox is a highly contagious disease characterized by an itchy skin rash and fever. Chickenpox usually begins with mild constitutional symptoms such as a mild headache, moderate fever and discomfort followed by an eruption appearing in itchy groups of flat or elevated spots and blisters, which form crusts. Shingles is a painful localized recurrence of the skin rash during adulthood. The rash consists of small, red spots that become inflamed and develop into small fluid-filled bumps or lesions. These lesions then become pus-filled before crusting and healing. Fever and muscle aches may precede the development of the rash. Before smallpox's eradication in 1980, mild cases may have been confused with varicella-zoster infection. (For more information on this disorder, choose varicella-zoster as your search term in the Rare Disease Database.)
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Related disorders of Smallpox. Symptoms of the following disorders can be similar to those of smallpox. Comparisons may be useful for a differential diagnosis: Monkeypox is a rare infectious disease caused by a virus that is related to the virus that causes smallpox. Individuals with monkeypox develop a rash that is similar to one associated with smallpox. Most cases of monkeypox occur in remote villages in Africa where there is close contact with infected animals. The vaccine developed to treat smallpox also protects against monkeypox. Varicella-zoster is an infectious disease caused by a common virus known as herpes virus. During childhood, infection with the varicella virus causes chickenpox . The varicella virus remains viable in body nerve cells for the rest of that individual's life. From time to time, the latent virus leaves its nerve cell home and travels down nerve rootlets to the skin, where it produces the typical rash and pain of the syndrome known as shingles. First infection with the varicella virus always causes chickenpox, even in adults who never had the infection as children. Chickenpox is a highly contagious disease characterized by an itchy skin rash and fever. Chickenpox usually begins with mild constitutional symptoms such as a mild headache, moderate fever and discomfort followed by an eruption appearing in itchy groups of flat or elevated spots and blisters, which form crusts. Shingles is a painful localized recurrence of the skin rash during adulthood. The rash consists of small, red spots that become inflamed and develop into small fluid-filled bumps or lesions. These lesions then become pus-filled before crusting and healing. Fever and muscle aches may precede the development of the rash. Before smallpox's eradication in 1980, mild cases may have been confused with varicella-zoster infection. (For more information on this disorder, choose varicella-zoster as your search term in the Rare Disease Database.)
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Diagnosis of Smallpox
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Diagnosis of Smallpox.
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Therapies of Smallpox
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In the United States before 1972, children received routine smallpox vaccinations. However, the duration of immunity granted by the vaccination may be only 10 to 15 years, so those who received the vaccine in childhood may no longer be immune to the disease.According to the Centers for Disease Control and Prevention (CDC), the smallpox vaccine can lessen the severity or prevent illness in individuals who are exposed to the smallpox virus if administered within four days after exposure.The smallpox vaccine contains another virus, vaccina, made from the cowpox virus. The United States currently has an emergency supply of the vaccine in storage at the CDC. During 2000 and 2001, the CDC contracted with pharmaceutical companies to manufacture more of the smallpox vaccine for use if smallpox is employed as a terrorism weapon.In rare cases, the administration of smallpox vaccine results in a severe reaction. Such reaction may be treated by a specialty antibody prepared from human plasma that has been approved by the FDA (February 2005). This vaccine, vaccinia immune globulin intravenous (human) is also known by the trade name VIGIV and is manufactured and marketed by:DynPort Vaccine Company LLC.64 Thomas Johnson DriveFrederick, Marylan. 21702.There is no specific treatment for individuals infected by smallpox. Treatment is supportive and directed at specific symptoms present in each individual. Supportive therapy may include antibiotics for secondary bacterial infections and/or medications for pain or fever.In 2002, the U.S. Food and Drug Administration (FDA) granted orphan status to the drug poly-ICLC (Hiltonol), to be used as an adjuvant to smallpox vaccination. Hiltonol is manufactured by Oncovir, Inc., a Washington, DC, pharmaceutical corporation. Additional information on this experimental product may be found at www.oncovir.com.Vaxgen, Inc., in partnership with the Chemo-Sero Research Institute in Japan, is developing a smallpox vaccine, LC16m8, that has been licensed for use in Japan for several years. Their goal is to develop a vaccine that is safer than Dryvax, but equally effective.
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Therapies of Smallpox. In the United States before 1972, children received routine smallpox vaccinations. However, the duration of immunity granted by the vaccination may be only 10 to 15 years, so those who received the vaccine in childhood may no longer be immune to the disease.According to the Centers for Disease Control and Prevention (CDC), the smallpox vaccine can lessen the severity or prevent illness in individuals who are exposed to the smallpox virus if administered within four days after exposure.The smallpox vaccine contains another virus, vaccina, made from the cowpox virus. The United States currently has an emergency supply of the vaccine in storage at the CDC. During 2000 and 2001, the CDC contracted with pharmaceutical companies to manufacture more of the smallpox vaccine for use if smallpox is employed as a terrorism weapon.In rare cases, the administration of smallpox vaccine results in a severe reaction. Such reaction may be treated by a specialty antibody prepared from human plasma that has been approved by the FDA (February 2005). This vaccine, vaccinia immune globulin intravenous (human) is also known by the trade name VIGIV and is manufactured and marketed by:DynPort Vaccine Company LLC.64 Thomas Johnson DriveFrederick, Marylan. 21702.There is no specific treatment for individuals infected by smallpox. Treatment is supportive and directed at specific symptoms present in each individual. Supportive therapy may include antibiotics for secondary bacterial infections and/or medications for pain or fever.In 2002, the U.S. Food and Drug Administration (FDA) granted orphan status to the drug poly-ICLC (Hiltonol), to be used as an adjuvant to smallpox vaccination. Hiltonol is manufactured by Oncovir, Inc., a Washington, DC, pharmaceutical corporation. Additional information on this experimental product may be found at www.oncovir.com.Vaxgen, Inc., in partnership with the Chemo-Sero Research Institute in Japan, is developing a smallpox vaccine, LC16m8, that has been licensed for use in Japan for several years. Their goal is to develop a vaccine that is safer than Dryvax, but equally effective.
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Overview of Smith Magenis Syndrome
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SummarySmith-Magenis syndrome (SMS) is a complex developmental disorder that affects multiple organ systems of the body. The disorder is characterized by a pattern of abnormalities that are present at birth (congenital) as well as behavioral and cognitive problems. Common symptoms include distinctive facial features, skeletal malformations, varying degrees of intellectual disability, speech and motor delays, sleep disturbances, and self-injurious or attention-seeking behaviors. The specific symptoms present in each patients can vary dramatically from one individual to another. Approximately 90% of cases are caused when a portion of chromosome is missing or deleted (monosomic). This deleted portion within chromosome 17p11.2 includes the RAI1 gene, which is believed to play a major role in the development of the disorder. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by mutations in the RAI1 gene. Other genes within the deleted segment may also play a role in variable features in the syndrome, but it is not fully understood how significant a role they play in the development of SMS. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by mutations in the RAI1 gene.IntroductionSmith-Magenis syndrome was first reported in the medical literature in 1982 by Ann Smith, a genetic counselor, and colleagues. In 1986, Smith and Dr. R. Ellen Magenis identified nine patients with the disorder further delineating the syndrome. Since that time numerous additional cases have been identified allowing physicians/clinicians to develop a better understanding about this complex neurodevelopmental disorder (NDD).
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Overview of Smith Magenis Syndrome. SummarySmith-Magenis syndrome (SMS) is a complex developmental disorder that affects multiple organ systems of the body. The disorder is characterized by a pattern of abnormalities that are present at birth (congenital) as well as behavioral and cognitive problems. Common symptoms include distinctive facial features, skeletal malformations, varying degrees of intellectual disability, speech and motor delays, sleep disturbances, and self-injurious or attention-seeking behaviors. The specific symptoms present in each patients can vary dramatically from one individual to another. Approximately 90% of cases are caused when a portion of chromosome is missing or deleted (monosomic). This deleted portion within chromosome 17p11.2 includes the RAI1 gene, which is believed to play a major role in the development of the disorder. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by mutations in the RAI1 gene. Other genes within the deleted segment may also play a role in variable features in the syndrome, but it is not fully understood how significant a role they play in the development of SMS. In the remaining cases, there is no deleted material on chromosome 17; these cases are caused by mutations in the RAI1 gene.IntroductionSmith-Magenis syndrome was first reported in the medical literature in 1982 by Ann Smith, a genetic counselor, and colleagues. In 1986, Smith and Dr. R. Ellen Magenis identified nine patients with the disorder further delineating the syndrome. Since that time numerous additional cases have been identified allowing physicians/clinicians to develop a better understanding about this complex neurodevelopmental disorder (NDD).
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Symptoms of Smith Magenis Syndrome
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Smith-Magenis syndrome is a highly variable disorder. The specific symptoms present and the overall severity of the disorder can vary from one person to another. It is important to understand that affected individuals will not have all of the symptoms discussed below and that every individual case is unique. Parents should talk to the physician and medical team about their child’s specific case, associated symptoms and overall prognosis.Many individuals with SMS have distinctive facial features including a broad, square-shaped facial appearance, a prominent forehead, deep-set eyes that are farther apart than usual (hypertelorism), an upslanting palpebral (eye) fissures, a broad bridge of the nose, hair growth between the eyebrows so it appears as one long eyebrow (synophrys), a down-turned (everted; cupid bow) upper lip, a short, full-tipped nose, and underdevelopment of the middle portion of the face (midface retrusion). The head may appear disproportionately short (brachycephaly). Some affected infants may have an abnormally small jaw (micrognathia) and the facial appearance is more “cherubic” with rosy cheeks. As affected individuals age, micrognathia may change so that the lower jaw abnormally protrudes outward (relative prognathia). In general, the distinctive facial features associated with SMS progress with age. Affected individuals may also exhibit absence (agenesis) of secondary (permanent) teeth, particularly premolars, and taurodauntism, a condition characterized by enlargement of the pulp chambers and reduction of the roots of teeth; open bite posture with large tongue (macroglossia) and history of bruxism (teeth grinding) are also common.Infants usually have diminished muscle tone (hypotonia), poor reflexes (hyporeflexia), and feeding difficulties such as poor sucking ability, which can contribute to failure to thrive. Failure to thrive is defined as the failure to grow and gain weight at a rate that would be expected based upon age and gender. Infants are generally quiet and complacent with infrequent crying and diminished vocalizations reflecting the marked early expressive speech delay. In addition, affected infants may nap for prolonged periods of time and exhibit generalized daytime lethargy. Gastroesophageal reflux is also common during infancy.Individuals with SMS have varying degrees of cognitive ability. Many individuals exhibit mild to moderate intellectual disability. Affected individuals often exhibit delays in attaining speech and motor skills and in reaching developmental milestones (developmental delays). Expressive language is often more delayed than receptive language skills. Specific behavioral problems (maladaptive behaviors) occur in children with SMS. A common initial sign is head banging during early childhood. Frequent upper body squeezes often described as “self-hugging” is also common. Affected children may also display impulsivity, hyperactivity and attention deficient disorder, frequent and prolonged tantrums, sudden mood changes, toilet training difficulties, disobedience, and aggressive or attention-seeking behaviors. In addition to head banging, affected children may develop other self-injurious behavior such as hand biting, face slapping, skin picking, and wrist biting. Repeated head banging can potentially cause detachment of the retina, which although a concern, is not a high risk. Older children may yank at fingernails and toenails (onychotillomania) or insert objects into body orifices (polyembolokoilamania). Affected children tend to be excitable and easily distracted. Although behavioral issues are common, many individuals tend to have endearing and engaging personalities, with great senses of humor, and facile long-term memory for faces, places and things.Affected children may experience chronic ear infections, including repeated middle ear infections (otitis media). Hearing loss is very common, typically ranging from slight to mild in degree and showing a pattern of fluctuating and progressive hearing decline with age. Both conductive and/or sensorineural hearing loss may develop. Conductive hearing loss is most common in early childhood (under 10 years), while sensorineural hearing loss occurs more frequently at older ages (11years – adulthood). Conductive hearing loss develops when sound waves are inappropriately conducted through the external or middle ear to the inner ear, resulting in decreased sensitivity to sound. Sensorineural hearing loss develops where there is damage to the inner ear (cochlea) or the nerve pathway from inner ear to the brain. Some affected children may be abnormally sensitive to certain sounds or frequencies (hyperacusis). Frequent sinus infections (sinusitis) are also common. Eye abnormalities such as progressive nearsightedness (myopia), crossed eyes (strabismus), and unusually smallness of the cornea (microcornea) may also occur.Affected children often have abnormalities affecting the larynx (voice box) or surrounding tissue. Laryngeal abnormalities include the formation of polyps and nodules or swelling due to fluid retention (edema). Paralysis of the vocal cords has also developed. Affected children may experience velopharyngeal insufficiency, in which the soft palate of the mouth does not close properly during speech. Oral sensorimotor dysfunction, in which affected individuals have difficulties controlling the lips, tongue and jaw muscles, may also develop and can cause tongue protrusion and frequent drooling. Due to such abnormalities, children may develop a hoarse, deep voice. These abnormalities also contribute to delays in speech development.Excessive weight gain and obesity may be seen in adolescence and approximately 90% of children may be overweight or obese by the age of 14. Affected individuals may exhibit short stature during childhood, although height is typically within the normal range as adults. Approximately 50% of children may have unusually high levels of cholesterol in the blood (hypercholesterolemia). Chronic constipation is also a frequent complication.The sleep disturbance that occurs in affected individuals is a chronic lifelong problem. In addition to sleep issues during infancy (generalized lethargy & “too sleepy”), affected individuals develop significant sleep disturbances from early childhood that continue into adolescence and adulthood. The sleep cycle is characterized by problems that can include difficulty falling asleep, shortened sleep cycles, an inability to enter REM sleep and frequently awaking during the night and early in the morning (5:30-6:30AM). In general, the hours of sleep are less than expected for age. As a consequence of the disrupted nighttime sleep cycle affected individuals may exhibit periods of drowsiness during the day, known as excessive daytime sleepiness or sleep debt, which remains a chronic issue. The sleep abnormalities are associated with an inverted circadian rhythm of melatonin, reported in over 90% of studied cases. A circadian rhythm sleep disorder occurs when a person’s biological clocks fails to synchronize to a normal 24-hour day. Specifically, melatonin, a normal occurring hormone, rises and falls; it rises, peaking at night and causes drowsiness. Melatonin levels lessen in the morning, reaching their lowest levels during the middle of the day. In individuals with an inverted circadian rhythm, the rising and falling of melatonin levels is reversed (daytime highs).Skeletal malformations are common in individuals with SMS and can include front-to-back curvature of the spine (lordosis), mild-to-moderate sideways curvature of the spine (scoliosis), abnormally small hands and feet, and markedly flat or highly arched feet that can cause an unusually manner of walking (abnormal broad-based gait). In rare cases, affected children have vertebral anomalies and forearm and elbow limitations.Less often, other symptoms or physical findings have occurred in individuals with SMS including immune system dysfunction, thyroid function abnormalities (hypothyroidism), heart (cardiac) defects, kidney (renal) and/or urinary tract malformations, cleft lip and cleft palate, and seizures. Seizure activity can occur subtly so that seizure goes unnoticed (subclinical seizures). Peripheral neuropathy, which is a general term for any disorder of the peripheral nervous system, may also occur. Peripheral neuropathy encompasses any disorder that primarily affects the nerves outside the central nervous system (i.e. brain and spinal cord). Symptoms may include a decreased sensitivity to pain commonly seen in SMS. Peripheral neuropathy is often associated with the loss of sensation or abnormal sensations such as tingling, burning, or pricking along the affected nerves, but it is unknown whether this occurs in individuals with SMS.
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Symptoms of Smith Magenis Syndrome. Smith-Magenis syndrome is a highly variable disorder. The specific symptoms present and the overall severity of the disorder can vary from one person to another. It is important to understand that affected individuals will not have all of the symptoms discussed below and that every individual case is unique. Parents should talk to the physician and medical team about their child’s specific case, associated symptoms and overall prognosis.Many individuals with SMS have distinctive facial features including a broad, square-shaped facial appearance, a prominent forehead, deep-set eyes that are farther apart than usual (hypertelorism), an upslanting palpebral (eye) fissures, a broad bridge of the nose, hair growth between the eyebrows so it appears as one long eyebrow (synophrys), a down-turned (everted; cupid bow) upper lip, a short, full-tipped nose, and underdevelopment of the middle portion of the face (midface retrusion). The head may appear disproportionately short (brachycephaly). Some affected infants may have an abnormally small jaw (micrognathia) and the facial appearance is more “cherubic” with rosy cheeks. As affected individuals age, micrognathia may change so that the lower jaw abnormally protrudes outward (relative prognathia). In general, the distinctive facial features associated with SMS progress with age. Affected individuals may also exhibit absence (agenesis) of secondary (permanent) teeth, particularly premolars, and taurodauntism, a condition characterized by enlargement of the pulp chambers and reduction of the roots of teeth; open bite posture with large tongue (macroglossia) and history of bruxism (teeth grinding) are also common.Infants usually have diminished muscle tone (hypotonia), poor reflexes (hyporeflexia), and feeding difficulties such as poor sucking ability, which can contribute to failure to thrive. Failure to thrive is defined as the failure to grow and gain weight at a rate that would be expected based upon age and gender. Infants are generally quiet and complacent with infrequent crying and diminished vocalizations reflecting the marked early expressive speech delay. In addition, affected infants may nap for prolonged periods of time and exhibit generalized daytime lethargy. Gastroesophageal reflux is also common during infancy.Individuals with SMS have varying degrees of cognitive ability. Many individuals exhibit mild to moderate intellectual disability. Affected individuals often exhibit delays in attaining speech and motor skills and in reaching developmental milestones (developmental delays). Expressive language is often more delayed than receptive language skills. Specific behavioral problems (maladaptive behaviors) occur in children with SMS. A common initial sign is head banging during early childhood. Frequent upper body squeezes often described as “self-hugging” is also common. Affected children may also display impulsivity, hyperactivity and attention deficient disorder, frequent and prolonged tantrums, sudden mood changes, toilet training difficulties, disobedience, and aggressive or attention-seeking behaviors. In addition to head banging, affected children may develop other self-injurious behavior such as hand biting, face slapping, skin picking, and wrist biting. Repeated head banging can potentially cause detachment of the retina, which although a concern, is not a high risk. Older children may yank at fingernails and toenails (onychotillomania) or insert objects into body orifices (polyembolokoilamania). Affected children tend to be excitable and easily distracted. Although behavioral issues are common, many individuals tend to have endearing and engaging personalities, with great senses of humor, and facile long-term memory for faces, places and things.Affected children may experience chronic ear infections, including repeated middle ear infections (otitis media). Hearing loss is very common, typically ranging from slight to mild in degree and showing a pattern of fluctuating and progressive hearing decline with age. Both conductive and/or sensorineural hearing loss may develop. Conductive hearing loss is most common in early childhood (under 10 years), while sensorineural hearing loss occurs more frequently at older ages (11years – adulthood). Conductive hearing loss develops when sound waves are inappropriately conducted through the external or middle ear to the inner ear, resulting in decreased sensitivity to sound. Sensorineural hearing loss develops where there is damage to the inner ear (cochlea) or the nerve pathway from inner ear to the brain. Some affected children may be abnormally sensitive to certain sounds or frequencies (hyperacusis). Frequent sinus infections (sinusitis) are also common. Eye abnormalities such as progressive nearsightedness (myopia), crossed eyes (strabismus), and unusually smallness of the cornea (microcornea) may also occur.Affected children often have abnormalities affecting the larynx (voice box) or surrounding tissue. Laryngeal abnormalities include the formation of polyps and nodules or swelling due to fluid retention (edema). Paralysis of the vocal cords has also developed. Affected children may experience velopharyngeal insufficiency, in which the soft palate of the mouth does not close properly during speech. Oral sensorimotor dysfunction, in which affected individuals have difficulties controlling the lips, tongue and jaw muscles, may also develop and can cause tongue protrusion and frequent drooling. Due to such abnormalities, children may develop a hoarse, deep voice. These abnormalities also contribute to delays in speech development.Excessive weight gain and obesity may be seen in adolescence and approximately 90% of children may be overweight or obese by the age of 14. Affected individuals may exhibit short stature during childhood, although height is typically within the normal range as adults. Approximately 50% of children may have unusually high levels of cholesterol in the blood (hypercholesterolemia). Chronic constipation is also a frequent complication.The sleep disturbance that occurs in affected individuals is a chronic lifelong problem. In addition to sleep issues during infancy (generalized lethargy & “too sleepy”), affected individuals develop significant sleep disturbances from early childhood that continue into adolescence and adulthood. The sleep cycle is characterized by problems that can include difficulty falling asleep, shortened sleep cycles, an inability to enter REM sleep and frequently awaking during the night and early in the morning (5:30-6:30AM). In general, the hours of sleep are less than expected for age. As a consequence of the disrupted nighttime sleep cycle affected individuals may exhibit periods of drowsiness during the day, known as excessive daytime sleepiness or sleep debt, which remains a chronic issue. The sleep abnormalities are associated with an inverted circadian rhythm of melatonin, reported in over 90% of studied cases. A circadian rhythm sleep disorder occurs when a person’s biological clocks fails to synchronize to a normal 24-hour day. Specifically, melatonin, a normal occurring hormone, rises and falls; it rises, peaking at night and causes drowsiness. Melatonin levels lessen in the morning, reaching their lowest levels during the middle of the day. In individuals with an inverted circadian rhythm, the rising and falling of melatonin levels is reversed (daytime highs).Skeletal malformations are common in individuals with SMS and can include front-to-back curvature of the spine (lordosis), mild-to-moderate sideways curvature of the spine (scoliosis), abnormally small hands and feet, and markedly flat or highly arched feet that can cause an unusually manner of walking (abnormal broad-based gait). In rare cases, affected children have vertebral anomalies and forearm and elbow limitations.Less often, other symptoms or physical findings have occurred in individuals with SMS including immune system dysfunction, thyroid function abnormalities (hypothyroidism), heart (cardiac) defects, kidney (renal) and/or urinary tract malformations, cleft lip and cleft palate, and seizures. Seizure activity can occur subtly so that seizure goes unnoticed (subclinical seizures). Peripheral neuropathy, which is a general term for any disorder of the peripheral nervous system, may also occur. Peripheral neuropathy encompasses any disorder that primarily affects the nerves outside the central nervous system (i.e. brain and spinal cord). Symptoms may include a decreased sensitivity to pain commonly seen in SMS. Peripheral neuropathy is often associated with the loss of sensation or abnormal sensations such as tingling, burning, or pricking along the affected nerves, but it is unknown whether this occurs in individuals with SMS.
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Causes of Smith Magenis Syndrome
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In approximately 90% of affected individuals, a portion of the short arm (p) of chromosome 17 (17q11.2) is missing, which is referred to as deleted or monosomic. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. 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 17p11.2” refers to band 11.2 on the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.In individuals with SMS, the deleted section of chromosome 17 includes the retinoic acid-induced 1 (RAI1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene is missing due to a monosomic chromosome abnormality, the protein product of that gene is reduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The specific functions of the protein produced (encoded) by the RAI1 gene are not fully understood.The exact cause of the chromosomal alteration in SMS is unknown. The medical literature has indicated that virtually all documented cases appear to be due to a spontaneous (de novo) genetic change that occurs for unknown reasons.In rare cases, SMS is the result of an error during very early embryonic development due to a chromosomal balanced translocation in one of the parents. A translocation is balanced if pieces of two or more chromosomes break off and trade places, creating an altered but balanced set of chromosomes. If a chromosomal rearrangement is balanced, it is usually harmless to the carrier. However, they may be associated with a higher risk of abnormal chromosomal development in the carrier’s offspring. In these cases, the clinical features of children may be influenced by additional imbalances of other chromosomes than 17. Chromosomal testing can determine whether a parent has a balanced translocation. In parents with a child with SMS who have a normal chromosome analysis the risk of recurrence in a future pregnancy is below 1%.The remaining 10% of cases of SMS are caused by mutations in the RAI1 gene. These mutations may occur randomly with no family history (i.e. new mutation) or be inherited in an autosomal dominant manner. 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 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 sex of the resulting child. Mutations in the RAI1 gene lead to insufficient levels of functional copies of the protein product normally produced by the gene.In two families reported in the medical literature, SMS occurred because of germline mosaicism. In germline mosaicism, some of a parent’s reproductive (germ) cells carry the RAI1 gene mutation or chromosome 17p deletion, while other germ cells do not (mosaicism). In addition, the other cells of a parent also do not have either to these chromosomal abnormalities; consequently, the parents are unaffected. However, as a result, one or more of the parent’s children may inherit the germ cell with a chromosomal abnormality, leading to the development of SMS. Germline mosaicism is suspected when apparently unaffected parents have more than one child with the disorder. The likelihood of a parent passing on a mosaic germline chromosomal abnormality to a child depends upon the percentage of the parent’s germ cells that have the abnormality versus the percentage that do not. There is no test for germline mutation or chromosome abnormality prior to pregnancy. Testing during pregnancy may be available and is best discussed with a genetic specialist.A child born to an individual with SMS is at a theoretical risk of 50% to inherit the deletion or RAI1 mutation that causes the disorder. The fertility in SMS in general is not fully understood; however, there is at least one report in the medical literature of a mother with SMS having a child with SMS.
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Causes of Smith Magenis Syndrome. In approximately 90% of affected individuals, a portion of the short arm (p) of chromosome 17 (17q11.2) is missing, which is referred to as deleted or monosomic. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. 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 17p11.2” refers to band 11.2 on the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.In individuals with SMS, the deleted section of chromosome 17 includes the retinoic acid-induced 1 (RAI1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene is missing due to a monosomic chromosome abnormality, the protein product of that gene is reduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The specific functions of the protein produced (encoded) by the RAI1 gene are not fully understood.The exact cause of the chromosomal alteration in SMS is unknown. The medical literature has indicated that virtually all documented cases appear to be due to a spontaneous (de novo) genetic change that occurs for unknown reasons.In rare cases, SMS is the result of an error during very early embryonic development due to a chromosomal balanced translocation in one of the parents. A translocation is balanced if pieces of two or more chromosomes break off and trade places, creating an altered but balanced set of chromosomes. If a chromosomal rearrangement is balanced, it is usually harmless to the carrier. However, they may be associated with a higher risk of abnormal chromosomal development in the carrier’s offspring. In these cases, the clinical features of children may be influenced by additional imbalances of other chromosomes than 17. Chromosomal testing can determine whether a parent has a balanced translocation. In parents with a child with SMS who have a normal chromosome analysis the risk of recurrence in a future pregnancy is below 1%.The remaining 10% of cases of SMS are caused by mutations in the RAI1 gene. These mutations may occur randomly with no family history (i.e. new mutation) or be inherited in an autosomal dominant manner. 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 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 sex of the resulting child. Mutations in the RAI1 gene lead to insufficient levels of functional copies of the protein product normally produced by the gene.In two families reported in the medical literature, SMS occurred because of germline mosaicism. In germline mosaicism, some of a parent’s reproductive (germ) cells carry the RAI1 gene mutation or chromosome 17p deletion, while other germ cells do not (mosaicism). In addition, the other cells of a parent also do not have either to these chromosomal abnormalities; consequently, the parents are unaffected. However, as a result, one or more of the parent’s children may inherit the germ cell with a chromosomal abnormality, leading to the development of SMS. Germline mosaicism is suspected when apparently unaffected parents have more than one child with the disorder. The likelihood of a parent passing on a mosaic germline chromosomal abnormality to a child depends upon the percentage of the parent’s germ cells that have the abnormality versus the percentage that do not. There is no test for germline mutation or chromosome abnormality prior to pregnancy. Testing during pregnancy may be available and is best discussed with a genetic specialist.A child born to an individual with SMS is at a theoretical risk of 50% to inherit the deletion or RAI1 mutation that causes the disorder. The fertility in SMS in general is not fully understood; however, there is at least one report in the medical literature of a mother with SMS having a child with SMS.
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Affects of Smith Magenis Syndrome
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Smith-Magenis syndrome affects males and females in equal numbers. The incidence is estimated to be 1 in 15,000-25,000 people in the general population in the United States. However, cases may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of SMS in the general population. SMS has been reported throughout the world and in all ethnic groups.
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Affects of Smith Magenis Syndrome. Smith-Magenis syndrome affects males and females in equal numbers. The incidence is estimated to be 1 in 15,000-25,000 people in the general population in the United States. However, cases may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of SMS in the general population. SMS has been reported throughout the world and in all ethnic groups.
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Related disorders of Smith Magenis Syndrome
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Symptoms of the following disorders can be similar to those of Smith-Magenis syndrome. Comparisons may be useful for a differential diagnosis.There are many different chromosomal disorders that have signs and symptoms that are similar to those seen in SMS. Such disorders include Down syndrome, Williams syndrome, Prader-Willi syndrome, Angelman syndrome, Sotos syndrome, fragile X syndrome, chromosome 22q11.2 deletion syndrome, 9q34 deletion syndrome (Kleefstra syndrome), 2q37 deletion syndrome, 2q23.1 deletion syndrome, and 1p36 deletion syndrome. Individuals with SMS often initially receive a psychiatric diagnosis including obsessive-compulsive disorder, pervasive developmental disorder, or attention deficit hyperactivity disorder. Some children with SMS are initially diagnosed with an autism spectrum disorder. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Smith Magenis Syndrome. Symptoms of the following disorders can be similar to those of Smith-Magenis syndrome. Comparisons may be useful for a differential diagnosis.There are many different chromosomal disorders that have signs and symptoms that are similar to those seen in SMS. Such disorders include Down syndrome, Williams syndrome, Prader-Willi syndrome, Angelman syndrome, Sotos syndrome, fragile X syndrome, chromosome 22q11.2 deletion syndrome, 9q34 deletion syndrome (Kleefstra syndrome), 2q37 deletion syndrome, 2q23.1 deletion syndrome, and 1p36 deletion syndrome. Individuals with SMS often initially receive a psychiatric diagnosis including obsessive-compulsive disorder, pervasive developmental disorder, or attention deficit hyperactivity disorder. Some children with SMS are initially diagnosed with an autism spectrum disorder. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Smith Magenis Syndrome
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A diagnosis of Smith-Magenis syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized genetic tests. The diagnosis of SMS is confirmed when deletion 17p11.2 (cytogenetic analysis or microarray) or RAI1 gene mutation is identified.Clinical Testing and Workup
In the past, a specific chromosomal study known as G-band analysis, which demonstrates missing (deleted) material on chromosome 17p, was used to help obtain a diagnosis of SMS. Chromosomes may be obtained from a blood sample. During this test the chromosomes are stained so that they can be more easily seen and then are examined under a microscope where the missing segment of chromosome 17p can be detected (karyotyping). To determine the precise breakpoint, a more sensitive test known as fluorescent in situ hybridization (FISH) may be necessary. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing researchers to better view that specific region of the chromosome.A newer technique known as chromosomal microarray analysis may also be used. During this exam, a person’s DNA is compared to the DNA of a person without a chromosomal abnormality (‘control’ person). A chromosome abnormality is noted when a difference is found between the DNA samples. Chromosomal microarray analysis allows for the detection of very small changes (missing or duplicated segments) or alterations.Molecular genetic testing can confirm a diagnosis in individuals suspected of having SMS due to a RAI1 gene mutation. Molecular genetic testing can detect mutations in the RAI1 gene known to cause SMS in specific cases, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Smith Magenis Syndrome. A diagnosis of Smith-Magenis syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized genetic tests. The diagnosis of SMS is confirmed when deletion 17p11.2 (cytogenetic analysis or microarray) or RAI1 gene mutation is identified.Clinical Testing and Workup
In the past, a specific chromosomal study known as G-band analysis, which demonstrates missing (deleted) material on chromosome 17p, was used to help obtain a diagnosis of SMS. Chromosomes may be obtained from a blood sample. During this test the chromosomes are stained so that they can be more easily seen and then are examined under a microscope where the missing segment of chromosome 17p can be detected (karyotyping). To determine the precise breakpoint, a more sensitive test known as fluorescent in situ hybridization (FISH) may be necessary. During a FISH exam, probes marked by a specific color of fluorescent dye are attached to a specific chromosome allowing researchers to better view that specific region of the chromosome.A newer technique known as chromosomal microarray analysis may also be used. During this exam, a person’s DNA is compared to the DNA of a person without a chromosomal abnormality (‘control’ person). A chromosome abnormality is noted when a difference is found between the DNA samples. Chromosomal microarray analysis allows for the detection of very small changes (missing or duplicated segments) or alterations.Molecular genetic testing can confirm a diagnosis in individuals suspected of having SMS due to a RAI1 gene mutation. Molecular genetic testing can detect mutations in the RAI1 gene known to cause SMS in specific cases, but is available only as a diagnostic service at specialized laboratories.
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Therapies of Smith Magenis Syndrome
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TreatmentTreatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, dental specialists, speech pathologists, audiologists, ophthalmologists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan and affect child’s treatment. Genetic counseling is of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.Treatment is symptomatic and supportive. Early intervention is important in ensuring that affected children reach their highest potential. Services that may be beneficial include special remedial education, speech/language therapy, physical therapy, occupational therapy, and sensory integration therapy, in which certain sensory activities are undertaken in order to help regulate a child’s response to sensory stimuli. Additional medical, social and vocational services may be recommended when appropriate.Certain medications may be used to treat behavioral problems such as attention deficit or hyperactivity. Specific medications have also been used to treat sleep disorders potentially associated with SMS. Melatonin supplementation, in order to normalize melatonin levels, taken at bedtime has shown benefit in anecdotal reports. Use of the B-blocker acebutolol in the morning to inhibit/suppress daytime melatonin secretion has shown some benefit in one French study. Feeding difficulties require identification and appropriate therapy. Additional treatment follows standard guidelines for the specific symptom. For example, anti-seizure medications (anti-convulsants) may be used to treat seizures.PrognosisBecause of the highly variable nature of SMS, it is impossible to generalize about prognosis for individual cases. Some affected individuals have been able to become employed and even live semi-independently with support from family and friends. However, others require constant care and may need to live with family or in a residential facility. As stated above, parents should talk to the physician and medical team about their child’s specific case and overall prognosis.
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Therapies of Smith Magenis Syndrome. TreatmentTreatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, dental specialists, speech pathologists, audiologists, ophthalmologists, psychologists, and other healthcare professionals may need to systematically and comprehensively plan and affect child’s treatment. Genetic counseling is of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.Treatment is symptomatic and supportive. Early intervention is important in ensuring that affected children reach their highest potential. Services that may be beneficial include special remedial education, speech/language therapy, physical therapy, occupational therapy, and sensory integration therapy, in which certain sensory activities are undertaken in order to help regulate a child’s response to sensory stimuli. Additional medical, social and vocational services may be recommended when appropriate.Certain medications may be used to treat behavioral problems such as attention deficit or hyperactivity. Specific medications have also been used to treat sleep disorders potentially associated with SMS. Melatonin supplementation, in order to normalize melatonin levels, taken at bedtime has shown benefit in anecdotal reports. Use of the B-blocker acebutolol in the morning to inhibit/suppress daytime melatonin secretion has shown some benefit in one French study. Feeding difficulties require identification and appropriate therapy. Additional treatment follows standard guidelines for the specific symptom. For example, anti-seizure medications (anti-convulsants) may be used to treat seizures.PrognosisBecause of the highly variable nature of SMS, it is impossible to generalize about prognosis for individual cases. Some affected individuals have been able to become employed and even live semi-independently with support from family and friends. However, others require constant care and may need to live with family or in a residential facility. As stated above, parents should talk to the physician and medical team about their child’s specific case and overall prognosis.
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Overview of Smith-Kingsmore Syndrome
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SummarySmith-Kingsmore syndrome (SKS) is a rare, neurodevelopmental genetic disorder caused by changes (disease-causing variants) in the MTOR gene. SKS impacts the digestive, endocrine, metabolic and nervous systems.Patients with SKS have a spectrum of medical, intellectual, and behavioral disabilities resulting in different and variable clinical outcomes. The most common findings in people with SKS are intellectual disability, developmental delay, large brain size (megalencephaly) and seizures. The symptoms vary and largely depend on the type of MTOR gene mutation that the patient has and its distribution in the body. Management of patients with SKS includes treatment of medical concerns, such as seizures as well as speech and physical therapy. Treatment is symptom-driven and there is currently no cure.IntroductionGenetic changes in the MTOR gene were first noted as a cause of a neurodevelopmental disorder in 2013. Studies are still needed to continue to define the characteristics associated with specific MTOR gene variants. Presently, genetic changes in MTOR can be separated into three clinical types.The first group includes patients with generalized brain overgrowth (megalencephaly), intellectual disability, autism and hypotonia. These are the patients who have been identified as having SKS.The second group includes patients with diffuse brain overgrowth, abnormalities of the surface of the brain (polymicrogyria) and skin pigmentation abnormalities.The third group includes patients with focal changes in the brain (focal cortical dysplasia or hemimegalencephaly) causing early-onset epilepsy.The distribution and levels of MTOR genetic changes in these three groups vary. The mutations in MTOR in patients with SKS are usually present in all cells of the body. Disease characteristics vary in patients with SKS, even if they have the same MTOR gene mutation. In contrast, genetic changes in MTOR in the second and third groups can be more localized or restricted to certain tissues (mosaic). This may cause these mutations to escape detection if a patient has genetic testing on a blood or saliva sample.
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Overview of Smith-Kingsmore Syndrome. SummarySmith-Kingsmore syndrome (SKS) is a rare, neurodevelopmental genetic disorder caused by changes (disease-causing variants) in the MTOR gene. SKS impacts the digestive, endocrine, metabolic and nervous systems.Patients with SKS have a spectrum of medical, intellectual, and behavioral disabilities resulting in different and variable clinical outcomes. The most common findings in people with SKS are intellectual disability, developmental delay, large brain size (megalencephaly) and seizures. The symptoms vary and largely depend on the type of MTOR gene mutation that the patient has and its distribution in the body. Management of patients with SKS includes treatment of medical concerns, such as seizures as well as speech and physical therapy. Treatment is symptom-driven and there is currently no cure.IntroductionGenetic changes in the MTOR gene were first noted as a cause of a neurodevelopmental disorder in 2013. Studies are still needed to continue to define the characteristics associated with specific MTOR gene variants. Presently, genetic changes in MTOR can be separated into three clinical types.The first group includes patients with generalized brain overgrowth (megalencephaly), intellectual disability, autism and hypotonia. These are the patients who have been identified as having SKS.The second group includes patients with diffuse brain overgrowth, abnormalities of the surface of the brain (polymicrogyria) and skin pigmentation abnormalities.The third group includes patients with focal changes in the brain (focal cortical dysplasia or hemimegalencephaly) causing early-onset epilepsy.The distribution and levels of MTOR genetic changes in these three groups vary. The mutations in MTOR in patients with SKS are usually present in all cells of the body. Disease characteristics vary in patients with SKS, even if they have the same MTOR gene mutation. In contrast, genetic changes in MTOR in the second and third groups can be more localized or restricted to certain tissues (mosaic). This may cause these mutations to escape detection if a patient has genetic testing on a blood or saliva sample.
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Symptoms of Smith-Kingsmore Syndrome
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Many symptoms and features are thought to be part of SKS. Some of these characteristics occur more frequently than others. Since there is great variability, not every person with SKS will have all these features. As research progresses, the formal description of SKS will likely change.Individuals with SKS often show symptoms in very early childhood, sometimes at birth or in the first six months of life. These children often have medical challenges and typically have developmental delays. For example, children with SKS may not reach developmental milestones such as rolling over, sitting up, walking, or talking at the expected time.Common features of SKS vary but may include:BEHAVIORAL• Autism / autistic traits / sensory processing disorder
• ADHD (attention-deficit/hyperactivity disorder)
• Non-verbal /speech anomalies, delayed or absent speech, distorted articulation
• Self-harming behaviorsNEUROLOGIC• Global developmental delays/intellectual disability
• Macrocephaly / megalencephaly / ventriculomegaly / polymicrogyria / other brain abnormalities on MRI / rapid head growth in the first 6 months
• Low muscle tone (hypotonia)
• Seizures (including nocturnal focal epilepsy)
• Sleep issues (insomnia, waking at night, sleep apnea)
• Hearing Impairment
• Cortical visual impairmentDIGESTION / GASTROINTESTINAL• Digestive issues (abdominal pain, constipation)
• Hyperphagia (abnormally increased appetite for food)PHYSICAL• Curly / wavy hair
• Abnormal facial features
• Frontal bossing, open mouth appearance, prominent and long philtrum, short nose with a flat nasal bridge, macrostomia, hypertelorism
• Macrosomia at birth (large for gestational age)
• Skin pigmentation / Blaschko lines / hypomelanosis/hypermelanosis in vito / Cafe au lait spots
• Decreased perspiration and heat intolerance
• Accelerated growth in first 18 months to 2 years
• Delayed bone age (scan at 2 years like a newborn) or slightly advanced bone age
• Motor skill deficits
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Symptoms of Smith-Kingsmore Syndrome. Many symptoms and features are thought to be part of SKS. Some of these characteristics occur more frequently than others. Since there is great variability, not every person with SKS will have all these features. As research progresses, the formal description of SKS will likely change.Individuals with SKS often show symptoms in very early childhood, sometimes at birth or in the first six months of life. These children often have medical challenges and typically have developmental delays. For example, children with SKS may not reach developmental milestones such as rolling over, sitting up, walking, or talking at the expected time.Common features of SKS vary but may include:BEHAVIORAL• Autism / autistic traits / sensory processing disorder
• ADHD (attention-deficit/hyperactivity disorder)
• Non-verbal /speech anomalies, delayed or absent speech, distorted articulation
• Self-harming behaviorsNEUROLOGIC• Global developmental delays/intellectual disability
• Macrocephaly / megalencephaly / ventriculomegaly / polymicrogyria / other brain abnormalities on MRI / rapid head growth in the first 6 months
• Low muscle tone (hypotonia)
• Seizures (including nocturnal focal epilepsy)
• Sleep issues (insomnia, waking at night, sleep apnea)
• Hearing Impairment
• Cortical visual impairmentDIGESTION / GASTROINTESTINAL• Digestive issues (abdominal pain, constipation)
• Hyperphagia (abnormally increased appetite for food)PHYSICAL• Curly / wavy hair
• Abnormal facial features
• Frontal bossing, open mouth appearance, prominent and long philtrum, short nose with a flat nasal bridge, macrostomia, hypertelorism
• Macrosomia at birth (large for gestational age)
• Skin pigmentation / Blaschko lines / hypomelanosis/hypermelanosis in vito / Cafe au lait spots
• Decreased perspiration and heat intolerance
• Accelerated growth in first 18 months to 2 years
• Delayed bone age (scan at 2 years like a newborn) or slightly advanced bone age
• Motor skill deficits
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Causes of Smith-Kingsmore Syndrome
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SKS is usually an autosomal dominant condition, which means that one copy of the altered MTOR gene in each cell is sufficient to cause the disorder.Changes in the MTOR gene are usually random events (sporadic or de novo) that happen in the egg or sperm prior to conception and are not inherited from either parent. This type of change is present in all cells of the affected individual and is called a germline variant.There are also some SKS patients who have an altered MTOR gene in some, but not all of their cells, and this is called somatic mosaicism. This type of change is also de novo (not inherited) and occurs at some point while a baby is developing during pregnancy. MTOR gene mutations in these SKS patients can only be detected in samples of affected tissues and might not be detected in a blood or saliva sample.Rarely, people with SKS inherit the altered gene from an unaffected parent who has a MTOR gene mutation only in their sperm or egg cells (germline tissues). This is called germline mosaicism and, although rare, it has been seen more frequently in SKS than in other diseases.The MTOR gene encodes the MTOR protein which plays a central role in the cell’s nutrient/energy sensing pathway. This pathway provides a way for cells to communicate information such as when to grow and how quickly to grow. Changes in the MTOR gene may change the instructions for the body and how the MTOR pathway works.Changes in MTOR can cause the pathway to become hyperactive (i.e., gain of function). As a result of pathway hyperactivation, the affected nerve cells (neurons) grow unusually large and misshapen, leading to brain malformations, cognitive delays and epilepsy.
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Causes of Smith-Kingsmore Syndrome. SKS is usually an autosomal dominant condition, which means that one copy of the altered MTOR gene in each cell is sufficient to cause the disorder.Changes in the MTOR gene are usually random events (sporadic or de novo) that happen in the egg or sperm prior to conception and are not inherited from either parent. This type of change is present in all cells of the affected individual and is called a germline variant.There are also some SKS patients who have an altered MTOR gene in some, but not all of their cells, and this is called somatic mosaicism. This type of change is also de novo (not inherited) and occurs at some point while a baby is developing during pregnancy. MTOR gene mutations in these SKS patients can only be detected in samples of affected tissues and might not be detected in a blood or saliva sample.Rarely, people with SKS inherit the altered gene from an unaffected parent who has a MTOR gene mutation only in their sperm or egg cells (germline tissues). This is called germline mosaicism and, although rare, it has been seen more frequently in SKS than in other diseases.The MTOR gene encodes the MTOR protein which plays a central role in the cell’s nutrient/energy sensing pathway. This pathway provides a way for cells to communicate information such as when to grow and how quickly to grow. Changes in the MTOR gene may change the instructions for the body and how the MTOR pathway works.Changes in MTOR can cause the pathway to become hyperactive (i.e., gain of function). As a result of pathway hyperactivation, the affected nerve cells (neurons) grow unusually large and misshapen, leading to brain malformations, cognitive delays and epilepsy.
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Affects of Smith-Kingsmore Syndrome
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MTOR-related disorders are extremely rare. The total patient population is still unknown, but it is estimated that there are about 10 people with MTOR gene disorders (with some MTOR mutations causing SKS) in every 10,000 individuals. However, SKS may go undiagnosed or misdiagnosed, making it extremely difficult to determine the true frequency in the general population. Based on the current understanding of this condition, SKS occurs worldwide in people of all ethnic groups.
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Affects of Smith-Kingsmore Syndrome. MTOR-related disorders are extremely rare. The total patient population is still unknown, but it is estimated that there are about 10 people with MTOR gene disorders (with some MTOR mutations causing SKS) in every 10,000 individuals. However, SKS may go undiagnosed or misdiagnosed, making it extremely difficult to determine the true frequency in the general population. Based on the current understanding of this condition, SKS occurs worldwide in people of all ethnic groups.
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Related disorders of Smith-Kingsmore Syndrome
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Related disorders of Smith-Kingsmore Syndrome.
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Diagnosis of Smith-Kingsmore Syndrome
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SKS is a rare condition that many physicians are not familiar with. A diagnosis of SKS is suspected based upon the identification of characteristic features, a detailed patient and family history and a thorough clinical evaluation.A diagnosis of SKS is confirmed with the detection of a germline or mosaic mutation in the MTOR gene. A genetic test performed on a sample of blood or saliva will detect a mutation that is present in all cells of the body (germline variants). To detect a mutation only present in some cells (somatic mosaicism), the genetic test must be performed on a sample of affected tissue.Some individuals with SKS may be diagnosed with a molecular genetic test that covers a subset of genes related to the individual’s symptoms (gene panel testing) while others may have whole exome sequencing (WES) or whole genome sequencing (WGS). These methods rely on new technologies that allow rapid sequencing of large amounts of genetic material known as next-generation sequencing (NGS).The appropriate testing should be discussed with the care team.
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Diagnosis of Smith-Kingsmore Syndrome. SKS is a rare condition that many physicians are not familiar with. A diagnosis of SKS is suspected based upon the identification of characteristic features, a detailed patient and family history and a thorough clinical evaluation.A diagnosis of SKS is confirmed with the detection of a germline or mosaic mutation in the MTOR gene. A genetic test performed on a sample of blood or saliva will detect a mutation that is present in all cells of the body (germline variants). To detect a mutation only present in some cells (somatic mosaicism), the genetic test must be performed on a sample of affected tissue.Some individuals with SKS may be diagnosed with a molecular genetic test that covers a subset of genes related to the individual’s symptoms (gene panel testing) while others may have whole exome sequencing (WES) or whole genome sequencing (WGS). These methods rely on new technologies that allow rapid sequencing of large amounts of genetic material known as next-generation sequencing (NGS).The appropriate testing should be discussed with the care team.
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Therapies of Smith-Kingsmore Syndrome
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Currently, there is no cure for SKS, and no treatments approved by the U.S. Food and Drug Administrations (FDA). Treatment is based on a child’s specific symptoms. Patients and their families typically visit one or more of the following medical specialists:Pediatrics• Annual visits to monitor growth and development
• Medical management of constipation is often needed
• Monitoring for illness due to abnormal immune cell functionDevelopmental Pediatrics• Developmental and behavioral evaluations to assess for challenges and recommend treatments
• Evaluate for appropriate therapies including physical, occupational, speech/feeding, behavioral, vision therapy
• Guide individualized education plans (IEPs)Pediatric Genetics and Genetic Counseling• Review genetic testing and results
• Provide information about recurrence risk
• Provide coordination of careNeurology• If seizures are suspected, an EEG (measurement of the brain’s
electrical activity) is recommended
• An MRI should be considered to identify any brain malformationsOphthalmologist/Neuro-ophthalmologist• Screening for cortical visual impairment (CVI)Audiology• Routine hearing screening (newborn and annually)Endocrinology• Consider a referral if hypoglycemia develops or if premature (precocious) puberty is suspected
Orthopedics/Physical Rehabilitation
• Evaluate the need for assistive devices due to hypotonia, motor deficits and/or bone abnormalitiesNeuropsychology• For school-age children, this assessment can help identify the most
appropriate educational support and schoolingRoutine dental and/or orthodontic care is also recommended as well as speech and language therapy, physical and occupational therapy and behavior therapy/psychological counseling.
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Therapies of Smith-Kingsmore Syndrome. Currently, there is no cure for SKS, and no treatments approved by the U.S. Food and Drug Administrations (FDA). Treatment is based on a child’s specific symptoms. Patients and their families typically visit one or more of the following medical specialists:Pediatrics• Annual visits to monitor growth and development
• Medical management of constipation is often needed
• Monitoring for illness due to abnormal immune cell functionDevelopmental Pediatrics• Developmental and behavioral evaluations to assess for challenges and recommend treatments
• Evaluate for appropriate therapies including physical, occupational, speech/feeding, behavioral, vision therapy
• Guide individualized education plans (IEPs)Pediatric Genetics and Genetic Counseling• Review genetic testing and results
• Provide information about recurrence risk
• Provide coordination of careNeurology• If seizures are suspected, an EEG (measurement of the brain’s
electrical activity) is recommended
• An MRI should be considered to identify any brain malformationsOphthalmologist/Neuro-ophthalmologist• Screening for cortical visual impairment (CVI)Audiology• Routine hearing screening (newborn and annually)Endocrinology• Consider a referral if hypoglycemia develops or if premature (precocious) puberty is suspected
Orthopedics/Physical Rehabilitation
• Evaluate the need for assistive devices due to hypotonia, motor deficits and/or bone abnormalitiesNeuropsychology• For school-age children, this assessment can help identify the most
appropriate educational support and schoolingRoutine dental and/or orthodontic care is also recommended as well as speech and language therapy, physical and occupational therapy and behavior therapy/psychological counseling.
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Overview of Smith-Lemli-Opitz Syndrome
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SummarySmith-Lemli-Opitz syndrome (SLOS) is a genetic condition that affects many parts of the body. It is an autosomal recessive genetic condition caused by changes in the DHCR7 gene. Problems associated with SLOS are usually noticeable before or shortly after birth (congenital). Common features of SLOS include slow growth, a small head (microcephaly) and mild to severe intellectual disability. Birth defects such as extra fingers and toes (polydactyly) are also common. SLOS is a variable condition. Some individuals with SLOS have normal development and only minor features. SLOS affects 1 in 20,000 to 1 in 60,000 babies born in the United States. People with SLOS cannot make cholesterol. Treatment with extra cholesterol may help with some signs of SLOS, however, no cure for SLOS currently exists.
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Overview of Smith-Lemli-Opitz Syndrome. SummarySmith-Lemli-Opitz syndrome (SLOS) is a genetic condition that affects many parts of the body. It is an autosomal recessive genetic condition caused by changes in the DHCR7 gene. Problems associated with SLOS are usually noticeable before or shortly after birth (congenital). Common features of SLOS include slow growth, a small head (microcephaly) and mild to severe intellectual disability. Birth defects such as extra fingers and toes (polydactyly) are also common. SLOS is a variable condition. Some individuals with SLOS have normal development and only minor features. SLOS affects 1 in 20,000 to 1 in 60,000 babies born in the United States. People with SLOS cannot make cholesterol. Treatment with extra cholesterol may help with some signs of SLOS, however, no cure for SLOS currently exists.
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Symptoms of Smith-Lemli-Opitz Syndrome
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The features of SLOS are not the same in every patient. Common findings are slowed growth before and after birth, a small head (microcephaly) and a spilt in the roof of the mouth (cleft palate). Most babies have differences in their fingers and/or toes. This includes fused toes (2-3 syndactyly) and extra fingers or toes (polydactyly). Males with SLOS can have underdeveloped genitals that may resemble female genitals. People with SLOS often experience behavioral problems, sleep problems and mild to severe intellectual disability.Individuals with SLOS have specific facial features. Their eyes may appear to be drooping (ptosis). There can also be a fold in the inner corner of the eye (epicanthal folds) and wrinkles on the eyelids. Children with SLOS can have a small nose and nostril differences (anteverted nares). Other common facial features include differences of the upper lip, a small jaw and large ears. Vision problems can occur, including cataracts. There may also be differences in the number and/or spacing of teeth.Less common findings include seizures, heart defects and low muscle tone (hypotonia). People with SLOS can have a narrowing at the top of the stomach (pyloric stenosis) and blockage (obstruction) of the bowel. A sensitivity to light (photosensitivity) is also common.
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Symptoms of Smith-Lemli-Opitz Syndrome. The features of SLOS are not the same in every patient. Common findings are slowed growth before and after birth, a small head (microcephaly) and a spilt in the roof of the mouth (cleft palate). Most babies have differences in their fingers and/or toes. This includes fused toes (2-3 syndactyly) and extra fingers or toes (polydactyly). Males with SLOS can have underdeveloped genitals that may resemble female genitals. People with SLOS often experience behavioral problems, sleep problems and mild to severe intellectual disability.Individuals with SLOS have specific facial features. Their eyes may appear to be drooping (ptosis). There can also be a fold in the inner corner of the eye (epicanthal folds) and wrinkles on the eyelids. Children with SLOS can have a small nose and nostril differences (anteverted nares). Other common facial features include differences of the upper lip, a small jaw and large ears. Vision problems can occur, including cataracts. There may also be differences in the number and/or spacing of teeth.Less common findings include seizures, heart defects and low muscle tone (hypotonia). People with SLOS can have a narrowing at the top of the stomach (pyloric stenosis) and blockage (obstruction) of the bowel. A sensitivity to light (photosensitivity) is also common.
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Causes of Smith-Lemli-Opitz Syndrome
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The chromosomes in our cells carry our genes which occur in pairs and are instructions to make proteins. One copy of each gene is inherited from the mother, and the other from the father. SLOS is caused by having a harmful change (mutation) in both copies of the DHCR7 gene. This causes lack of an enzyme (7-dehydrocholesterol reductase) which is needed to make cholesterol. Cholesterol is a waxy substance that is important for making cell structures. Cholesterol is necessary for development before and after birth. Mistakes in DHCR7 also leads to a buildup of 7-dehydrocholesterol (7-DHC) which is toxic to the body. Buildup of 7-DHC along with low cholesterol cause the features of SLOS.SLOS is an autosomal recessive genetic condition. Recessive genetic conditions occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 on the non-working 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 working genes from both parents is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same harmful gene change, which increases the risk to have children with a recessive genetic condition.
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Causes of Smith-Lemli-Opitz Syndrome. The chromosomes in our cells carry our genes which occur in pairs and are instructions to make proteins. One copy of each gene is inherited from the mother, and the other from the father. SLOS is caused by having a harmful change (mutation) in both copies of the DHCR7 gene. This causes lack of an enzyme (7-dehydrocholesterol reductase) which is needed to make cholesterol. Cholesterol is a waxy substance that is important for making cell structures. Cholesterol is necessary for development before and after birth. Mistakes in DHCR7 also leads to a buildup of 7-dehydrocholesterol (7-DHC) which is toxic to the body. Buildup of 7-DHC along with low cholesterol cause the features of SLOS.SLOS is an autosomal recessive genetic condition. Recessive genetic conditions occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 on the non-working 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 working genes from both parents is 25%. The risk is the same for males and females.Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same harmful gene change, which increases the risk to have children with a recessive genetic condition.
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Affects of Smith-Lemli-Opitz Syndrome
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About 1 in 20,000 to 1 in 60,000 people in the US have SLOS. This condition affects males and females equally. However, females are less likely to be diagnosed because they do not have genital differences. SLOS occurs more often in people of European ancestry.
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Affects of Smith-Lemli-Opitz Syndrome. About 1 in 20,000 to 1 in 60,000 people in the US have SLOS. This condition affects males and females equally. However, females are less likely to be diagnosed because they do not have genital differences. SLOS occurs more often in people of European ancestry.
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Related disorders of Smith-Lemli-Opitz Syndrome
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Meckel syndrome is also an autosomal recessive condition. There are 13 genes known to cause Meckel syndrome. It occurs in 1 in 13,250 to 1 in 140,000 people. Like SLOS, babies with Meckel syndrome may have extra fingers or toes (polydactyly). They often have large cyst-filled (polycystic) kidneys. Incorrect development of the brain and spinal cord (neural tube defects) can occur. Meckel syndrome can also affect the eyes, facial features, heart, bones, urinary system and genitals. Like SLOS, Meckel syndrome varies between people. (For more information on this condition, choose “Meckel syndrome” as your search term in the Rare Disease Database.)Squalene synthase deficiency also results from difficulty making cholesterol. It is an autosomal recessive condition caused by harmful changes in the FDFT1 gene. The signs and symptoms are very similar to SLOS. However, squalene synthase deficiency is much rarer. Only 3 individuals have been reported to have this condition. In squalene synthase deficiency there is no buildup of 7-DHC.Other related conditions include Desmosterolosis, Dubowitz syndrome, lathosterolosis, MEND syndrome, Nguyen syndrome, Noonan syndrome, Pallister-Hall syndrome and pseudotrisomy 13.
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Related disorders of Smith-Lemli-Opitz Syndrome. Meckel syndrome is also an autosomal recessive condition. There are 13 genes known to cause Meckel syndrome. It occurs in 1 in 13,250 to 1 in 140,000 people. Like SLOS, babies with Meckel syndrome may have extra fingers or toes (polydactyly). They often have large cyst-filled (polycystic) kidneys. Incorrect development of the brain and spinal cord (neural tube defects) can occur. Meckel syndrome can also affect the eyes, facial features, heart, bones, urinary system and genitals. Like SLOS, Meckel syndrome varies between people. (For more information on this condition, choose “Meckel syndrome” as your search term in the Rare Disease Database.)Squalene synthase deficiency also results from difficulty making cholesterol. It is an autosomal recessive condition caused by harmful changes in the FDFT1 gene. The signs and symptoms are very similar to SLOS. However, squalene synthase deficiency is much rarer. Only 3 individuals have been reported to have this condition. In squalene synthase deficiency there is no buildup of 7-DHC.Other related conditions include Desmosterolosis, Dubowitz syndrome, lathosterolosis, MEND syndrome, Nguyen syndrome, Noonan syndrome, Pallister-Hall syndrome and pseudotrisomy 13.
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Diagnosis of Smith-Lemli-Opitz Syndrome
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The diagnosis of SLOS is based on physical findings and either biochemical or genetic testing. Biochemical testing looks for protein levels in the blood. In patients with SLOS, the protein 7-dehydrocholesterol is elevated. Genetic testing looks for changes in a patient's genes. SLOS is diagnosed if there are harmful changes in both copies of the DHCR7 gene.Results from a test offered during pregnancy (maternal serum screen) may suggest SLOS. An amniocentesis can be performed to confirm the diagnosis. An amniocentesis uses a needle to take a small amount of fluid surrounding the baby during pregnancy. This fluid can be tested for 7-DHC levels or changes in the DHCR7 gene.
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Diagnosis of Smith-Lemli-Opitz Syndrome. The diagnosis of SLOS is based on physical findings and either biochemical or genetic testing. Biochemical testing looks for protein levels in the blood. In patients with SLOS, the protein 7-dehydrocholesterol is elevated. Genetic testing looks for changes in a patient's genes. SLOS is diagnosed if there are harmful changes in both copies of the DHCR7 gene.Results from a test offered during pregnancy (maternal serum screen) may suggest SLOS. An amniocentesis can be performed to confirm the diagnosis. An amniocentesis uses a needle to take a small amount of fluid surrounding the baby during pregnancy. This fluid can be tested for 7-DHC levels or changes in the DHCR7 gene.
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Therapies of Smith-Lemli-Opitz Syndrome
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TreatmentTreatment for SLOS is based on the child’s specific problems. Some children may require surgery to correct cleft palate, heart defects and genital anomalies. Early educational intervention is important for learning and developmental disabilities. Food with extra cholesterol and bile acid supplements may improve some of the symptoms of SLOS including growth. Statins, such as Simvastatin, can safely reduce DHC levels and may improve some behavioral problems.
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Therapies of Smith-Lemli-Opitz Syndrome. TreatmentTreatment for SLOS is based on the child’s specific problems. Some children may require surgery to correct cleft palate, heart defects and genital anomalies. Early educational intervention is important for learning and developmental disabilities. Food with extra cholesterol and bile acid supplements may improve some of the symptoms of SLOS including growth. Statins, such as Simvastatin, can safely reduce DHC levels and may improve some behavioral problems.
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Overview of Sneddon Syndrome
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Sneddon syndrome is a rare progressive disorder affecting small- and medium-sized blood vessels. The disorder is characterized by the association of a skin condition and neurological abnormalities. Characteristic findings include multiple episodes of reduced blood flow to the brain (cerebral ischemia) causing mini-strokes or stroke and bluish net-like patterns of discoloration on the skin surrounding normal-appearing skin (livedo reticularis). Additional symptoms may include headache, dizziness, abnormally high blood pressure (hypertension), and heart disease. Lesions may develop within the central nervous system as a result of reduced blood flow to the brain, which can cause reduced intellectual ability, memory loss, personality changes, and/or other neurological symptoms. The combination of stroke symptoms and livedo reticularis differentiates this syndrome from other disorders. The exact cause of Sneddon syndrome is not fully understood.IntroductionSneddon syndrome was first described a separate clinical entity in the medical literature by Dr. Sneddon and colleagues in 1965. Since that time, significant debate has existed as to whether Sneddon syndrome is a distinct disorder, part of a spectrum of disorders, or a subtype of antiphospholipid syndrome. Some researchers believe that Sneddon syndrome should be separated into primary and secondary cases. Primary Sneddon syndrome would denote cases where there was no known cause (idiopathic); secondary Sneddon syndrome would denote cases that are believed to occur secondary to another disorder or thrombophilic state. Some researchers believe that Sneddon syndrome should be differentiated by whether antiphospholipid antibodies are present (aPL-positive) or absent (aPL-negative), others discuss autoimmune/inflammatory etiopathogenesis versus thrombophilia.
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Overview of Sneddon Syndrome. Sneddon syndrome is a rare progressive disorder affecting small- and medium-sized blood vessels. The disorder is characterized by the association of a skin condition and neurological abnormalities. Characteristic findings include multiple episodes of reduced blood flow to the brain (cerebral ischemia) causing mini-strokes or stroke and bluish net-like patterns of discoloration on the skin surrounding normal-appearing skin (livedo reticularis). Additional symptoms may include headache, dizziness, abnormally high blood pressure (hypertension), and heart disease. Lesions may develop within the central nervous system as a result of reduced blood flow to the brain, which can cause reduced intellectual ability, memory loss, personality changes, and/or other neurological symptoms. The combination of stroke symptoms and livedo reticularis differentiates this syndrome from other disorders. The exact cause of Sneddon syndrome is not fully understood.IntroductionSneddon syndrome was first described a separate clinical entity in the medical literature by Dr. Sneddon and colleagues in 1965. Since that time, significant debate has existed as to whether Sneddon syndrome is a distinct disorder, part of a spectrum of disorders, or a subtype of antiphospholipid syndrome. Some researchers believe that Sneddon syndrome should be separated into primary and secondary cases. Primary Sneddon syndrome would denote cases where there was no known cause (idiopathic); secondary Sneddon syndrome would denote cases that are believed to occur secondary to another disorder or thrombophilic state. Some researchers believe that Sneddon syndrome should be differentiated by whether antiphospholipid antibodies are present (aPL-positive) or absent (aPL-negative), others discuss autoimmune/inflammatory etiopathogenesis versus thrombophilia.
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Symptoms of Sneddon Syndrome
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Sneddon syndrome is a slowly progressive disorder of small- and medium-sized arteries, which are the blood vessels that carry blood away from the heart. The disorder is characterized by blockages (occlusions) of the arteries that cause a reduction of blood flow to the brain and to the skin. Associated symptoms vary from one person to another based, in part, upon the specific arteries that are affected. An irregular, net-like pattern of bluish skin discoloration surrounding areas of normal-appearing skin (livedo reticularis) is characteristic of this disorder. The arms and legs are most often affected as well as the trunk, buttocks, and hands and feet. Livedo reticularis is worsened by cold and pregnancy. (In the European medical literature, the term livedo reticularis is used to describe the skin changes of the extremities only that disappear when the skin is warmed. Livedo racemosa is used to describe skin changes that involve also the buttocks and the trunk and do not disappear with warm temperatures. These two dermatologic conditions are separated because livedo reticularis is much more frequent, but the association with strokes exists for livedo racemosa only).Generally, livedo reticularis develops before the neurological symptoms by as much as 10 years, although sometimes the onset of skin symptoms may occur at approximately the same time. Only rarely, do the skin symptoms occur after the neurological symptoms. Painfully cold fingers and toes caused by dilation or constriction of small vessels in response to cold (Raynaud’s phenomenon) may also occur. Blues discoloration of the hands and feet due to the lack of blood flow (acrocyanosis) has also been reported.Recurrent episodes of mini-strokes (transient ischemic attacks) or strokes (cerebrovascular accidents) are a common finding of Sneddon syndrome. Less frequently, microbleeds and intracerebral hemorrhages also occur in Sneddon syndrome. The associated neurological symptoms vary depending upon the location of arterial blockages or bleedings. These symptoms may include difficulty concentrating, memory loss, confusion, personality changes, impaired vision, and weakness of one side of the body (hemiparesis). Sneddon syndrome may cause progressive reduction of mental and cognitive function, potentially resulting in dementia. Aphasia, which is defined as a communication disorder that impairs the ability to process language including impairing the ability to speak or understand others, is also common. Less often, seizures, muscle pain and stiffness, and abnormal movements caused by repetitive, jerky muscle contractions (chorea) may also occur.Generalized symptoms (e.g., headaches and migraines and/or dizziness or vertigo) may be present for several years before neurological symptoms and/or visible skin discoloration appears. High blood pressure (hypertension) is also common.Heart murmurs, heart disease resulting from reduced blood flow to heart tissue (ischemic heart disease), or thickening of the valves between the chambers of the heart (valvular stenosis) have also been diagnosed in people with Sneddon syndrome and may be associated with rheumatic heart disease or endocarditis. In rare cases, impairment of the kidneys may occur.
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Symptoms of Sneddon Syndrome. Sneddon syndrome is a slowly progressive disorder of small- and medium-sized arteries, which are the blood vessels that carry blood away from the heart. The disorder is characterized by blockages (occlusions) of the arteries that cause a reduction of blood flow to the brain and to the skin. Associated symptoms vary from one person to another based, in part, upon the specific arteries that are affected. An irregular, net-like pattern of bluish skin discoloration surrounding areas of normal-appearing skin (livedo reticularis) is characteristic of this disorder. The arms and legs are most often affected as well as the trunk, buttocks, and hands and feet. Livedo reticularis is worsened by cold and pregnancy. (In the European medical literature, the term livedo reticularis is used to describe the skin changes of the extremities only that disappear when the skin is warmed. Livedo racemosa is used to describe skin changes that involve also the buttocks and the trunk and do not disappear with warm temperatures. These two dermatologic conditions are separated because livedo reticularis is much more frequent, but the association with strokes exists for livedo racemosa only).Generally, livedo reticularis develops before the neurological symptoms by as much as 10 years, although sometimes the onset of skin symptoms may occur at approximately the same time. Only rarely, do the skin symptoms occur after the neurological symptoms. Painfully cold fingers and toes caused by dilation or constriction of small vessels in response to cold (Raynaud’s phenomenon) may also occur. Blues discoloration of the hands and feet due to the lack of blood flow (acrocyanosis) has also been reported.Recurrent episodes of mini-strokes (transient ischemic attacks) or strokes (cerebrovascular accidents) are a common finding of Sneddon syndrome. Less frequently, microbleeds and intracerebral hemorrhages also occur in Sneddon syndrome. The associated neurological symptoms vary depending upon the location of arterial blockages or bleedings. These symptoms may include difficulty concentrating, memory loss, confusion, personality changes, impaired vision, and weakness of one side of the body (hemiparesis). Sneddon syndrome may cause progressive reduction of mental and cognitive function, potentially resulting in dementia. Aphasia, which is defined as a communication disorder that impairs the ability to process language including impairing the ability to speak or understand others, is also common. Less often, seizures, muscle pain and stiffness, and abnormal movements caused by repetitive, jerky muscle contractions (chorea) may also occur.Generalized symptoms (e.g., headaches and migraines and/or dizziness or vertigo) may be present for several years before neurological symptoms and/or visible skin discoloration appears. High blood pressure (hypertension) is also common.Heart murmurs, heart disease resulting from reduced blood flow to heart tissue (ischemic heart disease), or thickening of the valves between the chambers of the heart (valvular stenosis) have also been diagnosed in people with Sneddon syndrome and may be associated with rheumatic heart disease or endocarditis. In rare cases, impairment of the kidneys may occur.
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Causes of Sneddon Syndrome
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The exact cause of Sneddon syndrome is unknown. Most cases occur randomly for no apparent reason (sporadically). Possible immunological, environmental, genetic, and/or other factors are under investigation as potential causes of the disorder.Sneddon syndrome has been reported in more than one family member (e.g., siblings) in a few cases, supporting the possibility of genetic susceptibility as a factor in some cases. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances.Symptoms of Sneddon syndrome are caused by a progressive increase in the number of cells in the walls of affected arteries (endothelial proliferation). The cell proliferation leads to a build-up of material, narrowing the arteries and decreasing blood flow. Arteries may become blocked (occluded) and prevent blood from reaching areas of tissue (thrombosis). Clumps of cells may break loose and circulate in the blood stream. The clumps may lodge in an artery and block blood flow (embolism). Tissue loss or damage may occur in areas deprived of blood flow.Some affected individuals have high levels of antiphospholipid antibodies in the blood. Antibodies are part of the body’s immune system and act against invading or foreign microorganisms (e.g., bacteria or viruses). Antiphospholipid antibodies mistakenly recognize phospholipids (part of a cell’s membrane) as foreign and act against them. The significance of antiphospholipid antibodies in approximately 40 to 50 % of patients with Sneddon syndrome is unknown. Some researchers believe that, in familial cases of Sneddon syndrome, affected individuals may have a genetic predisposition to the production of these antibodies. The presence of antiphospholipid antibodies in some cases suggests a possible association with an autoimmune disorder called antiphospholipid syndrome. However, the specific relationship between these two disorders is unknown.Antiphospholipid syndrome is an autoimmune disorder, a disorder that occurs when the body’s immune system mistakenly targets healthy tissue. Less often, Sneddon syndrome can be associated with other autoimmune disorders such as systemic lupus erythematosus (SLE), Behcet’s disease, or mixed connective tissue disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)It is unknown whether individuals with Sneddon syndrome with antiphospholipid antibodies have a different disorder from individuals with Sneddon syndrome without antiphospholipid antibodies. In 2003, researchers determined several members of one family who had Sneddon syndrome without antiphospholipid antibodies had an alteration (mutation) in the CERC1 gene.
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Causes of Sneddon Syndrome. The exact cause of Sneddon syndrome is unknown. Most cases occur randomly for no apparent reason (sporadically). Possible immunological, environmental, genetic, and/or other factors are under investigation as potential causes of the disorder.Sneddon syndrome has been reported in more than one family member (e.g., siblings) in a few cases, supporting the possibility of genetic susceptibility as a factor in some cases. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances.Symptoms of Sneddon syndrome are caused by a progressive increase in the number of cells in the walls of affected arteries (endothelial proliferation). The cell proliferation leads to a build-up of material, narrowing the arteries and decreasing blood flow. Arteries may become blocked (occluded) and prevent blood from reaching areas of tissue (thrombosis). Clumps of cells may break loose and circulate in the blood stream. The clumps may lodge in an artery and block blood flow (embolism). Tissue loss or damage may occur in areas deprived of blood flow.Some affected individuals have high levels of antiphospholipid antibodies in the blood. Antibodies are part of the body’s immune system and act against invading or foreign microorganisms (e.g., bacteria or viruses). Antiphospholipid antibodies mistakenly recognize phospholipids (part of a cell’s membrane) as foreign and act against them. The significance of antiphospholipid antibodies in approximately 40 to 50 % of patients with Sneddon syndrome is unknown. Some researchers believe that, in familial cases of Sneddon syndrome, affected individuals may have a genetic predisposition to the production of these antibodies. The presence of antiphospholipid antibodies in some cases suggests a possible association with an autoimmune disorder called antiphospholipid syndrome. However, the specific relationship between these two disorders is unknown.Antiphospholipid syndrome is an autoimmune disorder, a disorder that occurs when the body’s immune system mistakenly targets healthy tissue. Less often, Sneddon syndrome can be associated with other autoimmune disorders such as systemic lupus erythematosus (SLE), Behcet’s disease, or mixed connective tissue disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)It is unknown whether individuals with Sneddon syndrome with antiphospholipid antibodies have a different disorder from individuals with Sneddon syndrome without antiphospholipid antibodies. In 2003, researchers determined several members of one family who had Sneddon syndrome without antiphospholipid antibodies had an alteration (mutation) in the CERC1 gene.
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Affects of Sneddon Syndrome
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Sneddon syndrome has been reported more often in females than in males. Almost 80% of the patients are women with a median age of diagnosis at 40 years. Symptoms usually begin in early to middle adulthood, but can occur at any age including childhood. The incidence and prevalence are unknown. One estimate places the incidence at approximately one out of 250,000 individuals in the general population.
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Affects of Sneddon Syndrome. Sneddon syndrome has been reported more often in females than in males. Almost 80% of the patients are women with a median age of diagnosis at 40 years. Symptoms usually begin in early to middle adulthood, but can occur at any age including childhood. The incidence and prevalence are unknown. One estimate places the incidence at approximately one out of 250,000 individuals in the general population.
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Related disorders of Sneddon Syndrome
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Symptoms of the following disorders can be similar to those of Sneddon Syndrome. Comparisons may be useful for a differential diagnosis:Lupus is a chronic, inflammatory autoimmune disorder affecting the connective tissue. In autoimmune disorders, the body’s own immune system attacks healthy cells and tissues causing inflammation and malfunction of various organ systems. In lupus, the organ systems most often involved include the skin, kidneys, blood and joints. Many different symptoms are associated with lupus, and most affected individuals do not experience all of the symptoms. In some cases, lupus may be a mild disorder affecting only a few organ systems. In other cases, it may result in serious complications. Initial symptoms may include excessive fatigue, fever, swollen glands, loss of appetite (anorexia) and weight loss, and headaches. Vascular symptoms in people with Lupus may include a permanent increase in the diameter (dilation) of very small blood vessels (capillary telangiectasis), painfully cold fingers and toes caused by spasms of small blood vessels in response to cold (Raynaud’s phenomenon), and inflammation of the blood vessels (vasculitis). There are at least three forms of lupus: the classic form, systemic lupus erythematosus; a form that only affects the skin, discoid lupus erythematosus; and drug-induced lupus erythematosus. The term lupus is most often used to denote systemic lupus erythematosus. Polyarteritis nodosa (PAN) is a rare inflammatory systemic disease of the arteries characterized by the presence of granular nodules along the length of small and medium-sized arteries and may be associated with rheumatic heart disease. The initial symptoms may include fever, chills, fatigue, and/or weight loss. People with this disorder may also experience abdominal pain, tingling sensations in the hands and feet (peripheral neuropathy), skin eruptions, joint pain, and/or generalized muscle pain. Polyarteritis nodosa may cause narrowing of the arteries that results in a lack of oxygen to various organs (ischemia), and blood clots. (For more information on this disorder, choose “Polyarteritis Nodosa” as your search term in the Rare Disease Database.)Divry van Bogaert Syndrome (DBS) is a familial juvenile-onset disorder characterized by livedo racemosa, white matter disease, dementia, epilepsy and by the typical angiographic feature of angiomatosis.Fabry disease (FD) is an X-linked lysosomal storage disease as the result of mutation in the α-galactosidase A (GLA) gene. These mutations cause a deficiency in α-galactosidase A enzyme and an accumulation of glycosphingolipid in tissue, which leads to dysfunction of many cell types including a systemic vasculopathy. As a result, patients have a markedly increased risk of developing ischemic stroke, small-fiber peripheral neuropathy, cutaneous lesions, cardiac dysfunction and chronic kidney disease. (For more information on this disorder, choose “Fabry” as your search term in the Rare Disease Database.)
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Related disorders of Sneddon Syndrome. Symptoms of the following disorders can be similar to those of Sneddon Syndrome. Comparisons may be useful for a differential diagnosis:Lupus is a chronic, inflammatory autoimmune disorder affecting the connective tissue. In autoimmune disorders, the body’s own immune system attacks healthy cells and tissues causing inflammation and malfunction of various organ systems. In lupus, the organ systems most often involved include the skin, kidneys, blood and joints. Many different symptoms are associated with lupus, and most affected individuals do not experience all of the symptoms. In some cases, lupus may be a mild disorder affecting only a few organ systems. In other cases, it may result in serious complications. Initial symptoms may include excessive fatigue, fever, swollen glands, loss of appetite (anorexia) and weight loss, and headaches. Vascular symptoms in people with Lupus may include a permanent increase in the diameter (dilation) of very small blood vessels (capillary telangiectasis), painfully cold fingers and toes caused by spasms of small blood vessels in response to cold (Raynaud’s phenomenon), and inflammation of the blood vessels (vasculitis). There are at least three forms of lupus: the classic form, systemic lupus erythematosus; a form that only affects the skin, discoid lupus erythematosus; and drug-induced lupus erythematosus. The term lupus is most often used to denote systemic lupus erythematosus. Polyarteritis nodosa (PAN) is a rare inflammatory systemic disease of the arteries characterized by the presence of granular nodules along the length of small and medium-sized arteries and may be associated with rheumatic heart disease. The initial symptoms may include fever, chills, fatigue, and/or weight loss. People with this disorder may also experience abdominal pain, tingling sensations in the hands and feet (peripheral neuropathy), skin eruptions, joint pain, and/or generalized muscle pain. Polyarteritis nodosa may cause narrowing of the arteries that results in a lack of oxygen to various organs (ischemia), and blood clots. (For more information on this disorder, choose “Polyarteritis Nodosa” as your search term in the Rare Disease Database.)Divry van Bogaert Syndrome (DBS) is a familial juvenile-onset disorder characterized by livedo racemosa, white matter disease, dementia, epilepsy and by the typical angiographic feature of angiomatosis.Fabry disease (FD) is an X-linked lysosomal storage disease as the result of mutation in the α-galactosidase A (GLA) gene. These mutations cause a deficiency in α-galactosidase A enzyme and an accumulation of glycosphingolipid in tissue, which leads to dysfunction of many cell types including a systemic vasculopathy. As a result, patients have a markedly increased risk of developing ischemic stroke, small-fiber peripheral neuropathy, cutaneous lesions, cardiac dysfunction and chronic kidney disease. (For more information on this disorder, choose “Fabry” as your search term in the Rare Disease Database.)
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Diagnosis of Sneddon Syndrome
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The diagnosis of Sneddon syndrome is usually suggested by the combination the pattern of skin discoloration called livedo reticularis and neurological symptoms, particularly unexplained stroke in young individuals. Diagnosis of cerebrovascular damage is confirmed when imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) reveal lesions (infarcts) in the brain.Surgical removal and microscopic study of tissue samples (skin biopsy) may confirm the progressive arterial disease (arteriopathy) characteristic of Sneddon syndrome demonstrating occlusion of the vessel lumina with no vasculitis. Blood tests may reveal the presence of antiphospholipid antibodies in some affected individuals.
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Diagnosis of Sneddon Syndrome. The diagnosis of Sneddon syndrome is usually suggested by the combination the pattern of skin discoloration called livedo reticularis and neurological symptoms, particularly unexplained stroke in young individuals. Diagnosis of cerebrovascular damage is confirmed when imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) reveal lesions (infarcts) in the brain.Surgical removal and microscopic study of tissue samples (skin biopsy) may confirm the progressive arterial disease (arteriopathy) characteristic of Sneddon syndrome demonstrating occlusion of the vessel lumina with no vasculitis. Blood tests may reveal the presence of antiphospholipid antibodies in some affected individuals.
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Therapies of Sneddon Syndrome
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TreatmentThere is no specific treatment for Sneddon syndrome. Treatment is symptomatic and supportive, but there are no standardized treatment protocols or guidelines. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Sneddon syndrome. Anti-aggregants such as aspirin or direct oral anticoagulants (DOAC) or vitamin K-antagonsists such as warfarin may be given to thin the blood and to prevent the formation of blood clots. Some physicians recommend that individuals with Sneddon syndrome without antiphospholipid antibodies should be treated in a less aggressive manner through antiplatelet therapy with aspirin and patients with antiphospholipid antibodies should receive DOAC or warfarin with an international normalize ratio (INR) target of 2 to 3. But even with heart valve involvement, antiplatelet therapy was not inferior in comparison to anticoagulation. And always the risk of microbleeds and intracerebral hemorrhage must be taken into account.The use of anti-inflammatory or immunosuppressive therapies is discussed controversial, but may be considered in patients with biopsy or laboratory findings indicative of an inflammation. Always the association with an autoimmune disorder like lupus must be excluded.
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Therapies of Sneddon Syndrome. TreatmentThere is no specific treatment for Sneddon syndrome. Treatment is symptomatic and supportive, but there are no standardized treatment protocols or guidelines. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Sneddon syndrome. Anti-aggregants such as aspirin or direct oral anticoagulants (DOAC) or vitamin K-antagonsists such as warfarin may be given to thin the blood and to prevent the formation of blood clots. Some physicians recommend that individuals with Sneddon syndrome without antiphospholipid antibodies should be treated in a less aggressive manner through antiplatelet therapy with aspirin and patients with antiphospholipid antibodies should receive DOAC or warfarin with an international normalize ratio (INR) target of 2 to 3. But even with heart valve involvement, antiplatelet therapy was not inferior in comparison to anticoagulation. And always the risk of microbleeds and intracerebral hemorrhage must be taken into account.The use of anti-inflammatory or immunosuppressive therapies is discussed controversial, but may be considered in patients with biopsy or laboratory findings indicative of an inflammation. Always the association with an autoimmune disorder like lupus must be excluded.
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Overview of Snyder-Robinson Syndrome
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SummarySnyder-Robinson syndrome (SRS) is a rare X-linked intellectual disability (XLID) disorder in which affected males have a slender build with long limbs, angular profile, and prominent muscles or bones (asthenic habitus), low muscle mass, some abnormal facial features (dysmorphism), speech abnormalities, outward curvature and lateral curvature of the spine (kyphoscoliosis) and decreased bone mass leading to fragile bones (osteoporosis). Seizures are also rather common. The syndrome results from an inactivating mutation in the spermine synthase (SMS) gene resulting in an inability to convert spermidine to spermine.IntroductionSnyder-Robinson syndrome was first described in a single family by Snyder and Robinson in 1969 as a non-syndromic X-linked disorder. Arena et al. (1996) re-examined the family and determined the affected males represented a novel X-linked syndrome. In 2003 Cason and colleagues determined that SRS resulted from a mutation in the SMS gene located at Xp21.3-p22.12. Since then, utilization of biochemical analysis (lack of SMS activity, altered spermidine/spermine ratio) to validate SMS mutations has allowed the identification of an additional 21families (most not published) with SRS.
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Overview of Snyder-Robinson Syndrome. SummarySnyder-Robinson syndrome (SRS) is a rare X-linked intellectual disability (XLID) disorder in which affected males have a slender build with long limbs, angular profile, and prominent muscles or bones (asthenic habitus), low muscle mass, some abnormal facial features (dysmorphism), speech abnormalities, outward curvature and lateral curvature of the spine (kyphoscoliosis) and decreased bone mass leading to fragile bones (osteoporosis). Seizures are also rather common. The syndrome results from an inactivating mutation in the spermine synthase (SMS) gene resulting in an inability to convert spermidine to spermine.IntroductionSnyder-Robinson syndrome was first described in a single family by Snyder and Robinson in 1969 as a non-syndromic X-linked disorder. Arena et al. (1996) re-examined the family and determined the affected males represented a novel X-linked syndrome. In 2003 Cason and colleagues determined that SRS resulted from a mutation in the SMS gene located at Xp21.3-p22.12. Since then, utilization of biochemical analysis (lack of SMS activity, altered spermidine/spermine ratio) to validate SMS mutations has allowed the identification of an additional 21families (most not published) with SRS.
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Symptoms of Snyder-Robinson Syndrome
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The symptoms, progression and severity of SRS exhibit some variability across families and individual patients. Affected children have a “gestalt” consisting of facial dysmorphism with a prominent lower lip, an asthenic build, low muscle mass, kyphoscohosis and speech abnormalities. Males with SRS have low muscle tone (hypotonia) at birth. Symptoms appear early, especially the facial features. Developmental milestones are also not met early in life. The developmental delay progresses such that many boys with SRS have some motor disability. Osteoporosis develops which can result in numerous fractures without a causative event. Seizures have been noted in many affected males and severity varies.
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Symptoms of Snyder-Robinson Syndrome. The symptoms, progression and severity of SRS exhibit some variability across families and individual patients. Affected children have a “gestalt” consisting of facial dysmorphism with a prominent lower lip, an asthenic build, low muscle mass, kyphoscohosis and speech abnormalities. Males with SRS have low muscle tone (hypotonia) at birth. Symptoms appear early, especially the facial features. Developmental milestones are also not met early in life. The developmental delay progresses such that many boys with SRS have some motor disability. Osteoporosis develops which can result in numerous fractures without a causative event. Seizures have been noted in many affected males and severity varies.
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Causes of Snyder-Robinson Syndrome
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All presently known cases of Snyder-Robinson syndrome are caused by changes (mutations) in the SMS gene. Thus far, 21 mutations are known although not all have been published. Since the gene resides on the X chromosome only males are affected. If the mother of a male with SRS carries the mutation, there is a 50% chance another son will have SRS and a daughter will be a carrier. The rate of new mutations appears to be low as only a single case exists in which the mother of the boy with SRS was not a carrier.
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Causes of Snyder-Robinson Syndrome. All presently known cases of Snyder-Robinson syndrome are caused by changes (mutations) in the SMS gene. Thus far, 21 mutations are known although not all have been published. Since the gene resides on the X chromosome only males are affected. If the mother of a male with SRS carries the mutation, there is a 50% chance another son will have SRS and a daughter will be a carrier. The rate of new mutations appears to be low as only a single case exists in which the mother of the boy with SRS was not a carrier.
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Affects of Snyder-Robinson Syndrome
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Snyder-Robinson syndrome is a rare X-linked intellectual disability disorder and as such it is difficult to estimate its prevalence. As SRS has been identified in patients located in the United States, South America and Europe, it is likely not restricted to any ethnic population geographical locale.
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Affects of Snyder-Robinson Syndrome. Snyder-Robinson syndrome is a rare X-linked intellectual disability disorder and as such it is difficult to estimate its prevalence. As SRS has been identified in patients located in the United States, South America and Europe, it is likely not restricted to any ethnic population geographical locale.
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Related disorders of Snyder-Robinson Syndrome
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Many XLID disorders present with hypotonia very early in life. However, SRS is the only human disorder related to an abnormality in polyamine biosynthesis.
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Related disorders of Snyder-Robinson Syndrome. Many XLID disorders present with hypotonia very early in life. However, SRS is the only human disorder related to an abnormality in polyamine biosynthesis.
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Diagnosis of Snyder-Robinson Syndrome
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A diagnosis of Snyder-Robinson syndrome can be made based on the clinical presentation and confirmed by sequencing of the SMS gene. However, since SRS is a rare XLID condition, more likely the diagnosis is made after whole exome sequencing (WES) identifies a mutation in the SMS gene. Additionally, since at present only one mutation in SMS has appeared more than once, biochemical studies (SMS activity and cellular spermidine/spermine ratios) should be conducted to absolutely insure a proper diagnosis of SRS.
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Diagnosis of Snyder-Robinson Syndrome. A diagnosis of Snyder-Robinson syndrome can be made based on the clinical presentation and confirmed by sequencing of the SMS gene. However, since SRS is a rare XLID condition, more likely the diagnosis is made after whole exome sequencing (WES) identifies a mutation in the SMS gene. Additionally, since at present only one mutation in SMS has appeared more than once, biochemical studies (SMS activity and cellular spermidine/spermine ratios) should be conducted to absolutely insure a proper diagnosis of SRS.
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Therapies of Snyder-Robinson Syndrome
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TreatmentThere is no treatment which effectively treats Snyder-Robinson syndrome. Initially, as SRS results from a lack of spermine being produced by cells within the body, it was thought spermine supplementation might treat the disorder. However, this approach has proved to be unsuccessful. Thus, treatment is directed towards alleviating some of the symptoms of SRS. Speech, physical, occupational therapies have been helpful but results have varied. Calcium supplementation to improve bone mineral density has been tried to counteract osteoporosis. Again, results have varied. Nonetheless, because of the osteoporosis and an increased risk for fractures, patients with SRS should be monitored regularly and calcium supplementation should be initiated once decreased bone mineral density is observed. Treatment of seizures can be attempted with various drugs. However, success with any one drug has been variable and some seizures have been refractory to treatment.
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Therapies of Snyder-Robinson Syndrome. TreatmentThere is no treatment which effectively treats Snyder-Robinson syndrome. Initially, as SRS results from a lack of spermine being produced by cells within the body, it was thought spermine supplementation might treat the disorder. However, this approach has proved to be unsuccessful. Thus, treatment is directed towards alleviating some of the symptoms of SRS. Speech, physical, occupational therapies have been helpful but results have varied. Calcium supplementation to improve bone mineral density has been tried to counteract osteoporosis. Again, results have varied. Nonetheless, because of the osteoporosis and an increased risk for fractures, patients with SRS should be monitored regularly and calcium supplementation should be initiated once decreased bone mineral density is observed. Treatment of seizures can be attempted with various drugs. However, success with any one drug has been variable and some seizures have been refractory to treatment.
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Overview of Soft Tissue Sarcoma
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Summary
Sarcomas are malignant (cancerous) tumors that arise from cells that make up the connective tissues, which are the tissues that connect, support and surround structures and organs in the body. They can be broadly broken down into bone, visceral and soft tissue forms. Soft tissues are tissues of the body that have not hardened or calcified like bone has. Soft tissues are found all over the body and include muscles, tendons, ligaments, nerves, fat, blood vessels and lymph vessels. Soft tissue sarcomas can arise from fat, muscle, nerve, tendons and blood and lymph vessel tissue. For some sarcomas the tissue of origin is uncertain such as pleiomorphic undifferentiated sarcoma. Synovial sarcoma is a misnomer as it does not arise from synovial tissue (as was originally thought). Sarcomas can occur almost anywhere in the body, but the most common areas are the arms and legs, the back of the abdomen (retroperitoneum) and head and neck. They can affect adults or children. These tumors are diverse with significantly different signs and symptoms, progression and often different treatment regimens. The exact, underlying cause of these tumors is not fully understood. Most likely, complex genetic and environmental factors play a role in their development. As researchers learn more about the genetic factors associated with these disorders, newer, targeted therapies may become available. Sarcomas are rate tumors that account for approximately 1% of tumors in humans.Introduction
Soft tissue sarcomas are a form of cancer. Cancer is characterized by abnormal, uncontrolled growth of cells that invades surrounding tissue and can sometimes spread (metastasize) to distant areas of the body via the bloodstream, the lymphatic system or other means. Different forms of cancer, including soft tissue sarcomas, may be classified based upon the cell type involved, the specific nature of the malignancy and the clinical course of the disease. According to the World Health Organization classification, there are more than 100 different histologic subtypes of soft tissue sarcomas.This report is a general overview of soft tissue sarcomas as a group. NORD has individual reports on several types of soft tissue sarcoma, including alveolar soft part sarcoma; desmoid tumors; extraosseous Ewing sarcoma; gastrointestinal stromal tumors (GIST); leiomyosarcoma; leiomyosarcoma of the inferior vena cava; liposarcoma; mesenchymal chondrosarcoma; pleuropulmonary blastoma; tenosynovial giant cell tumors and uterine leiomyosarcoma. These forms of soft tissue sarcoma are not discussed in this report. Individual reports go into greater detail concerning the signs and symptoms and treatment options for these rare cancers. (For more information, choose the specific name as the search term for the Rare Disease Database.)
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Overview of Soft Tissue Sarcoma. Summary
Sarcomas are malignant (cancerous) tumors that arise from cells that make up the connective tissues, which are the tissues that connect, support and surround structures and organs in the body. They can be broadly broken down into bone, visceral and soft tissue forms. Soft tissues are tissues of the body that have not hardened or calcified like bone has. Soft tissues are found all over the body and include muscles, tendons, ligaments, nerves, fat, blood vessels and lymph vessels. Soft tissue sarcomas can arise from fat, muscle, nerve, tendons and blood and lymph vessel tissue. For some sarcomas the tissue of origin is uncertain such as pleiomorphic undifferentiated sarcoma. Synovial sarcoma is a misnomer as it does not arise from synovial tissue (as was originally thought). Sarcomas can occur almost anywhere in the body, but the most common areas are the arms and legs, the back of the abdomen (retroperitoneum) and head and neck. They can affect adults or children. These tumors are diverse with significantly different signs and symptoms, progression and often different treatment regimens. The exact, underlying cause of these tumors is not fully understood. Most likely, complex genetic and environmental factors play a role in their development. As researchers learn more about the genetic factors associated with these disorders, newer, targeted therapies may become available. Sarcomas are rate tumors that account for approximately 1% of tumors in humans.Introduction
Soft tissue sarcomas are a form of cancer. Cancer is characterized by abnormal, uncontrolled growth of cells that invades surrounding tissue and can sometimes spread (metastasize) to distant areas of the body via the bloodstream, the lymphatic system or other means. Different forms of cancer, including soft tissue sarcomas, may be classified based upon the cell type involved, the specific nature of the malignancy and the clinical course of the disease. According to the World Health Organization classification, there are more than 100 different histologic subtypes of soft tissue sarcomas.This report is a general overview of soft tissue sarcomas as a group. NORD has individual reports on several types of soft tissue sarcoma, including alveolar soft part sarcoma; desmoid tumors; extraosseous Ewing sarcoma; gastrointestinal stromal tumors (GIST); leiomyosarcoma; leiomyosarcoma of the inferior vena cava; liposarcoma; mesenchymal chondrosarcoma; pleuropulmonary blastoma; tenosynovial giant cell tumors and uterine leiomyosarcoma. These forms of soft tissue sarcoma are not discussed in this report. Individual reports go into greater detail concerning the signs and symptoms and treatment options for these rare cancers. (For more information, choose the specific name as the search term for the Rare Disease Database.)
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Symptoms of Soft Tissue Sarcoma
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The signs and symptoms of soft tissue sarcomas can vary greatly from one person to another. Specific findings depend on numerous factors including the specific subtype, the exact location of the tumor, the extent of the tumor into nearby tissue or organs, the specific organs involved and whether the disease has remained localized or spread to other areas of the body (metastasized).Often, soft tissue sarcomas will not be associated with any noticeable symptoms early in the course of the disease. At some point, affected individuals may notice a slow-growing, painless mass in the affected area. Tumors can become very large and cause pain or symptoms related to pressing against (compression of) nearby organs, nerves or structures in the body. Large tumors in the arms or legs can lead to a sensation of numbness, burning or tingling in the hands or feet (paresthesia). Tumors in the stomach or abdomen can cause abdominal pain or blood in the stool. Swelling (edema) can occur in areas where tumors push up against lymph vessels. Tumors near the skin can damage the skin, causing open sores (ulceration).Sometimes, soft tissue sarcomas can cause nonspecific symptoms. These are symptoms that are common to many different disorders and conditions. These symptoms include nausea, vomiting, loss of appetite, unintended weight loss, unexplained fatigue and a general feeling of poor health (malaise).SUBTYPES
According to the World Health Organization, there are more than 100 histologic subtypes of soft tissue sarcoma. Several of the better-known subtypes are briefly discussed below.Angiosarcoma
This form of cancer starts in cells that make up the walls of blood vessels. When it affects lymphatic tissue, it is called a lymphangiosarcoma. The lymphatic system is part of the immune system and helps to protect the body against infection and disease. It consists of tubular channels (lymph vessels) that drain a watery fluid known as lymph from different areas of the body into the bloodstream.Angiosarcoma can occur in almost any area of the body and is often aggressive with spread to other areas. The skin of the head and neck is a commonly affected site. Angiosarcoma of soft tissue can present in the lower extremities, the space behind the abdominal cavity (retroperitoneum) or the soft tissue of the chest (mediastinum). Angiosarcoma of the breast can present as either a mass within the breast or as a cutaneous angiosarcoma seen as a rare late effect of radiation for breast cancer.In most instances, there are no obvious symptoms early in their development. Angiosarcoma are prone to bleeding (hemorrhaging). When angiosarcoma affects the skin, there may be reddish or purplish discoloration that looks like a bruise. A lesion may form that is prone to bleeding and swelling. When angiosarcoma affects an organ, symptoms depend upon the exact size and location of the tumor. Prior radiation exposure may play a role in the development of secondary angiosarcoma. Recent investigations have demonstrated differing genetic patterns between primary and secondary angiosarcoma.A rare form of angiosarcoma, called lymphangiosarcoma or Stewart-Treves syndrome, develops in people with long-standing primary or secondary lymphedema.Angiosarcoma may also present as a primary tumor in bone.Clear cell sarcoma
This form accounts for less than 1% of all soft tissue sarcomas. These tumors arise in tendons, the tough, flexible tissue that attaches muscle to bone. They usually develop in the arms and legs, specifically the foot and ankle region. They usually develop as a slow-growing lump or mass that may or may not be tender or painful. Eventually, the tumor spreads to nearby tissue. They are most common in young adults. Under a microscope, the cells of these tumors resemble those of a skin cancer called melanoma, and sometimes distinguishing these two cancers can be difficult.Dermatofibrosarcoma protuberans
This form of soft tissue sarcoma arises in the inner layer of skin called the dermis. They may present as a slow-growing bump (nodule) or as a spot of hardened skin or a deep-seated pimple. They may involve nearby tissue, but usually do not spread to other areas of the body. These tumors may recur after surgery. The risk of distant spread is increased when these tumors undergo fibrosarcomatous transformation.Desmoplastic small round cell tumor
This is an extremely rare form of soft tissue sarcoma that usually arises in the abdomen or pelvis, although it can develop elsewhere in the body. It is aggressive and often spreads to other areas of the body, particularly the lungs or liver. These tumors can cause pain and a mass can usually be felt in the abdomen. This form most commonly affects Caucasian men between 10 and 30 years of age but can also affect young women and young children. These tumors can recur after treatment.Epithelioid sarcoma
This form usually develops in the soft tissue just underneath the skin, most often in the fingers, hand, forearms and lower legs or feet. These tumors can potentially form almost anywhere in the body. They often begin as a small growth or bump and are usually painless. Sometimes, there are open sores on the skin above the tumor that may be mistaken for areas of infection. Eventually, multiple growths or bumps may develop. Epithelioid sarcoma can move into nearby tissue and spread to other areas of the body. This type of sarcoma tends to spread to lymph nodes. It often recurs after treatment.Malignant peripheral nerve sheath tumors
These tumors arise in the protective lining that covers the nerves of the peripheral nervous system. These are the nerves outside of the brain and spinal cord. They appear as a lump or mass and can develop throughout the body. They can cause pain, weakness or difficulty moving the affected body part. When they press up against (compress) nerves, they can cause a sensation of burning, tingling or numbness in certain areas. They tend to recur after treatment. They may be associated with a rare genetic disorder called neurofibromatosis type 1 but can also occur without a genetic predisposition.Myxofibrosarcoma
This form of soft tissue sarcoma is usually found most often in the arms or legs. It begins as a slow-growing bump or bumps and can move into nearby tissue or spread to other areas of the body. They are usually painless. These tumors often recur after treatment. They usually develop in people over the age of 50 and occur slightly more often in men than women. It is one of the most common forms of sarcoma found in adult patients.Rhabdomyosarcoma
One of the most common types of soft tissue sarcoma, these tumors usually develop from cells which have features related to striated muscle cells. Striated muscle tissue is the muscle that is attached to the skeleton by tendons and is part of the voluntary muscle system. These are the muscles that are controlled by a person’s conscious thought as opposed to muscles that act involuntarily like the heart or muscles found within organs like the bladder or intestines.Rhabdomyosarcomas arise from cells within the developing fetus called rhabdomyoblasts. These are immature cells that grow into the cells that help to form skeletal and striated muscle. These tumors can develop anywhere in the body, even areas of the body where there isn’t skeletal muscle tissue. The head and neck area, the urinary system including the bladder, the arms and legs, and the reproductive system including the vagina, uterus and testes are common sites of rhabdomyosarcoma development. The signs and symptoms depend on where the tumor is located.Rhabdomyosarcomas are the most common form of soft tissue sarcoma in children. They are far more common in children but can sometimes occur in adults. Adults tend to have a faster growing form of the disorder.Solitary fibrous tumor
These are individual, slow-growing tumors. Although they can develop almost anywhere in the body, they most often arise in the lining of the lungs (pleura), pelvis or the dura, which is the thick, outer layer of the three membranes (meninges) that cover and protect the brain and spinal cord. These tumors tend to grow very slowly and do not cause any symptoms until they are very large. Most are noncancerous (benign), but malignant (cancerous) tumors can develop. Despite their name, these tumors can be multifocal. The behavior of these tumors can vary with some tumors having a favorable course and some capable of local recurrence or metastasis.Synovial sarcoma
This form of soft tissue sarcoma usually develops in the arms or legs, often near a joint but rarely, if ever, within a joint. It can also develop in the trunk or abdomen. They usually present as a small growth or lump and are sometimes associated with pain. Eventually, a synovial sarcoma can cause limitation in the movement of the nearby joint. Doctors do not know what type of cell causes synovial sarcoma. They are called synovial sarcomas because the cells of the tumor were felt to resemble cells of the synovium, which is a layer of connective tissue that lines joints. They most often occur in young adults. These tumors sometimes recur after treatment and are capable of metastasis.Tenosynovial giant cell tumor is a tumor that arises from the lining of joints or the tendon sheath that covers a tendon. It can be locally aggressive and recur after surgical resection. If it recurs it can be the source of significant morbidity with pain and loss of function of the affected area.Undifferentiated pleomorphic sarcoma
This is an aggressive form of soft tissue sarcoma that can develop in soft tissue or bone in any part of the body. These tumors tend to affect older adults in their 50s or older. They most often develop in the lower legs (especially the thighs), the upper arms, behind the membrane that lines the abdomen and covers the abdominal organs (retroperitoneum) and the main organs of the body, especially those of the abdomen (viscera). In childhood, they most often form in the head or neck. They usually grow quickly and often spread to other areas of the body, especially the lungs. They often cause pain or swelling in the affected area. They can recur after treatment. This form of soft tissue sarcoma was once referred to as malignant fibrous histiocytoma.
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Symptoms of Soft Tissue Sarcoma. The signs and symptoms of soft tissue sarcomas can vary greatly from one person to another. Specific findings depend on numerous factors including the specific subtype, the exact location of the tumor, the extent of the tumor into nearby tissue or organs, the specific organs involved and whether the disease has remained localized or spread to other areas of the body (metastasized).Often, soft tissue sarcomas will not be associated with any noticeable symptoms early in the course of the disease. At some point, affected individuals may notice a slow-growing, painless mass in the affected area. Tumors can become very large and cause pain or symptoms related to pressing against (compression of) nearby organs, nerves or structures in the body. Large tumors in the arms or legs can lead to a sensation of numbness, burning or tingling in the hands or feet (paresthesia). Tumors in the stomach or abdomen can cause abdominal pain or blood in the stool. Swelling (edema) can occur in areas where tumors push up against lymph vessels. Tumors near the skin can damage the skin, causing open sores (ulceration).Sometimes, soft tissue sarcomas can cause nonspecific symptoms. These are symptoms that are common to many different disorders and conditions. These symptoms include nausea, vomiting, loss of appetite, unintended weight loss, unexplained fatigue and a general feeling of poor health (malaise).SUBTYPES
According to the World Health Organization, there are more than 100 histologic subtypes of soft tissue sarcoma. Several of the better-known subtypes are briefly discussed below.Angiosarcoma
This form of cancer starts in cells that make up the walls of blood vessels. When it affects lymphatic tissue, it is called a lymphangiosarcoma. The lymphatic system is part of the immune system and helps to protect the body against infection and disease. It consists of tubular channels (lymph vessels) that drain a watery fluid known as lymph from different areas of the body into the bloodstream.Angiosarcoma can occur in almost any area of the body and is often aggressive with spread to other areas. The skin of the head and neck is a commonly affected site. Angiosarcoma of soft tissue can present in the lower extremities, the space behind the abdominal cavity (retroperitoneum) or the soft tissue of the chest (mediastinum). Angiosarcoma of the breast can present as either a mass within the breast or as a cutaneous angiosarcoma seen as a rare late effect of radiation for breast cancer.In most instances, there are no obvious symptoms early in their development. Angiosarcoma are prone to bleeding (hemorrhaging). When angiosarcoma affects the skin, there may be reddish or purplish discoloration that looks like a bruise. A lesion may form that is prone to bleeding and swelling. When angiosarcoma affects an organ, symptoms depend upon the exact size and location of the tumor. Prior radiation exposure may play a role in the development of secondary angiosarcoma. Recent investigations have demonstrated differing genetic patterns between primary and secondary angiosarcoma.A rare form of angiosarcoma, called lymphangiosarcoma or Stewart-Treves syndrome, develops in people with long-standing primary or secondary lymphedema.Angiosarcoma may also present as a primary tumor in bone.Clear cell sarcoma
This form accounts for less than 1% of all soft tissue sarcomas. These tumors arise in tendons, the tough, flexible tissue that attaches muscle to bone. They usually develop in the arms and legs, specifically the foot and ankle region. They usually develop as a slow-growing lump or mass that may or may not be tender or painful. Eventually, the tumor spreads to nearby tissue. They are most common in young adults. Under a microscope, the cells of these tumors resemble those of a skin cancer called melanoma, and sometimes distinguishing these two cancers can be difficult.Dermatofibrosarcoma protuberans
This form of soft tissue sarcoma arises in the inner layer of skin called the dermis. They may present as a slow-growing bump (nodule) or as a spot of hardened skin or a deep-seated pimple. They may involve nearby tissue, but usually do not spread to other areas of the body. These tumors may recur after surgery. The risk of distant spread is increased when these tumors undergo fibrosarcomatous transformation.Desmoplastic small round cell tumor
This is an extremely rare form of soft tissue sarcoma that usually arises in the abdomen or pelvis, although it can develop elsewhere in the body. It is aggressive and often spreads to other areas of the body, particularly the lungs or liver. These tumors can cause pain and a mass can usually be felt in the abdomen. This form most commonly affects Caucasian men between 10 and 30 years of age but can also affect young women and young children. These tumors can recur after treatment.Epithelioid sarcoma
This form usually develops in the soft tissue just underneath the skin, most often in the fingers, hand, forearms and lower legs or feet. These tumors can potentially form almost anywhere in the body. They often begin as a small growth or bump and are usually painless. Sometimes, there are open sores on the skin above the tumor that may be mistaken for areas of infection. Eventually, multiple growths or bumps may develop. Epithelioid sarcoma can move into nearby tissue and spread to other areas of the body. This type of sarcoma tends to spread to lymph nodes. It often recurs after treatment.Malignant peripheral nerve sheath tumors
These tumors arise in the protective lining that covers the nerves of the peripheral nervous system. These are the nerves outside of the brain and spinal cord. They appear as a lump or mass and can develop throughout the body. They can cause pain, weakness or difficulty moving the affected body part. When they press up against (compress) nerves, they can cause a sensation of burning, tingling or numbness in certain areas. They tend to recur after treatment. They may be associated with a rare genetic disorder called neurofibromatosis type 1 but can also occur without a genetic predisposition.Myxofibrosarcoma
This form of soft tissue sarcoma is usually found most often in the arms or legs. It begins as a slow-growing bump or bumps and can move into nearby tissue or spread to other areas of the body. They are usually painless. These tumors often recur after treatment. They usually develop in people over the age of 50 and occur slightly more often in men than women. It is one of the most common forms of sarcoma found in adult patients.Rhabdomyosarcoma
One of the most common types of soft tissue sarcoma, these tumors usually develop from cells which have features related to striated muscle cells. Striated muscle tissue is the muscle that is attached to the skeleton by tendons and is part of the voluntary muscle system. These are the muscles that are controlled by a person’s conscious thought as opposed to muscles that act involuntarily like the heart or muscles found within organs like the bladder or intestines.Rhabdomyosarcomas arise from cells within the developing fetus called rhabdomyoblasts. These are immature cells that grow into the cells that help to form skeletal and striated muscle. These tumors can develop anywhere in the body, even areas of the body where there isn’t skeletal muscle tissue. The head and neck area, the urinary system including the bladder, the arms and legs, and the reproductive system including the vagina, uterus and testes are common sites of rhabdomyosarcoma development. The signs and symptoms depend on where the tumor is located.Rhabdomyosarcomas are the most common form of soft tissue sarcoma in children. They are far more common in children but can sometimes occur in adults. Adults tend to have a faster growing form of the disorder.Solitary fibrous tumor
These are individual, slow-growing tumors. Although they can develop almost anywhere in the body, they most often arise in the lining of the lungs (pleura), pelvis or the dura, which is the thick, outer layer of the three membranes (meninges) that cover and protect the brain and spinal cord. These tumors tend to grow very slowly and do not cause any symptoms until they are very large. Most are noncancerous (benign), but malignant (cancerous) tumors can develop. Despite their name, these tumors can be multifocal. The behavior of these tumors can vary with some tumors having a favorable course and some capable of local recurrence or metastasis.Synovial sarcoma
This form of soft tissue sarcoma usually develops in the arms or legs, often near a joint but rarely, if ever, within a joint. It can also develop in the trunk or abdomen. They usually present as a small growth or lump and are sometimes associated with pain. Eventually, a synovial sarcoma can cause limitation in the movement of the nearby joint. Doctors do not know what type of cell causes synovial sarcoma. They are called synovial sarcomas because the cells of the tumor were felt to resemble cells of the synovium, which is a layer of connective tissue that lines joints. They most often occur in young adults. These tumors sometimes recur after treatment and are capable of metastasis.Tenosynovial giant cell tumor is a tumor that arises from the lining of joints or the tendon sheath that covers a tendon. It can be locally aggressive and recur after surgical resection. If it recurs it can be the source of significant morbidity with pain and loss of function of the affected area.Undifferentiated pleomorphic sarcoma
This is an aggressive form of soft tissue sarcoma that can develop in soft tissue or bone in any part of the body. These tumors tend to affect older adults in their 50s or older. They most often develop in the lower legs (especially the thighs), the upper arms, behind the membrane that lines the abdomen and covers the abdominal organs (retroperitoneum) and the main organs of the body, especially those of the abdomen (viscera). In childhood, they most often form in the head or neck. They usually grow quickly and often spread to other areas of the body, especially the lungs. They often cause pain or swelling in the affected area. They can recur after treatment. This form of soft tissue sarcoma was once referred to as malignant fibrous histiocytoma.
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Causes of Soft Tissue Sarcoma
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As with many forms of cancer, the exact, underlying cause of soft tissue sarcoma is not fully understood. In most affected individuals, this cancer is thought to occur randomly, for no specific reason (sporadically). Sporadic occurrence of cancer is thought to occur because of multiple factors acting together. This can include genetic and environmental factors. Current research suggests that abnormalities in DNA, which is the carrier of the body’s genetic code, are the underlying basis that causes cells to become cancerous (malignant). The specific cell that becomes cancerous differs depending upon the specific subtype of soft tissue sarcoma. In most instances, these changes in DNA are acquired during life and are not inherited, nor do soft tissue sarcomas tend to run in families, unless affected individuals also have a genetic cancer-predisposition syndrome.Changes (variations) in certain genes have been noted to occur in greater frequency in individuals with soft tissue sarcoma than in people without this form of cancer. Many soft tissue sarcomas are associated with reciprocal translocations. Reciprocal translocations occur when regions of chromosomes break off and “trade places.” This results in the shifting of genetic material and an altered set of chromosomes. These translocations can involve oncogenes. Genes normally produce (encode) proteins that have several functions in the body. Oncogenes control cell growth. Reciprocal translocations can sometimes result in the abnormal fusion of two genes. This abnormal fusion results in a “fusion” gene that produces an abnormal protein product. Researchers believe that this abnormal protein product may contribute to the growth and spread of cancer in such instances.Some forms of soft tissue sarcoma are associated with a variation (mutation) in a single oncogene, which is believed to drive the growth of cancer. An altered (mutation) oncogene may produce a protein that is ineffective, overproduced, or underproduced. Usually, oncogenes are activated or “turned on” when they are not supposed to allow for the growth and replication of cells. Some oncogenes function as tumor suppressor genes and their loss or inactivation allows for the growth of tumors.Some forms of soft tissue sarcomas have a complex karyotype. Karyotype refers to the number and appearance of chromosomes in a person. Chromosomes, which are present in the nucleus of human cells, carry genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. A complex karyotype means that there are a few to several variations to the chromosome makeup (e.g., translocations, etc.).Some sarcomas have neither chromosomal translocations nor complex karyotypes. Rather they have amplification of a gene such as MDM2 in dedifferentiated liposarcoma, deletions of genes or loss of gene function such as INI1 in epithelioid sarcoma.The underlying genetic factors associated with soft tissue sarcoma are very complex and more research is necessary for doctors to figure out all of the genetic interactions that contribute to the development of these tumors. Although the causes and genetic aspects of soft tissue sarcomas are not fully understood, several risk factors have been identified. Risk factors are anything that increases a person’s risk of developing a disease. Having a risk factor does not mean a person will definitely develop that disease, and people who do not have any risk factors can still develop the disease.Environmental factors that have been associated with soft tissue sarcomas include radiation therapy (often to treat a different form of cancer) and exposure to certain chemicals including vinyl chloride, arsenic and thorium dioxide. In certain forms, damage to the lymphatic system, specifically long-standing lymphedema (swelling of the lymph vessels because of the abnormal accumulation of fluid), is a risk factor.Soft tissue sarcomas occur with greater frequency in people or families that have rare genetic cancer-predisposing syndromes such as hereditary retinoblastoma, Li-Fraumeni syndrome, neurofibromatosis type I, familial adenomatous polyposis (FAP), tuberous sclerosis, nevoid basal cell carcinoma syndrome (Gorlin syndrome) or Werner syndrome. These disorders are associated with specific genes that are shown to increase the risk of specific forms of cancer. These disorders can be inherited. People who have these disorders are more likely to develop soft tissue sarcoma than the general population. Recent data has suggested genetics may play a greater role in the risk of developing sarcoma than previously felt.
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Causes of Soft Tissue Sarcoma. As with many forms of cancer, the exact, underlying cause of soft tissue sarcoma is not fully understood. In most affected individuals, this cancer is thought to occur randomly, for no specific reason (sporadically). Sporadic occurrence of cancer is thought to occur because of multiple factors acting together. This can include genetic and environmental factors. Current research suggests that abnormalities in DNA, which is the carrier of the body’s genetic code, are the underlying basis that causes cells to become cancerous (malignant). The specific cell that becomes cancerous differs depending upon the specific subtype of soft tissue sarcoma. In most instances, these changes in DNA are acquired during life and are not inherited, nor do soft tissue sarcomas tend to run in families, unless affected individuals also have a genetic cancer-predisposition syndrome.Changes (variations) in certain genes have been noted to occur in greater frequency in individuals with soft tissue sarcoma than in people without this form of cancer. Many soft tissue sarcomas are associated with reciprocal translocations. Reciprocal translocations occur when regions of chromosomes break off and “trade places.” This results in the shifting of genetic material and an altered set of chromosomes. These translocations can involve oncogenes. Genes normally produce (encode) proteins that have several functions in the body. Oncogenes control cell growth. Reciprocal translocations can sometimes result in the abnormal fusion of two genes. This abnormal fusion results in a “fusion” gene that produces an abnormal protein product. Researchers believe that this abnormal protein product may contribute to the growth and spread of cancer in such instances.Some forms of soft tissue sarcoma are associated with a variation (mutation) in a single oncogene, which is believed to drive the growth of cancer. An altered (mutation) oncogene may produce a protein that is ineffective, overproduced, or underproduced. Usually, oncogenes are activated or “turned on” when they are not supposed to allow for the growth and replication of cells. Some oncogenes function as tumor suppressor genes and their loss or inactivation allows for the growth of tumors.Some forms of soft tissue sarcomas have a complex karyotype. Karyotype refers to the number and appearance of chromosomes in a person. Chromosomes, which are present in the nucleus of human cells, carry genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. A complex karyotype means that there are a few to several variations to the chromosome makeup (e.g., translocations, etc.).Some sarcomas have neither chromosomal translocations nor complex karyotypes. Rather they have amplification of a gene such as MDM2 in dedifferentiated liposarcoma, deletions of genes or loss of gene function such as INI1 in epithelioid sarcoma.The underlying genetic factors associated with soft tissue sarcoma are very complex and more research is necessary for doctors to figure out all of the genetic interactions that contribute to the development of these tumors. Although the causes and genetic aspects of soft tissue sarcomas are not fully understood, several risk factors have been identified. Risk factors are anything that increases a person’s risk of developing a disease. Having a risk factor does not mean a person will definitely develop that disease, and people who do not have any risk factors can still develop the disease.Environmental factors that have been associated with soft tissue sarcomas include radiation therapy (often to treat a different form of cancer) and exposure to certain chemicals including vinyl chloride, arsenic and thorium dioxide. In certain forms, damage to the lymphatic system, specifically long-standing lymphedema (swelling of the lymph vessels because of the abnormal accumulation of fluid), is a risk factor.Soft tissue sarcomas occur with greater frequency in people or families that have rare genetic cancer-predisposing syndromes such as hereditary retinoblastoma, Li-Fraumeni syndrome, neurofibromatosis type I, familial adenomatous polyposis (FAP), tuberous sclerosis, nevoid basal cell carcinoma syndrome (Gorlin syndrome) or Werner syndrome. These disorders are associated with specific genes that are shown to increase the risk of specific forms of cancer. These disorders can be inherited. People who have these disorders are more likely to develop soft tissue sarcoma than the general population. Recent data has suggested genetics may play a greater role in the risk of developing sarcoma than previously felt.
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Affects of Soft Tissue Sarcoma
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Soft tissue sarcomas affect males and females and individuals of any age and every racial and ethnic group. This is a large group of tumors, but overall, they are still classified as rare disorders. Estimates of their frequency varies. The American Cancer Society estimates that soft tissue sarcomas account for about 2% of all cancers in the United States. However, because rare diseases often go misdiagnosed or undiagnosed, determining their true frequency in the general population is difficult.
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Affects of Soft Tissue Sarcoma. Soft tissue sarcomas affect males and females and individuals of any age and every racial and ethnic group. This is a large group of tumors, but overall, they are still classified as rare disorders. Estimates of their frequency varies. The American Cancer Society estimates that soft tissue sarcomas account for about 2% of all cancers in the United States. However, because rare diseases often go misdiagnosed or undiagnosed, determining their true frequency in the general population is difficult.
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Related disorders of Soft Tissue Sarcoma
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Symptoms of the following disorders can be similar to those of soft tissue sarcomas. Comparisons may be useful for a differential diagnosis.Benign (noncancerous) tumors of the soft tissue must be differentiated from soft tissue sarcomas. These include benign fatty tumors called lipomas, benign tumors that are made up of blood vessels (hemangiomas), benign tumors of the lymph vessels (lymphangiomas), benign tumors of skeletal and heart muscle (rhabdomyomas), benign tumors of the joint tissue (tenosynovial giant cell tumor) and benign tumors of smooth muscle (leiomyomas). Smooth muscles are the muscles that respond without conscious thought like the muscle that lines the walls of the digestive tract.
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Related disorders of Soft Tissue Sarcoma. Symptoms of the following disorders can be similar to those of soft tissue sarcomas. Comparisons may be useful for a differential diagnosis.Benign (noncancerous) tumors of the soft tissue must be differentiated from soft tissue sarcomas. These include benign fatty tumors called lipomas, benign tumors that are made up of blood vessels (hemangiomas), benign tumors of the lymph vessels (lymphangiomas), benign tumors of skeletal and heart muscle (rhabdomyomas), benign tumors of the joint tissue (tenosynovial giant cell tumor) and benign tumors of smooth muscle (leiomyomas). Smooth muscles are the muscles that respond without conscious thought like the muscle that lines the walls of the digestive tract.
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Diagnosis of Soft Tissue Sarcoma
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A diagnosis of soft tissue sarcoma is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A physical examination can reveal a mass or growth that can be painless.Clinical Testing and Workup
A biopsy is the only way to definitively tell if a mass or tumor is a sarcoma. A biopsy is a test where a piece of tissue is taken from the tumor and examined under a microscope. This allows a special doctor called a pathologist to see the specific cells and characteristics of the tissue sample. Doctors can then distinguish a soft tissue sarcoma from other types of benign and cancerous tumors as well as determine the specific subtype of soft tissue sarcoma that is present. Additional testing of the tumor may involve specialized pathology techniques such as immunohistochemistry. Some tumors will be tested for specific genetic characteristics by either fluorescent in-situ hybridization (FISH) analysis or next generation sequencing.Many doctors and medical centers recommend a core needle biopsy. A core needle biopsy is generally considered to be more accurate than fine needle aspiration. During a core needle biopsy, a wide, hollow needle is inserted into the mass or growth to take a piece of tissue. The needle is moved into and out of the tumor by a spring. A cylindrical-shaped piece of tissue called a core is removed. Several cores are taken.Fine needle aspiration is another type of biopsy. It involves a thinner, hollow needle, which is inserted into the tumor to remove tissue. The needle is attached to a syringe, which is used to draw out (aspirate) a sample of tissue and fluid from the mass or tumor. This type of biopsy is not generally recommended for initial diagnosis of a suspected sarcoma but may be useful for documenting local recurrence or a site of distant spread.Imaging techniques may be used before or after a biopsy is taken. Imaging techniques will be used to evaluate the size, placement, and extension of the tumor (e.g., into the soft tissue or surrounding areas), to determine whether the tumor has spread (metastasized) to the lungs or other areas of the body, and to serve as an aid for future surgical procedures. Conventional x-rays (plain radiographs) of the lungs are often recommended because the lungs are the most common site of spread (metastasis) with soft tissue sarcomas. Some treatment centers recommend all newly diagnosed individuals with soft tissue sarcoma in the arms and legs, or trunk receive a chest x-ray or chest CT scan.Specialized imaging techniques are also used to help with the diagnosis or assessment of soft tissue sarcoma. These techniques can include magnetic resonance imaging (MRI), computerized tomography (CT scan), and ultrasound. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues including bone marrow and soft tissue. Sometimes, CT scans may be used for people who cannot have (or tolerate) an MRI. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Ultrasound uses reflected sound waves to create pictures of internal organs and other structures and is effective at detecting small areas of cancer that are near the surface of the body (superficially located). An ultrasound may also be used to determine whether fluid is present in an unidentified mass.Another advanced imaging technique known as positron emission tomography or PET scan may also be used. During a PET scan, radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading and will soak up the radioactive sugar. When the scan is taken, areas that take up the radioactive sugar including soft tissue sarcomas may show up as bright spots on the film. A PET scan is often used to help show whether a soft tissue sarcoma has spread or how well it is responding to treatment. PET scanning may not be routinely performed. Techniques which combine modalities such as PER/CT or MRI/PET are available and may be useful in certain situations.
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Diagnosis of Soft Tissue Sarcoma. A diagnosis of soft tissue sarcoma is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A physical examination can reveal a mass or growth that can be painless.Clinical Testing and Workup
A biopsy is the only way to definitively tell if a mass or tumor is a sarcoma. A biopsy is a test where a piece of tissue is taken from the tumor and examined under a microscope. This allows a special doctor called a pathologist to see the specific cells and characteristics of the tissue sample. Doctors can then distinguish a soft tissue sarcoma from other types of benign and cancerous tumors as well as determine the specific subtype of soft tissue sarcoma that is present. Additional testing of the tumor may involve specialized pathology techniques such as immunohistochemistry. Some tumors will be tested for specific genetic characteristics by either fluorescent in-situ hybridization (FISH) analysis or next generation sequencing.Many doctors and medical centers recommend a core needle biopsy. A core needle biopsy is generally considered to be more accurate than fine needle aspiration. During a core needle biopsy, a wide, hollow needle is inserted into the mass or growth to take a piece of tissue. The needle is moved into and out of the tumor by a spring. A cylindrical-shaped piece of tissue called a core is removed. Several cores are taken.Fine needle aspiration is another type of biopsy. It involves a thinner, hollow needle, which is inserted into the tumor to remove tissue. The needle is attached to a syringe, which is used to draw out (aspirate) a sample of tissue and fluid from the mass or tumor. This type of biopsy is not generally recommended for initial diagnosis of a suspected sarcoma but may be useful for documenting local recurrence or a site of distant spread.Imaging techniques may be used before or after a biopsy is taken. Imaging techniques will be used to evaluate the size, placement, and extension of the tumor (e.g., into the soft tissue or surrounding areas), to determine whether the tumor has spread (metastasized) to the lungs or other areas of the body, and to serve as an aid for future surgical procedures. Conventional x-rays (plain radiographs) of the lungs are often recommended because the lungs are the most common site of spread (metastasis) with soft tissue sarcomas. Some treatment centers recommend all newly diagnosed individuals with soft tissue sarcoma in the arms and legs, or trunk receive a chest x-ray or chest CT scan.Specialized imaging techniques are also used to help with the diagnosis or assessment of soft tissue sarcoma. These techniques can include magnetic resonance imaging (MRI), computerized tomography (CT scan), and ultrasound. An MRI uses a magnetic field and radio waves to produce cross-sectional images of organs and bodily tissues including bone marrow and soft tissue. Sometimes, CT scans may be used for people who cannot have (or tolerate) an MRI. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Ultrasound uses reflected sound waves to create pictures of internal organs and other structures and is effective at detecting small areas of cancer that are near the surface of the body (superficially located). An ultrasound may also be used to determine whether fluid is present in an unidentified mass.Another advanced imaging technique known as positron emission tomography or PET scan may also be used. During a PET scan, radioactive sugar is injected into the body. This sugar will collect in areas of the body where there is a higher demand for energy. Tumors require a lot of energy to keep growing and spreading and will soak up the radioactive sugar. When the scan is taken, areas that take up the radioactive sugar including soft tissue sarcomas may show up as bright spots on the film. A PET scan is often used to help show whether a soft tissue sarcoma has spread or how well it is responding to treatment. PET scanning may not be routinely performed. Techniques which combine modalities such as PER/CT or MRI/PET are available and may be useful in certain situations.
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Therapies of Soft Tissue Sarcoma
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Treatment
The therapeutic management of individuals with soft tissue sarcoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), oncologists, physicians who specialize in the treatment of cancer with radiation (radiation oncologists), physicians who specialize in examining tissues and cells to find disease and determine what disease is present (pathologists), surgeons who specialize in removing cancer by surgery (oncology surgeon or orthopedic oncology surgeon), nurses who specialize in the car and treatment of cancer (oncology nurses), psychiatrists, nutritionists and other healthcare specialists. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size and specific location; specific soft tissue sarcoma subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of surgery, particular drug regimens, and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.It is recommended that individuals with soft tissue sarcoma be seen by a physician or team of physicians with experience with these disorders. In the United States, there are Sarcoma Centers, which are medical centers and hospitals that specialize in the diagnosis and treatment of people with soft tissue sarcoma. At Sarcoma Centers, patients will be seen by a medical team of specialists with experience with these types of tumors.The three main treatments used for soft tissue sarcoma are surgery, chemotherapy, and radiation therapy. Surgery involves removing (resecting) the entire tumor and a small amount of surrounding healthy tissue to ensure all the cancer is eliminated. Tumors affecting the arms and legs are treated by limb-sparing surgery, if possible, which is designed to remove the tumor, but preserve the function of the limb as well as the physical appearance of the limb.Chemotherapy is the use of certain medications to slow down or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. In soft tissue sarcoma, chemotherapy may be used to treat affected individuals. Sometimes, it is used along with a primary form of treatment, usually surgery. This is called neoadjuvant or adjuvant therapy. When used along with surgery, chemotherapy may be given before surgery (neoadjuvant) to shrink a tumor or following surgery (adjuvant) to eliminate any remaining cancer cells and lessen the risk of a recurrence. Sometimes, chemotherapy may be given before and after surgery. Different combinations of medications may be used; this is called a chemotherapy regimen. The role of chemotherapy in the adjuvant or neoadjuvant setting remains controversial with some studies suggesting a benefit but other studies failing to show a benefit. An online tool called the Sarculator has been developed and validated that tries to predict overall survival and the risk for distant metastasis for extremity sarcomas. In addition, the Sarculator tries to predict overall survival and disease-free survival for retroperitoneal sarcomas. Patients and their physicians may use these tools as a guide when considering the use of adjuvant chemotherapy.Chemotherapy can also be considered for patients with recurrence, unresectable or metastatic disease.Radiation therapy is the use of high doses of radiation to kill cancer cells and shrink tumors. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. Radiation is passed through affected tissue to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages the cells’ genetic material, preventing or slowing their growth and replication. Radiation therapy has been shown to decrease the local recurrence rate when added to surgery in either the pre-operative or post-operative setting.FDA-Approved Therapies
The U.S. Food and Drug Administration (FDA) has approved several therapies for the treatment of specific subtypes of soft tissue sarcoma or for several different forms, collectively. These therapies include:Eribulin (Halaven) is approved for use in metastatic or unresectable liposarcoma after progression on a anthracycline-containing regimen.Votrient (pazopanib), which is approved for the treatment of individuals with advanced soft tissue sarcoma who have received prior chemotherapy (excludes liposarcoma).Cosmegen (dactinomycin) has been approved for the treatment of childhood rhabdomyosarcoma. The drug vincristine sulfate in conjunction with other chemotherapeutic agents has also been approved for rhabdomyosarcoma.The drug Gleevec (imatinib mesylate) is approved to treat adults with dermatofibrosarcoma protuberans that cannot be treated by surgery (unresectable), has recurred or has spread (metastasized). Gleevec is also approved for gastrointestinal stromal tumors (GIST).Yondelis (trabectedin) is approved for use in advanced liposarcoma or leiomyosarcoma. Sutent (sunitinib) is approved as a second line agent for gastrointestinal stromal tumor (GIST). Stivarga (regorafenib) is approved as a third line agent for gastrointestinal stromal tumor (GIST).Qinlock(ripretinib) is approved as a fourth line agent for gastrointestinal stromal tumor.Tazverik (tazemetostat) is approved to treat adults and pediatric patients aged 16 and older with metastatic or locally advanced epithelioid sarcoma that cannot be surgically removed. Tazverik is the first treatment option to be approved specifically for patients with epithelioid sarcoma, which accounts for less than one percent of all soft tissue sarcomas.Fyarro (Sirolimue Protein-Particles) is approved for use in PEComa.Turalio (Pexidartinib) is approved for adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations not amenable to improvement with surgery.
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Therapies of Soft Tissue Sarcoma. Treatment
The therapeutic management of individuals with soft tissue sarcoma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), oncologists, physicians who specialize in the treatment of cancer with radiation (radiation oncologists), physicians who specialize in examining tissues and cells to find disease and determine what disease is present (pathologists), surgeons who specialize in removing cancer by surgery (oncology surgeon or orthopedic oncology surgeon), nurses who specialize in the car and treatment of cancer (oncology nurses), psychiatrists, nutritionists and other healthcare specialists. Psychosocial support for the entire family is essential as well.Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease stage; tumor size and specific location; specific soft tissue sarcoma subtype; the presence or absence of certain symptoms; an individual’s age and general health; and/or other elements. Decisions concerning the use of surgery, particular drug regimens, and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.It is recommended that individuals with soft tissue sarcoma be seen by a physician or team of physicians with experience with these disorders. In the United States, there are Sarcoma Centers, which are medical centers and hospitals that specialize in the diagnosis and treatment of people with soft tissue sarcoma. At Sarcoma Centers, patients will be seen by a medical team of specialists with experience with these types of tumors.The three main treatments used for soft tissue sarcoma are surgery, chemotherapy, and radiation therapy. Surgery involves removing (resecting) the entire tumor and a small amount of surrounding healthy tissue to ensure all the cancer is eliminated. Tumors affecting the arms and legs are treated by limb-sparing surgery, if possible, which is designed to remove the tumor, but preserve the function of the limb as well as the physical appearance of the limb.Chemotherapy is the use of certain medications to slow down or stop the growth of cancer cells. Cancers cells grow and divide rapidly, which makes them susceptible to chemotherapy medications. In soft tissue sarcoma, chemotherapy may be used to treat affected individuals. Sometimes, it is used along with a primary form of treatment, usually surgery. This is called neoadjuvant or adjuvant therapy. When used along with surgery, chemotherapy may be given before surgery (neoadjuvant) to shrink a tumor or following surgery (adjuvant) to eliminate any remaining cancer cells and lessen the risk of a recurrence. Sometimes, chemotherapy may be given before and after surgery. Different combinations of medications may be used; this is called a chemotherapy regimen. The role of chemotherapy in the adjuvant or neoadjuvant setting remains controversial with some studies suggesting a benefit but other studies failing to show a benefit. An online tool called the Sarculator has been developed and validated that tries to predict overall survival and the risk for distant metastasis for extremity sarcomas. In addition, the Sarculator tries to predict overall survival and disease-free survival for retroperitoneal sarcomas. Patients and their physicians may use these tools as a guide when considering the use of adjuvant chemotherapy.Chemotherapy can also be considered for patients with recurrence, unresectable or metastatic disease.Radiation therapy is the use of high doses of radiation to kill cancer cells and shrink tumors. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. Radiation is passed through affected tissue to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages the cells’ genetic material, preventing or slowing their growth and replication. Radiation therapy has been shown to decrease the local recurrence rate when added to surgery in either the pre-operative or post-operative setting.FDA-Approved Therapies
The U.S. Food and Drug Administration (FDA) has approved several therapies for the treatment of specific subtypes of soft tissue sarcoma or for several different forms, collectively. These therapies include:Eribulin (Halaven) is approved for use in metastatic or unresectable liposarcoma after progression on a anthracycline-containing regimen.Votrient (pazopanib), which is approved for the treatment of individuals with advanced soft tissue sarcoma who have received prior chemotherapy (excludes liposarcoma).Cosmegen (dactinomycin) has been approved for the treatment of childhood rhabdomyosarcoma. The drug vincristine sulfate in conjunction with other chemotherapeutic agents has also been approved for rhabdomyosarcoma.The drug Gleevec (imatinib mesylate) is approved to treat adults with dermatofibrosarcoma protuberans that cannot be treated by surgery (unresectable), has recurred or has spread (metastasized). Gleevec is also approved for gastrointestinal stromal tumors (GIST).Yondelis (trabectedin) is approved for use in advanced liposarcoma or leiomyosarcoma. Sutent (sunitinib) is approved as a second line agent for gastrointestinal stromal tumor (GIST). Stivarga (regorafenib) is approved as a third line agent for gastrointestinal stromal tumor (GIST).Qinlock(ripretinib) is approved as a fourth line agent for gastrointestinal stromal tumor.Tazverik (tazemetostat) is approved to treat adults and pediatric patients aged 16 and older with metastatic or locally advanced epithelioid sarcoma that cannot be surgically removed. Tazverik is the first treatment option to be approved specifically for patients with epithelioid sarcoma, which accounts for less than one percent of all soft tissue sarcomas.Fyarro (Sirolimue Protein-Particles) is approved for use in PEComa.Turalio (Pexidartinib) is approved for adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations not amenable to improvement with surgery.
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Overview of Sotos Syndrome
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Sotos syndrome is a genetic disorder, described in 1964, characterized by excessive growth before and after birth, a large, elongated (dolichocephalic) head, distinctive facial configuration, and a non-progressive neurological disorder with intellectual disability. Advanced bone age is present in approximately 75 to 85% of patients.
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Overview of Sotos Syndrome. Sotos syndrome is a genetic disorder, described in 1964, characterized by excessive growth before and after birth, a large, elongated (dolichocephalic) head, distinctive facial configuration, and a non-progressive neurological disorder with intellectual disability. Advanced bone age is present in approximately 75 to 85% of patients.
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Symptoms of Sotos Syndrome
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The main clinical finding is prenatal and postnatal overgrowth. The growth velocity is particularly excessive in the first 3 to 4 years of life and subsequently proceeds at the normal rate, but in the high percentiles. The mean height is usually 2 to 3 years ahead of peers during childhood. The weight is usually appropriate for the height and the bone age is advanced mean by 2 to 4 years over chronological age, during childhood. Adult height usually exceeds the average of normal men or women. Some individuals may reach excessive adult heights; males of 193 cm to 203 cm (6 ft. 4 in. to 6 ft. 8 in.) and females up to 188 cm (6 ft. 2 in.) are known.The craniofacial configuration is most characteristic, with a prominent forehead and receding forehead hairline in 96% of patients, dolichocephalic head, widely spaced eyes (hypertelorism), down slanting of the eye lids and folds (palpebral features), high narrow palate, pointed chin, a long narrow face and a head shape that is similar to an inverted pear. The typical facial features are most apparent in childhood. As the child matures, the chin becomes more prominent and square in shape. In adults, the craniofacial characteristics are less distinctive but the chin is prominent and the dolichocephalic and receding hairline (frontal bossing) remain.Central nervous system manifestations are frequent. Delay in the attainment of milestones of development, walking and talking and in particular speech, is almost always present and clumsiness is frequent (60 to 80%), as is low muscle tone (hypotonia) and lax joints. Intellectual disability is present in 80 to 85% of the patients, with an average IQ of 72 and a range from 40 to borderline mild intellectual disability. Fifteen to 20% may have normal intelligence. Seizures may occur in 30% of those affected. Some brain abnormalities (enlarged ventricles) may occur.Individuals with Sotos syndrome can also experience behavioral problems at all ages that can make it difficult for them to develop relationships with others.Newborns often have jaundice, difficulty feeding and low muscle tone (hypotonia). Heart defects are present in about 8 to 35% of children with Sotos syndrome but are usually not severe. Abnormalities in the genital and/or urinary systems occur in about 20% of affected individuals. Other findings associated with Sotos syndrome include conductive hearing loss that may be associated with an increased frequency of upper respiratory infections, eye abnormalities such as crossed eyes (strabismus), and skeletal problems. A curved spine (scoliosis) is present in about 40% of those affected but is usually not severe enough to require bracing or surgery. Premature eruption of teeth occurs in 60 to 80%. Approximately 2.2 to 3.9% of patients develop tumors including sacrococcygeal teratoma, neuroblastoma, presacral ganglioma and acute lymphoblastic leukemia.Affected infants and children usually experience a delay in achieving certain developmental milestones (e.g., sitting, crawling, walking, etc.). They may not begin to walk until approximately 15 to 17 months of age. Affected children may also experience difficulty performing certain tasks requiring coordination (such as riding a bicycle or playing sports), fine motor skills (e.g., the ability to grasp small objects), and may demonstrate unusual clumsiness. Children with this disorder typically experience delays in attaining language skills. In many cases, affected children may not begin to speak until approximately two to three years of age.
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Symptoms of Sotos Syndrome. The main clinical finding is prenatal and postnatal overgrowth. The growth velocity is particularly excessive in the first 3 to 4 years of life and subsequently proceeds at the normal rate, but in the high percentiles. The mean height is usually 2 to 3 years ahead of peers during childhood. The weight is usually appropriate for the height and the bone age is advanced mean by 2 to 4 years over chronological age, during childhood. Adult height usually exceeds the average of normal men or women. Some individuals may reach excessive adult heights; males of 193 cm to 203 cm (6 ft. 4 in. to 6 ft. 8 in.) and females up to 188 cm (6 ft. 2 in.) are known.The craniofacial configuration is most characteristic, with a prominent forehead and receding forehead hairline in 96% of patients, dolichocephalic head, widely spaced eyes (hypertelorism), down slanting of the eye lids and folds (palpebral features), high narrow palate, pointed chin, a long narrow face and a head shape that is similar to an inverted pear. The typical facial features are most apparent in childhood. As the child matures, the chin becomes more prominent and square in shape. In adults, the craniofacial characteristics are less distinctive but the chin is prominent and the dolichocephalic and receding hairline (frontal bossing) remain.Central nervous system manifestations are frequent. Delay in the attainment of milestones of development, walking and talking and in particular speech, is almost always present and clumsiness is frequent (60 to 80%), as is low muscle tone (hypotonia) and lax joints. Intellectual disability is present in 80 to 85% of the patients, with an average IQ of 72 and a range from 40 to borderline mild intellectual disability. Fifteen to 20% may have normal intelligence. Seizures may occur in 30% of those affected. Some brain abnormalities (enlarged ventricles) may occur.Individuals with Sotos syndrome can also experience behavioral problems at all ages that can make it difficult for them to develop relationships with others.Newborns often have jaundice, difficulty feeding and low muscle tone (hypotonia). Heart defects are present in about 8 to 35% of children with Sotos syndrome but are usually not severe. Abnormalities in the genital and/or urinary systems occur in about 20% of affected individuals. Other findings associated with Sotos syndrome include conductive hearing loss that may be associated with an increased frequency of upper respiratory infections, eye abnormalities such as crossed eyes (strabismus), and skeletal problems. A curved spine (scoliosis) is present in about 40% of those affected but is usually not severe enough to require bracing or surgery. Premature eruption of teeth occurs in 60 to 80%. Approximately 2.2 to 3.9% of patients develop tumors including sacrococcygeal teratoma, neuroblastoma, presacral ganglioma and acute lymphoblastic leukemia.Affected infants and children usually experience a delay in achieving certain developmental milestones (e.g., sitting, crawling, walking, etc.). They may not begin to walk until approximately 15 to 17 months of age. Affected children may also experience difficulty performing certain tasks requiring coordination (such as riding a bicycle or playing sports), fine motor skills (e.g., the ability to grasp small objects), and may demonstrate unusual clumsiness. Children with this disorder typically experience delays in attaining language skills. In many cases, affected children may not begin to speak until approximately two to three years of age.
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Causes of Sotos Syndrome
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Sotos syndrome is caused by mutations (abnormalities) in the NSD1 (nuclear receptor-binding SET domain protein 1) gene. Mutations in this gene have been identified in approximately 90% of affected patients (Sotos syndrome 1). A few years ago, mutations in the NFIX gene (nuclear factor I, X type) were identified in 5 patients with Sotos syndrome (Sotos syndrome 2). In 2015, a loss-of-function mutation in the APC2 (adenomatous polyposis coli 2) gene was reported in 2 siblings with some neural features of Sotos syndrome including intellectual disability, abnormal brain structure, and typical facial features, but no other features such as bone or heart abnormalities (Sotos syndrome 3). The parents were blood relatives (consanguineous). The APC2 gene is specifically expressed in the nervous system, and is a crucial downstream gene of NSD1. In other words, mutations in the NSD1 gene affects the APC2 gene and results in the neural abnormalities.Sotos syndrome is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal variant of a gene is necessary to cause a particular disease. The abnormal variant gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal variant gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Most people with Sotos syndrome have the NSD1 mutation as the result of a new mutation that was not inherited from a parent. When the parents are unaffected, the risk of having another child with the syndrome is very low (<1%).
The symptoms of Sotos syndrome can vary from person to person, even when they have the same NSD1 gene mutation. Sotos syndrome 3 is an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits an abnormal variant of a gene from each parent. If an individual receives one normal gene and one abnormal variant 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 abnormal variant 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 is 25%. The risk is the same for males and females.
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Causes of Sotos Syndrome. Sotos syndrome is caused by mutations (abnormalities) in the NSD1 (nuclear receptor-binding SET domain protein 1) gene. Mutations in this gene have been identified in approximately 90% of affected patients (Sotos syndrome 1). A few years ago, mutations in the NFIX gene (nuclear factor I, X type) were identified in 5 patients with Sotos syndrome (Sotos syndrome 2). In 2015, a loss-of-function mutation in the APC2 (adenomatous polyposis coli 2) gene was reported in 2 siblings with some neural features of Sotos syndrome including intellectual disability, abnormal brain structure, and typical facial features, but no other features such as bone or heart abnormalities (Sotos syndrome 3). The parents were blood relatives (consanguineous). The APC2 gene is specifically expressed in the nervous system, and is a crucial downstream gene of NSD1. In other words, mutations in the NSD1 gene affects the APC2 gene and results in the neural abnormalities.Sotos syndrome is an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal variant of a gene is necessary to cause a particular disease. The abnormal variant gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal variant gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Most people with Sotos syndrome have the NSD1 mutation as the result of a new mutation that was not inherited from a parent. When the parents are unaffected, the risk of having another child with the syndrome is very low (<1%).
The symptoms of Sotos syndrome can vary from person to person, even when they have the same NSD1 gene mutation. Sotos syndrome 3 is an autosomal recessive condition. Recessive genetic disorders occur when an individual inherits an abnormal variant of a gene from each parent. If an individual receives one normal gene and one abnormal variant 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 abnormal variant 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 is 25%. The risk is the same for males and females.
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Affects of Sotos Syndrome
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Sotos syndrome affects males and females in equal numbers, occurs in all ethnic groups and has been detected throughout the world. This condition occurs in about one in 14,000 live births.
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Affects of Sotos Syndrome. Sotos syndrome affects males and females in equal numbers, occurs in all ethnic groups and has been detected throughout the world. This condition occurs in about one in 14,000 live births.
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Related disorders of Sotos Syndrome
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Symptoms of the following disorders may be similar to those of Sotos syndrome. Comparisons may be useful for a differential diagnosis. Confirmation of any of the syndromes can be obtained by genetic testing.Weaver syndrome, also known as Weaver-Smith syndrome, is an extremely rare disorder characterized by accelerated growth. Affected individuals have a particular facial appearance that is similar to Sotos syndrome in that a high broad forehead is often present, but the face is usually round in shape (not elongated) with widely spaced eyes (ocular hypertelorism) and an abnormally small jaw. Children often have increased muscle tone (hypertonia) and joint problems. The cause is now known to be a mutation in the EXH2 gene. (For more information on this disorder, choose “Weaver” as your search term in the Rare Disease Database.)Beckwith-Wiedemann syndrome is a rare inherited disorder characterized by overgrowth, an abnormally large tongue (macroglossia), abnormal creases on the earlobes, protrusion of part of the intestines through an abnormal opening in the muscular abdominal wall near the umbilical cord (omphalocele) and abnormal enlargement of certain abdominal organs (visceromegaly) such as the liver, kidney, and/or pancreas and hypoglycemia (low blood glucose) early in life. Most individuals with Beckwith-Wiedemann syndrome have an abnormality in one of several genes located on the number 11 chromosome. Molecular genetic testing can help to determine the proper treatment for these patients. (For more information on this disorder, choose “Beckwith-Wiedemann” as your search term in the Rare Disease Database.)Simpson dysmorphia syndrome, also known as Simpson-Golabi-Behmel syndrome, is an X-linked recessive genetic disorder characterized by overgrowth before and after birth, a particular facial appearance that is different from Sotos syndrome, extra fingers and toes, extra nipples, separation of muscles in the abdominal wall (diastasis recti), and a skeletal abnormality in which the chest bone is depressed (pectus excavatum). This syndrome results from abnormalities (mutations or microdeletions) of one of two genes on chromosomes X. (For more information on this disorder, choose “Simpson dysmorphia” as your search term in the Rare Disease Database.)Fragile X syndrome is a genetic disorder caused by an abnormality in a gene on the X chromosome, with more severe symptoms in males and is characterized by intellectual disability, language delays, behavioral problems, autism or autistic-like behavior (including poor eye contact and hand-flapping), enlarged external genitalia (macroorchidism), large or prominent ears, hyperactivity, delayed motor development and/or poor sensory skills. Affected individuals may also have an abnormally increased growth rate before puberty. Molecular genetic testing can differentiate fragile X syndrome from Sotos syndrome. (For more information on this disorder, choose “fragile X” as your search term in the Rare Disease Database.)
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Related disorders of Sotos Syndrome. Symptoms of the following disorders may be similar to those of Sotos syndrome. Comparisons may be useful for a differential diagnosis. Confirmation of any of the syndromes can be obtained by genetic testing.Weaver syndrome, also known as Weaver-Smith syndrome, is an extremely rare disorder characterized by accelerated growth. Affected individuals have a particular facial appearance that is similar to Sotos syndrome in that a high broad forehead is often present, but the face is usually round in shape (not elongated) with widely spaced eyes (ocular hypertelorism) and an abnormally small jaw. Children often have increased muscle tone (hypertonia) and joint problems. The cause is now known to be a mutation in the EXH2 gene. (For more information on this disorder, choose “Weaver” as your search term in the Rare Disease Database.)Beckwith-Wiedemann syndrome is a rare inherited disorder characterized by overgrowth, an abnormally large tongue (macroglossia), abnormal creases on the earlobes, protrusion of part of the intestines through an abnormal opening in the muscular abdominal wall near the umbilical cord (omphalocele) and abnormal enlargement of certain abdominal organs (visceromegaly) such as the liver, kidney, and/or pancreas and hypoglycemia (low blood glucose) early in life. Most individuals with Beckwith-Wiedemann syndrome have an abnormality in one of several genes located on the number 11 chromosome. Molecular genetic testing can help to determine the proper treatment for these patients. (For more information on this disorder, choose “Beckwith-Wiedemann” as your search term in the Rare Disease Database.)Simpson dysmorphia syndrome, also known as Simpson-Golabi-Behmel syndrome, is an X-linked recessive genetic disorder characterized by overgrowth before and after birth, a particular facial appearance that is different from Sotos syndrome, extra fingers and toes, extra nipples, separation of muscles in the abdominal wall (diastasis recti), and a skeletal abnormality in which the chest bone is depressed (pectus excavatum). This syndrome results from abnormalities (mutations or microdeletions) of one of two genes on chromosomes X. (For more information on this disorder, choose “Simpson dysmorphia” as your search term in the Rare Disease Database.)Fragile X syndrome is a genetic disorder caused by an abnormality in a gene on the X chromosome, with more severe symptoms in males and is characterized by intellectual disability, language delays, behavioral problems, autism or autistic-like behavior (including poor eye contact and hand-flapping), enlarged external genitalia (macroorchidism), large or prominent ears, hyperactivity, delayed motor development and/or poor sensory skills. Affected individuals may also have an abnormally increased growth rate before puberty. Molecular genetic testing can differentiate fragile X syndrome from Sotos syndrome. (For more information on this disorder, choose “fragile X” as your search term in the Rare Disease Database.)
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Diagnosis of Sotos Syndrome
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There is no biochemical marker for the disease. The diagnosis is based on clinical grounds. The most characteristic manifestations are the craniofacial configuration, excessive growth, and developmental delay. The diagnosis of a patient with the typical craniofacial configuration and excessive growth can be made at the first site. The craniofacial configuration is the most distinctive, and only rarely (~ 1%), is not present. Ten percent of the children and adolescents may be below +2 SD in height and 10 or 15% of the patients may not have developmental delay. Advanced bone age may be present in 76 to 86% of the patients and is helpful but not specific. Brain abnormalities are present in 60 to 80% of patients, such as communicating hydrocephalous, and others, but are not diagnostic and are non-specific.The diagnosis can be confirmed by DNA studies by FISH (fluorescence in situ hybridization) analysis to detect microdeletions or MLPA (multiplex ligation-dependent probe amplification), a simple and reliable method to detect chromosome 5q35 microdeletions and partial NSD1 gene deletions, which account for approximately 10-15% of the cases in western populations. DNA analysis by genome sequencing can determine the specific NSD1 gene mutations.In patients without NSD1 gene mutations, genetic testing for mutations in NFIX and APC2 genes should be obtained.
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Diagnosis of Sotos Syndrome. There is no biochemical marker for the disease. The diagnosis is based on clinical grounds. The most characteristic manifestations are the craniofacial configuration, excessive growth, and developmental delay. The diagnosis of a patient with the typical craniofacial configuration and excessive growth can be made at the first site. The craniofacial configuration is the most distinctive, and only rarely (~ 1%), is not present. Ten percent of the children and adolescents may be below +2 SD in height and 10 or 15% of the patients may not have developmental delay. Advanced bone age may be present in 76 to 86% of the patients and is helpful but not specific. Brain abnormalities are present in 60 to 80% of patients, such as communicating hydrocephalous, and others, but are not diagnostic and are non-specific.The diagnosis can be confirmed by DNA studies by FISH (fluorescence in situ hybridization) analysis to detect microdeletions or MLPA (multiplex ligation-dependent probe amplification), a simple and reliable method to detect chromosome 5q35 microdeletions and partial NSD1 gene deletions, which account for approximately 10-15% of the cases in western populations. DNA analysis by genome sequencing can determine the specific NSD1 gene mutations.In patients without NSD1 gene mutations, genetic testing for mutations in NFIX and APC2 genes should be obtained.
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Therapies of Sotos Syndrome
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TreatmentThe treatment of Sotos 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 endocrinologists, geneticists, neurologists, surgeons, speech pathologists, specialists who diagnose and treat skeletal disorders (orthopedists), physicians who diagnose and treat eye disorders (ophthalmologists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.When a child is diagnosed with Sotos syndrome, a heart examination and kidney ultrasound should be performed and if abnormalities are identified, an appropriate specialist should be consulted. Children with Sotos syndrome should have a thorough examination every one to two years that includes a back exam for scoliosis, eye exam, blood pressure measurement, and a speech and language evaluation. Appropriate specialists should be consulted as needed.Clinical evaluation should be conducted early in development and on a continuing basis to help confirm the presence and extent of developmental delay, psychomotor delay, and/or intellectual disability. Such evaluation and early intervention may help ensure that appropriate steps are taken to help affected individuals reach their highest potential. Special services that may be beneficial to affected children may include infant stimulation, special education, special social support, physical therapy, occupational therapy, speech therapy, and adaptive physical education.A small percentage (2.2 to 3.9%) of individuals with Sotos syndrome may be more prone to developing certain benign tumors and malignancies than the general population. Owing to the low risk for these problems, that the age of onset or detection is from infancy to adulthood and the location variable (~1/3 intra-abdominal, 2/3 extra-abdominal), there is no recommended routine screening.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Sotos Syndrome. TreatmentThe treatment of Sotos 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 endocrinologists, geneticists, neurologists, surgeons, speech pathologists, specialists who diagnose and treat skeletal disorders (orthopedists), physicians who diagnose and treat eye disorders (ophthalmologists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.When a child is diagnosed with Sotos syndrome, a heart examination and kidney ultrasound should be performed and if abnormalities are identified, an appropriate specialist should be consulted. Children with Sotos syndrome should have a thorough examination every one to two years that includes a back exam for scoliosis, eye exam, blood pressure measurement, and a speech and language evaluation. Appropriate specialists should be consulted as needed.Clinical evaluation should be conducted early in development and on a continuing basis to help confirm the presence and extent of developmental delay, psychomotor delay, and/or intellectual disability. Such evaluation and early intervention may help ensure that appropriate steps are taken to help affected individuals reach their highest potential. Special services that may be beneficial to affected children may include infant stimulation, special education, special social support, physical therapy, occupational therapy, speech therapy, and adaptive physical education.A small percentage (2.2 to 3.9%) of individuals with Sotos syndrome may be more prone to developing certain benign tumors and malignancies than the general population. Owing to the low risk for these problems, that the age of onset or detection is from infancy to adulthood and the location variable (~1/3 intra-abdominal, 2/3 extra-abdominal), there is no recommended routine screening.Genetic counseling is recommended for affected individuals and their families.
| 1,139 |
Sotos Syndrome
|
nord_1140_0
|
Overview of Spastic Paraplegia 47
|
SummarySpastic paraplegia 47 (SPG47) is both a neurodevelopmental and a slowly progressive neurological disorder that generally presents with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures and progressive motor symptoms. Hypotonia (low-muscle tone) develops into hypertonia (high-muscle tone), resulting in spasticity of the legs that leads to the inability to walk (non-ambulation) and wheelchair reliance. Spasticity may progress to the upper extremities, leading to the partial or total loss of use of all four limbs and torso (tetraplegia).
|
Overview of Spastic Paraplegia 47. SummarySpastic paraplegia 47 (SPG47) is both a neurodevelopmental and a slowly progressive neurological disorder that generally presents with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures and progressive motor symptoms. Hypotonia (low-muscle tone) develops into hypertonia (high-muscle tone), resulting in spasticity of the legs that leads to the inability to walk (non-ambulation) and wheelchair reliance. Spasticity may progress to the upper extremities, leading to the partial or total loss of use of all four limbs and torso (tetraplegia).
| 1,140 |
Spastic Paraplegia 47
|
nord_1140_1
|
Symptoms of Spastic Paraplegia 47
|
Most children with SPG47 have:• a “floppy” appearance in infancy due to low muscle tone
• delayed motor development
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• microcephaly
• intellectual disability
• poor or absent speech developmentOther known features of SPG47 can include the following (not every child will have these features):• short stature
• late walking and later loss of the ability to walk independently.
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
• seizures including frequent seizures in the setting of fever.
|
Symptoms of Spastic Paraplegia 47. Most children with SPG47 have:• a “floppy” appearance in infancy due to low muscle tone
• delayed motor development
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• microcephaly
• intellectual disability
• poor or absent speech developmentOther known features of SPG47 can include the following (not every child will have these features):• short stature
• late walking and later loss of the ability to walk independently.
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
• seizures including frequent seizures in the setting of fever.
| 1,140 |
Spastic Paraplegia 47
|
nord_1140_2
|
Causes of Spastic Paraplegia 47
|
The gene that is involved in SPG47 is called AP4B1, and SPG47 is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
|
Causes of Spastic Paraplegia 47. The gene that is involved in SPG47 is called AP4B1, and SPG47 is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
| 1,140 |
Spastic Paraplegia 47
|
nord_1140_3
|
Affects of Spastic Paraplegia 47
|
SPG47 affects males and females of many ethnic groups from around the world.
The prevalence of SPG47 is unknown. SPG47 is likely under-recognized since the symptoms (phenotypic spectrum) largely overlaps with that of cerebral palsy and, in the absence of genetic testing, many patients may be misdiagnosed as having cerebral palsy.
|
Affects of Spastic Paraplegia 47. SPG47 affects males and females of many ethnic groups from around the world.
The prevalence of SPG47 is unknown. SPG47 is likely under-recognized since the symptoms (phenotypic spectrum) largely overlaps with that of cerebral palsy and, in the absence of genetic testing, many patients may be misdiagnosed as having cerebral palsy.
| 1,140 |
Spastic Paraplegia 47
|
nord_1140_4
|
Related disorders of Spastic Paraplegia 47
|
AP-4-associated hereditary spastic paraplegia (HSP) is a group of neurodevelopmental and slowly progressive neurological disorders that generally present with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, microcephaly, seizures and progressive motor symptoms. The conditions included in this group are SPG47, SPG50, SPG51 and SPG52 and all have similar symptoms. These conditions are inherited in an autosomal recessive pattern and are caused by variants in genes that result in production of an abnormal version of adaptor protein complex 4.
|
Related disorders of Spastic Paraplegia 47. AP-4-associated hereditary spastic paraplegia (HSP) is a group of neurodevelopmental and slowly progressive neurological disorders that generally present with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, microcephaly, seizures and progressive motor symptoms. The conditions included in this group are SPG47, SPG50, SPG51 and SPG52 and all have similar symptoms. These conditions are inherited in an autosomal recessive pattern and are caused by variants in genes that result in production of an abnormal version of adaptor protein complex 4.
| 1,140 |
Spastic Paraplegia 47
|
nord_1140_5
|
Diagnosis of Spastic Paraplegia 47
|
Since many of the initial clinical manifestations of SPG47 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability and seizures, the diagnosis is often only made after further diagnostic testing. This may include a brain MRI showing characteristic features such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.
|
Diagnosis of Spastic Paraplegia 47. Since many of the initial clinical manifestations of SPG47 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability and seizures, the diagnosis is often only made after further diagnostic testing. This may include a brain MRI showing characteristic features such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.
| 1,140 |
Spastic Paraplegia 47
|
nord_1140_6
|
Therapies of Spastic Paraplegia 47
|
Ages 0-3 years
Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators and sensory-impairment specialists.Ages 3-5 years
In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social and/or cognitive delay. The early intervention program typically assists with this transition.Ages 5-21 years
In the United States, an IEP based on the individual’s level of function should be developed by the local public school district and will dictate specially designed instruction/related services. Discussion about transition plans including financial and medical arrangements should begin at the age of 12 years. Developmental pediatricians can help with transition to adulthood.Motor Dysfunction
Gross motor dysfunction
• Physical therapy is recommended to maximize mobility.
• Consider the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).Fine motor dysfunction
Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing and writing.Oral-motor dysfunction
Oral-motor dysfunction should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained.Communication issues
Speech therapy is recommended. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.Multidisciplinary Care
Care should be provided by a multidisciplinary care team that includes input from neurology, physiatry, orthopedics, developmental medicine and others is recommended.
|
Therapies of Spastic Paraplegia 47. Ages 0-3 years
Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators and sensory-impairment specialists.Ages 3-5 years
In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social and/or cognitive delay. The early intervention program typically assists with this transition.Ages 5-21 years
In the United States, an IEP based on the individual’s level of function should be developed by the local public school district and will dictate specially designed instruction/related services. Discussion about transition plans including financial and medical arrangements should begin at the age of 12 years. Developmental pediatricians can help with transition to adulthood.Motor Dysfunction
Gross motor dysfunction
• Physical therapy is recommended to maximize mobility.
• Consider the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).Fine motor dysfunction
Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing and writing.Oral-motor dysfunction
Oral-motor dysfunction should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained.Communication issues
Speech therapy is recommended. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.Multidisciplinary Care
Care should be provided by a multidisciplinary care team that includes input from neurology, physiatry, orthopedics, developmental medicine and others is recommended.
| 1,140 |
Spastic Paraplegia 47
|
nord_1141_0
|
Overview of Spastic Paraplegia 50
|
Spastic paraplegia 50 (SPG50) is both a neurodevelopmental and a slowly progressive neurological disorder that generally presents with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures and progressive motor symptoms. Hypotonia (low-muscle tone) develops into hypertonia (high-muscle tone), resulting in spasticity of the legs that leads to non-ambulation and wheelchair reliance. Spasticity may progress to the upper extremities, leading to the partial or total loss of use of all four limbs and torso (tetraplegia).
|
Overview of Spastic Paraplegia 50. Spastic paraplegia 50 (SPG50) is both a neurodevelopmental and a slowly progressive neurological disorder that generally presents with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures and progressive motor symptoms. Hypotonia (low-muscle tone) develops into hypertonia (high-muscle tone), resulting in spasticity of the legs that leads to non-ambulation and wheelchair reliance. Spasticity may progress to the upper extremities, leading to the partial or total loss of use of all four limbs and torso (tetraplegia).
| 1,141 |
Spastic Paraplegia 50
|
nord_1141_1
|
Symptoms of Spastic Paraplegia 50
|
Most children with SPG50 have:• a “floppy” appearance in infancy due to low muscle tone
• delayed motor development
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• microcephaly
• intellectual disability
• poor or absent speech developmentOther known features of SPG50 can include the following (not every child will have these features):• short stature
• late walking and later loss of the ability to walk independently
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
• seizures including frequent seizures in the setting of fever
|
Symptoms of Spastic Paraplegia 50. Most children with SPG50 have:• a “floppy” appearance in infancy due to low muscle tone
• delayed motor development
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• microcephaly
• intellectual disability
• poor or absent speech developmentOther known features of SPG50 can include the following (not every child will have these features):• short stature
• late walking and later loss of the ability to walk independently
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
• seizures including frequent seizures in the setting of fever
| 1,141 |
Spastic Paraplegia 50
|
nord_1141_2
|
Causes of Spastic Paraplegia 50
|
The gene that is involved in SPG50 is called AP4M1, and SPG50 is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
|
Causes of Spastic Paraplegia 50. The gene that is involved in SPG50 is called AP4M1, and SPG50 is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
| 1,141 |
Spastic Paraplegia 50
|
nord_1141_3
|
Affects of Spastic Paraplegia 50
|
SPG50 affects males and females of many ethnic groups from around the world.
The prevalence of SPG50 is unknown. SPG50 is likely under-recognized since the symptoms (phenotypic spectrum) largely overlaps with that of cerebral palsy and, in the absence of genetic testing, many patients may be misdiagnosed as having cerebral palsy.
|
Affects of Spastic Paraplegia 50. SPG50 affects males and females of many ethnic groups from around the world.
The prevalence of SPG50 is unknown. SPG50 is likely under-recognized since the symptoms (phenotypic spectrum) largely overlaps with that of cerebral palsy and, in the absence of genetic testing, many patients may be misdiagnosed as having cerebral palsy.
| 1,141 |
Spastic Paraplegia 50
|
nord_1141_4
|
Related disorders of Spastic Paraplegia 50
|
AP-4-associated hereditary spastic paraplegia (HSP) is a group of neurodevelopmental and slowly progressive neurological disorders that generally present with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, microcephaly, seizures and progressive motor symptoms. The conditions included in this group are SPG47, SPG50, SPG51 and SPG52 and all have similar symptoms. These conditions are inherited in an autosomal recessive pattern and are caused by variants in genes that result in production of an abnormal version of adaptor protein complex 4.
|
Related disorders of Spastic Paraplegia 50. AP-4-associated hereditary spastic paraplegia (HSP) is a group of neurodevelopmental and slowly progressive neurological disorders that generally present with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, microcephaly, seizures and progressive motor symptoms. The conditions included in this group are SPG47, SPG50, SPG51 and SPG52 and all have similar symptoms. These conditions are inherited in an autosomal recessive pattern and are caused by variants in genes that result in production of an abnormal version of adaptor protein complex 4.
| 1,141 |
Spastic Paraplegia 50
|
nord_1141_5
|
Diagnosis of Spastic Paraplegia 50
|
Since many of the initial clinical manifestations of SPG50 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability and seizures, the diagnosis is often only made after further diagnostic testing. This may include a brain MRI showing characteristic features such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.
|
Diagnosis of Spastic Paraplegia 50. Since many of the initial clinical manifestations of SPG50 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability and seizures, the diagnosis is often only made after further diagnostic testing. This may include a brain MRI showing characteristic features such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.
| 1,141 |
Spastic Paraplegia 50
|
nord_1141_6
|
Therapies of Spastic Paraplegia 50
|
Management of Symptoms
Ages 0-3 years
Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators and sensory-impairment specialists.Ages 3-5 years
In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social and/or cognitive delay. The early intervention program typically assists with this transition.Ages 5-21 years
In the United States, an IEP based on the individual’s level of function should be developed by the local public school district and will dictate specially designed instruction/related services. Discussion about transition plans including financial and medical arrangements should begin at the age of 12 years. Developmental pediatricians can help with transition to adulthood.Motor Dysfunction
Gross motor dysfunction
• Physical therapy is recommended to maximize mobility.
• Consider the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).Fine motor dysfunction
Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing and writing.Oral-motor dysfunction
Oral-motor dysfunction should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained.Communication issues
Speech therapy is recommended. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.Multidisciplinary Care
Care should be provided by a multidisciplinary care team that includes input from neurology, physiatry, orthopedics, developmental medicine and others is recommended.
|
Therapies of Spastic Paraplegia 50. Management of Symptoms
Ages 0-3 years
Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as mental health services, special educators and sensory-impairment specialists.Ages 3-5 years
In the United States, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social and/or cognitive delay. The early intervention program typically assists with this transition.Ages 5-21 years
In the United States, an IEP based on the individual’s level of function should be developed by the local public school district and will dictate specially designed instruction/related services. Discussion about transition plans including financial and medical arrangements should begin at the age of 12 years. Developmental pediatricians can help with transition to adulthood.Motor Dysfunction
Gross motor dysfunction
• Physical therapy is recommended to maximize mobility.
• Consider the use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).Fine motor dysfunction
Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing and writing.Oral-motor dysfunction
Oral-motor dysfunction should be reassessed in regular intervals and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained.Communication issues
Speech therapy is recommended. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.Multidisciplinary Care
Care should be provided by a multidisciplinary care team that includes input from neurology, physiatry, orthopedics, developmental medicine and others is recommended.
| 1,141 |
Spastic Paraplegia 50
|
nord_1142_0
|
Overview of Spastic Paraplegia 51
|
Summary
Spastic paraplegia 51 (SPG51) is both a neurodevelopmental and a slowly progressive neurological disorder that generally presents with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures and progressive motor symptoms. Hypotonia (low-muscle tone) develops into hypertonia (high-muscle tone), resulting in spasticity of the legs that leads to the inability to walk (non-ambulation) and wheelchair reliance. Spasticity may progress to the upper extremities, leading to the partial or total loss of use of all four limbs and torso (tetraplegia).
|
Overview of Spastic Paraplegia 51. Summary
Spastic paraplegia 51 (SPG51) is both a neurodevelopmental and a slowly progressive neurological disorder that generally presents with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, small head size (microcephaly), seizures and progressive motor symptoms. Hypotonia (low-muscle tone) develops into hypertonia (high-muscle tone), resulting in spasticity of the legs that leads to the inability to walk (non-ambulation) and wheelchair reliance. Spasticity may progress to the upper extremities, leading to the partial or total loss of use of all four limbs and torso (tetraplegia).
| 1,142 |
Spastic Paraplegia 51
|
nord_1142_1
|
Symptoms of Spastic Paraplegia 51
|
Most children with SPG51 have:• a “floppy” appearance in infancy due to low muscle tone
• delayed motor development
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• microcephaly
• intellectual disability
• poor or absent speech developmentOther known features of SPG51 can include the following (not every child will have these features):• short stature
• late walking and later loss of the ability to walk independently.
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
• seizures including frequent seizures in the setting of fever.
|
Symptoms of Spastic Paraplegia 51. Most children with SPG51 have:• a “floppy” appearance in infancy due to low muscle tone
• delayed motor development
• increasing spasticity and paralysis in the lower limbs starting in early childhood
• microcephaly
• intellectual disability
• poor or absent speech developmentOther known features of SPG51 can include the following (not every child will have these features):• short stature
• late walking and later loss of the ability to walk independently.
• dystonia (involuntary muscle contractions)
• ataxia (impaired balance and coordination)
• seizures including frequent seizures in the setting of fever.
| 1,142 |
Spastic Paraplegia 51
|
nord_1142_2
|
Causes of Spastic Paraplegia 51
|
The gene that is involved in SPG51 is called AP4E1, and SPG51 is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
|
Causes of Spastic Paraplegia 51. The gene that is involved in SPG51 is called AP4E1, and SPG51 is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated 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 mutated gene and have an affected child is 25% with each pregnancy. The risk of having 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 is 25%. The risk is the same for males and females.
| 1,142 |
Spastic Paraplegia 51
|
nord_1142_3
|
Affects of Spastic Paraplegia 51
|
SPG51 affects males and females of many ethnic groups from around the world.
The prevalence of SPG51 is unknown. SPG51 is likely under-recognized since the symptoms (phenotypic spectrum) largely overlaps with that of cerebral palsy and, in the absence of genetic testing, patients may be misdiagnosed as having cerebral palsy.
|
Affects of Spastic Paraplegia 51. SPG51 affects males and females of many ethnic groups from around the world.
The prevalence of SPG51 is unknown. SPG51 is likely under-recognized since the symptoms (phenotypic spectrum) largely overlaps with that of cerebral palsy and, in the absence of genetic testing, patients may be misdiagnosed as having cerebral palsy.
| 1,142 |
Spastic Paraplegia 51
|
nord_1142_4
|
Related disorders of Spastic Paraplegia 51
|
AP-4-associated hereditary spastic paraplegia (HSP) is a group of neurodevelopmental and slowly progressive neurological disorders that generally present with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, microcephaly, seizures and progressive motor symptoms. The conditions included in this group are SPG47, SPG50, SPG51 and SPG52 and all have similar symptoms. These conditions are inherited in an autosomal recessive pattern and are caused by variants in genes that result in production of an abnormal adaptor protein complex 4 (or AP-4).
|
Related disorders of Spastic Paraplegia 51. AP-4-associated hereditary spastic paraplegia (HSP) is a group of neurodevelopmental and slowly progressive neurological disorders that generally present with global developmental delay, moderate to severe intellectual disability, impaired/absent speech, microcephaly, seizures and progressive motor symptoms. The conditions included in this group are SPG47, SPG50, SPG51 and SPG52 and all have similar symptoms. These conditions are inherited in an autosomal recessive pattern and are caused by variants in genes that result in production of an abnormal adaptor protein complex 4 (or AP-4).
| 1,142 |
Spastic Paraplegia 51
|
nord_1142_5
|
Diagnosis of Spastic Paraplegia 51
|
Since many of the initial clinical manifestations of SPG51 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability and seizures, the diagnosis is often only made after further diagnostic testing. This may include a brain MRI showing characteristic features, such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.
|
Diagnosis of Spastic Paraplegia 51. Since many of the initial clinical manifestations of SPG51 are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability and seizures, the diagnosis is often only made after further diagnostic testing. This may include a brain MRI showing characteristic features, such as a thin corpus callosum, wide lateral ventricles and changes in the white matter. A definitive diagnosis is reached by genetic testing.
| 1,142 |
Spastic Paraplegia 51
|
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