A rare, congenital defect of the small intestine characterized by disruption in the normal small intestine continuity, resulting in intestinal obstruction. The malformation may be classified in four different types of small bowel atresia (SBA) based on the anatomical obstruction.

Summary:
Epidemiology
The prevalence at birth ranges from 1/7,000-25,000 in Europe with equal male/female distribution. About one third of patients are premature. Other congenital anomalies are present in < 10% and occur more frequently with type IIIb or type IV atresia.
Clinical description
The type of SBA is important for surgical treatment and prognosis. Type I corresponds to a narrowed intestine with intact walls and mesentery, and a mucous membrane obstructing the lumen. Type II is a true short segment atresia with a fibrous cord between the upper and lower pouch, without a mesenteric defect. Type IIIa consists of a ''V''-shaped mesenteric defect and a blind-ending, dilated proximal pouch without fibrous connection to the distal part. Type IIIb (''apple-peel'', ''Christmas tree'' atresia) is characterized by proximal jejunal atresia, absence of the superior mesenteric artery and a large mesenteric defect with the small bowel assuming a helical configuration around a single perfusing vessel with possible distal type I or II atresia. Type IV is the combination of multiple atresias. Clinical presentation of all types occurs in the first 24-48h of life, depending on the proximity of the first atretic tract to the Treitz ligament, with signs of bowel obstruction (feeding intolerance, bilious vomiting, abdominal distention). Meconium can be passed normally. Complicated cases might present abruptly, with signs of perforation, intussusception, volvulus or internal hernia. Perforation of the proximal dilated bowel can occur in both the antenatal and postnatal life causing meconium peritonitis. In the case of low atresia or incomplete obstruction, clinical manifestations and diagnosis are usually delayed, with failure to thrive and progressive intestinal obstruction.
Etiology
The prevailing hypothesis is that an ischemic insult affecting single or multiple segments of the developed fetal intestine with subsequent necrosis and resorption is the main cause of SBA. Disruption of an embryologic pathway has been suggested for familial forms but no causative genes have yet been identified.
Diagnostic methods
Diagnosis relies on clinical evaluation, pre- and post-natal history, together with abdominal X-rays that reveal a distended proximal bowel with no air distally. Abdominal ultrasonography shows dilated small intestinal loops with fluid collection. In case of intestinal perforation free air is present. In children with distal defects and/or poor sucking, radiological and clinical findings can be delayed. A contrast enema can be useful.
Differential diagnosis
Differential diagnosis includes: colonic atresia, midgut volvulus, meconium ileus, duplication cysts, internal hernias, paralytic ileus, high Hirschsprung´s disease and hypothyroidism.
Antenatal diagnosis
About 30-50% of cases are suspected antenatally. Dilated bowel loops and polyhydramnios are the typical findings.
Genetic counseling
Whilst the majority of cases are sporadic, familial cases have been reported and thus genetic counselling is always recommended. An autosomal recessive pattern of inheritance of multiple atresias has been documented.
Management and treatment
Bowel decompression via naso-gastric tube, fluid resuscitation and antibiotics are the bridge to surgical correction (restoration of bowel continuity). Surgery must not be delayed, in order to avoid complications. Preserving the largest amount of small bowel tissue is mandatory during surgery. Resections and tapering must be considered. Prolonged parenteral nutrition is often required, particularly in the case of short bowel syndrome. In children on permanent parenteral nutrition, intestinal lengthening procedures may be considered to decrease the need for parenteral nutrition.
Prognosis
The current survival rate is over 90%. Prognosis mainly depends on the length of the remaining bowel and the subsequent possibility of a short bowel syndrome. Type IIIb and type IV carry a worse prognosis.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Dr Francesco FASCETTI LEON | ERNICA* - Pr Niels QVIST | ERNICA* - Dr Alessandra RANCAN

                                * European Reference Network


Small cell carcinoma of the bladder (SCCB) is a very rare, poorly differentiated neuroendocrine epithelial bladder tumor characterized clinically by hematuria and/or dysuria and a highly aggressive course.

Summary:
Epidemiology
SCCB is extremely rare with an annual incidence of less than 1-9/1,000,000. Since 1980, fewer than 1,500 cases have been identified. The demographic profile of SCCB is similar to that of patients with bladder transitional cell carcinoma (TCC). The majority of patients are male, with a mean sex ratio of 5:1, and a range between 1:1 to 16:1. The vast majority of cases were reported in the Caucasian population.
Clinical description
Most knowledge on SCCB is based on retrospective investigations and on a few prospective studies. Mean age at diagnosis is 67 years (range 32 to 91 years). The clinical features of SCCB are similar to those of bladder TCC and reflect the presence of a tumoral mass. The main symptom is gross hematuria (63 to 88% of cases) with dysuria as the second most common symptom. Urinary obstruction, abdominal pain, urinary tract infection and weigh loss are occasionally present. SCCB often occurs with other types of carcinoma and is frequently found combined with other histological forms of bladder cancer: TCC, adenocarcinoma and squamous cell carcinoma. SCCB is generally believed to have a high metastatic potential. Rare cases of paraneoplastic syndromes such as ectopic ACTH secretion and hypercalcemia have also been reported.
Etiology
The etiology of the disease is unknown but a multipotent stem cell anomaly is thought to be a likely mechanism. A history of smoking is found in 65% to 79% of cases.
Diagnostic methods
Histology and immunohistochemistry show a tumor that is indistinguishable from small cell lung cancer (SCLC; see this term). Diagnosis of SCCB relies mainly on histopathological data obtained by cystoscopy and transurethral resection of the bladder tumor. Immunochemistry staining is useful in establishing the diagnosis. Light microscopy reveals packed cells having scant cytoplasm containing few organelles. Tumors are composed of nests of small round malignant cells with pyknotic round to oval nuclei and evenly dispersed ''salt and pepper chromatin''. More than 95% of SCCB cases are diagnosed at muscle invasive stage T2 or later.
Differential diagnosis
The differential diagnosis includes direct invasion of the bladder by SCC of the prostate, metastatic SCC from another source, usually the lung, and primary lymphomas of the bladder.
Management and treatment
The staging system used is the TNM-staging of bladder transitional cell carcinoma. Treatment is extrapolated from that of SCLC. However, many patients with SCCB undergo radical resection which is rarely performed in SCLC. Patients with surgically resectable disease should be managed with multimodal therapy associating chemotherapy, surgery and/or radiotherapy. Neoadjuvant chemotherapy using 4 chemotherapy cycles followed by radical cystectomy is the most effective therapeutic sequence. Patients with unresectable disease should be managed with palliative chemotherapy based on neuroendocrine-type regimens comprising a platinum drug (cisplatin in fit patients). Prophylactic cranial irradiation should be considered in stages III/IV bladder SCC.
Prognosis
The prognosis of the disease is poor mainly in the case of pure small cell carcinoma.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr NABIL ISMAILI


Small cell carcinoma of the ovary is a rare, highly aggressive, poorly differentiated ovarian neoplasm, often associated with paraneoplastic hypercalcemia. It is usually diagnosed in childhood or young adulthood at an advanced stage and presents with abdominal or pelvic mass or, rarely, symptoms related to hypercalcemia. Occasional familial cases have been reported.


Small cell lung cancer (SCLC) is a highly aggressive malignant neoplasm, accounting for 10-15% of lung cancer cases, characterized by rapid growth, and early metastasis. SCLC usually manifests as a large hilar mass with bulky mediastinal lymphadenopathy presenting clinically with chest pain, persistent cough, dyspnea, wheezing, hoarseness, hemoptysis, loss of appetite, weight loss, and neurological and endocrine paraneoplastic syndromes. SCLC is primarily reported in elderly people with a history of long-term tobacco exposure.


A rare soft tissue tumor characterized by a compressive mass located in the mediastinum and/or pleura and lung, including prominent lymph node involvement, histologically poorly differentiated and frequently showing rhabdoid features. Loss of SMARCA4 is typically accompanied by SMARCA2-deficiency. Presenting symptoms include dyspnea, cough, chest pain, or dysphagia, among others. The tumors are aggressive with limited response to chemotherapies, rapid local progression, high recurrence rate after surgical resection, and short median survival times. There is a strong association with smoking.


Smith-Lemli-Opitz syndrome (SLOS) is characterized by multiple congenital anomalies, intellectual deficit, and behavioral problems.

Summary:
Epidemiology
SLOS is most common in central and northern Europe with an estimated incidence of around 1/ 20,000 to 1/ 40,000 births.
Clinical description
The disease is present at birth, but may be detected in later childhood or adulthood in mild forms. Patients present with growth retardation and intellectual deficit. Behavioral problems include multiple autistic traits, hyperactivity, self-injurious behavior and sleep disturbances. The structural brain anomalies may include hypoplasia or absence of the corpus callosum, and holoprosencephaly. Microcephaly (80% of cases), bitemporal narrowing, ptosis, a broad nasal bridge, short nasal root, anteverted nares (90% of cases), a small chin, and micrognathia are common craniofacial features. Occasionally, cataract, strabismus, and nystagmus are observed. Other clinical features include cleft palate or bifid uvula (1/3 of patients), photosensitivity, rhizomelia and postaxial polydactyly of the hands or feet, syndactyly of the 2nd and 3rd toes (95% of cases), and short and proximally placed thumbs. Genital anomalies (small penis, hypospadias, ambiguous genitalia) are frequent in males (70% of cases). Cardiovascular anomalies (atrial and ventricular septal defects, patent ductus arteriosus, atrioventricular canal) can be present. Gastrointestinal anomalies including poor feeding, gastroesophageal reflux, pyloric stenosis, malrotation, and colonic aganglionosis are frequent.
Etiology
SLOS is due to an inborn error of cholesterol synthesis and is caused by mutations in the DHCR7 gene (11q13.4) leading to deficiency of the enzyme 3 beta-hydroxysterol-delta 7-reductase that converts 7-dehydrocholesterol (7DHC) to cholesterol.
Diagnostic methods
Diagnosis is based on the detection of elevated 7DHC levels in plasma or tissues. Mutation analysis confirms the diagnosis. Imaging studies (CT, MRI, echocardiogram) may be performed to detect malformations.
Differential diagnosis
he differential diagnosis includes lathosterolosis, desmosterolosis, Dubowitz syndrome, Cornelia De Lange syndrome, oculo-digito-esophago-duodenal syndrome, Noonan syndrome, Pallister-Hall syndrome, trisomy 13 and trisomy 18 (see these terms), and pseudotrisomy 13.
Antenatal diagnosis
Prenatal diagnosis may be suspected at fetal ultrasonography and should be confirmed by analysis of amniotic fluid or chorionic villous samples, measurements of 7DHC content and mutation analysis if DHCR7 mutations have already been identified in the family.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Management is symptomatic and most patients are treated with dietary cholesterol supplementation. Treatment trials are underway investigating combined treatment with cholesterol supplementation and a HMG CoA reductase inhibitor (simvastatin). Surgery is proposed in case of secondary problems due to malformations.
Prognosis
Prognosis depends on the severity of the disease and on the associated malformations. Heart disease and brain malformations may be lethal. Some individuals live into adulthood. Mildly affected individuals may be able to live and work in a group home setting.

                            Last update:
                            November 2009

                            - Expert reviewer(s):
                            Dr Simona BIANCONI  - Dr Forbes PORTER


A rare, genetic, neurodevelopmental disorder characterized by cognitive impairment of variable severity, behavioral abnormalities, and sleep disturbance. Patients present with distinctive physical features and a wide range of malformations (e.g. cardiac, renal).

Summary:
Epidemiology
Smith-Magenis syndrome (SMS) has an estimated prevalence of 1/15,000-25,000 and has been identified worldwide in all ethnic groups, but is probably underdiagnosed. Males and females are affected equally.
Clinical description
Patients have a recognizable clinical picture. Craniofacial features include brachycephaly, a broad square-shaped face, synophrys, mildy upslanted palpebral fissures, midface retrusion with relative prognathism with age, and an everted upper lip with a ''tented'' appearance. Short stature is common in young patients, with height typically in the normal range as adults. Excess weight and/or obesity in teens and adults are common. Other skeletal anomalies include brachydactyly, clinodactyly of the 5th finger, 2-3 toe syndactyly and scoliosis. Otolaryngological problems such as velopharyngeal insufficiency, laryngeal anomalies, a hoarse deep voice and otitis media occur frequently. Hearing loss is frequent and may be mild to moderate. Ophthalmologic features (>80%) include strabismus, myopia, iris anomalies and retinal detachment (often resulting from violent behaviors). The majority of individuals function in the mild to moderate range of intellectual disability. Significant speech delay and maladaptive behaviors (outbursts/temper tantrums, nail yanking, insertion of foreign objects into body orifices, self-injurious behaviors, attention seeking, and anxiety) are common. Sleep disturbance is due to an inversion of the circadian rhythm of melatonin. Organ malformations include cardiac, renal and central nervous system abnormalities.
Etiology
SMS is typically a sporadic disorder caused either by a 17p11.2 deletion encompassing the retinoic acid-induced 1 (RAI1) gene (90%) or a mutation of the gene (10%). Patients with a mutation can have a less severe phenotype, and manifestations may have a later onset in the least severe cases.
Diagnostic methods
Diagnosis is based on initial clinical suspicion followed by molecular confirmation of the genetic defect. Careful history-taking for birth defects, sleep disturbance, delayed milestones, chronic ear infections, self-injurious behaviors, and family history are important to recognize the characteristic features.
Differential diagnosis
Differential diagnoses include Down syndrome, Williams syndrome, brachydactyly-intellectual deficit syndrome (del 2q37), and Kleefstra syndrome.
Antenatal diagnosis
Almost all cases correspond to a single occurrence in a family, but prenatal testing can be offered for at-risk pregnancies where the genetic alteration has been previously identified in an affected family member.
Genetic counseling
The disorder is autosomal dominant with most cases arising sporadically. Genetic counseling is recommended to affected families due the possibility of vertical transmission, parental germline mosaicism, and complex familial chromosome rearrangements. When a chromosomal deletion is identified, parental chromosomal testing is recommended to rule-out any translocation or other rearrangements that might affect the recurrence risk.
Management and treatment
Appropriate assessment of the degree of cognitive, developmental, and behavioral deficits and of systemic/organ abnormality is essential for appropriate and specific management. Treatment is symptomatic and may include psychotropics intended to increase attention, decrease hyperactivity and stabilize behavior and treatment for sleep disorders. However, no single regimen has shown consistent efficacy. Family psychosocial support is recommended.
Prognosis
Prognosis depends on age of diagnosis, disease severity, and precocity of therapeutic interventions.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Laurence PERRIN | ITHACA*

                                * European Reference Network


Smith-McCort dysplasia (SMC) is a rare spondylo-epi-metaphyseal dysplasia characterized by the clinical manifestations of coarse facies, short neck, short trunk dwarfism with barrel-shaped chest and rhizomelic limb shortening, as well as specific radiological features (i.e. generalized platyspondyly with double-humped vertebral end plates and iliac crests with a lace-like appearance) and normal intelligence. The clinical and skeletal features are similar to those seen in the allelic disorder Dyggve-Melchior-Clausen syndrome (DMC; see this term), but can be distinguished from this syndrome by the absence of intellectual deficiency and microcephaly in SMC.


A rare, slowly progressive form of systemic mastocytosis (SM) characterized by gradual accumulation of neoplastic mast cells in the visceral organs. Patients typically present with splenomegaly, hypercellular marrow and, in most cases, urticaria pigmentosa-like skin lesions.

Summary:
Epidemiology
The prevalence and incidence is unknown.
Clinical description
The age of onset of smoldering systemic mastocytosis (SSM) is in adulthood, with patients tending to be slightly older than those with isolated SM (ISM). The disease is defined by the presence of at least two B-findings, indicative of a high mast cell (MC) burden, and no C findings (organ dysfunction). There is a pronounced MC infiltration (>30% in bone marrow (BM) biopsy), organomegaly and tryptase levels above 200 ng/ml. The clinical course is characterized by slow progression without signs of aggressive disease or an associated hematologic neoplasm (AHN). Patients may remain stable for years or may progress into a more advanced variant (aggressive SM (ASM), mast cell leukemia (MCL) or SM with an AHN).
Etiology
Although the etiology of SSM is not fully understood, an activating mutation of KIT, usually KIT D816V, is found in the MCs of virtually all SSM cases. This mutation probably accounts for the abnormal accumulation of MCs in organ(s)/tissue(s). Multilineage KIT D816V involvement is constantly found in SSM patients.
Diagnostic methods
Diagnosis of SSM is achieved by first establishing a diagnosis of SM, based on the WHO consensus criteria. The disease is then categorized according to the presence of B-findings and C-findings. For SSM, at least two B-findings (but no C-findings) should be present.
Differential diagnosis
Differential diagnoses include all the other forms of SM, as well as other causes of MC activation syndromes (MCAS): primary (clonal, but not fulfilling SM diagnostic criteria) MCAS; secondary MCAS where an IgE-dependent allergy or another reactive inflammatory disease process is present; and idiopathic MCAS where neither clonal MC nor an IgE-dependent allergy or another underlying condition/disease can be documented. Additional differential diagnoses include other forms of mastocytosis (pure cutaneous mastocytosis, indolent SM, aggressive SM), endocrine disorders (adrenal tumors, VIPoma, gastrinoma), and some gastrointestinal pathologies. Waldenström disease should also be distinguished.
Management and treatment
In stable SSM patients, symptomatic treatment may be the only therapy. Avoidance of known triggers, prophylactic prescription of an epi-pen, and medications such as antihistamines, antileukotrienes, cromolyn sodium, omalizumab and aspirin may all have a role in the prevention or treatment of MC-mediated symptoms. Regular follow-up and assessment for transformation to more aggressive disease variants is required. Serum tryptase, which may be used to assess disease response, may be evaluated biannually to monitor disease activity and appropriately adjust therapy. In patients who progress to more advanced variants of the disease, introduction of targeted or non-targeted cytoreductive therapy may be discussed. Whilst favorable results have been seen with the current targeted and non-targeted treatment, a consensus on treatment in patients with SSM has not been reached.
Prognosis
Some SSM patients may remain stable for years, while others may progress to more advanced variants of the disease (ASM or MCL), with a poorer prognosis. In general, the prognosis of SSM regarding progression-free survival and overall survival is better than that of ASM or MCL, but poorer than in typical ISM.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Pr Michel AROCK


A rare disorder due to poisoning caused by toxins in the bite of a venomous snake. Envenoming can also be caused by spraying of venom into the eyes. Depending on venom composition and other factors, consequences range from local tissue damage to potentially life-threatening systemic effects. Severe manifestations include paralysis, bleeding disorders, kidney failure, or permanent disability and limb amputation due to severe local tissue destruction. Children may suffer more severe effects because of their lower body mass. Immediate medical attention, in particular administration of antivenom, is critical.


Sneddon's syndrome (SS) is a rare non-inflammatory thrombotic vasculopathy characterized by the combination of cerebrovascular disease with livedo racemosa.

Summary:
Epidemiology
SS has an estimated annual incidence of approximately 1/250,000. The disease predominantly affects women in young adulthood.
Clinical description
The mean age of onset of neurological symptoms is 39 years, though the livedo is generally observed up to 10 years earlier and sometimes since childhood. Livedo racemosa is a persistent net-like violaceous-cyanotic, mottled discoloration of the skin affecting primarily the legs and arms, but also involving the buttocks and the trunk, and that is exacerbated by cold or pregnancy. Livedo reticularis, that is limited to the extremities and is visible only in the cold, has also been observed in some cases. Neurological manifestations include recurrent transient ischemic attacks (TIAs) and infarcts, often of the middle cerebral artery territory resulting in contralateral hemiparesis, aphasia, and/or visual field defects. Rarely, spinal strokes or intracranial or subarachnoid hemorrhages occur. Headache and vertigo may precede the onset of livedo racemosa and cerebrovascular manifestations by several years. In the course of the disease, memory disturbances, personality changes, and cognitive decline leading to dementia occur frequently. Rare neurologic symptoms include seizures, chorea, or myelopathies. Secondary hypertension is common, as are valvular heart disease, ocular and kidney involvement.
Etiology
While about 50% of cases are idiopathic, SS can be associated with autoimmune diseases like systemic lupus erythematosus, antiphospholipid syndrome, Behçet disease, and mixed connective tissue disease (see these terms). The manifestations of SS are caused by a progressive, non-inflammatory arteriopathy, usually of the small to medium arteries, leading to occlusion of these arteries by excessive endothelial proliferation with impaired blood flow and clotting. Genetic factors may play a role in the pathogenesis of SS. Loss-of-function mutations in cat eye syndrome chromosome region candidate 1 CECR1 (22q11.2) encoding adenosine deaminase 2 have been found.
Diagnostic methods
SS is suspected on the basis of the clinical picture. It has to be considered in cases of unexplained stroke at a young age, cognitive decline without stroke, and assumed autoimmune-related vasculitis in which immunosuppressive therapy has proven ineffective. Skin biopsy may confirm the diagnosis, revealing occlusion of arterioles by intimal proliferation. MRI typically reveals white matter changes, infarcts, microbleeds or atrophy, and is more sensitive than CT. Laboratory testing for antiphospholipid antibodies may be positive in about 60% of cases.
Differential diagnosis
Differential diagnoses include reversible cerebral vasoconstriction syndrome, MELAS syndrome, cerebrovascular dementia (see these terms), migraine, the autoimmune diseases with which SS can be associated, and cerebral angiitis.
Genetic counseling
Most cases are sporadic but some familial cases with an autosomal dominant inheritance have been reported. In these cases, a genetic susceptibility is likely.
Management and treatment
The most widely accepted treatment is anticoagulation with warfarin. Some suggest that aPL-negative patients should follow a less aggressive approach consisting of antiplatelet therapy with aspirin, while others recommend warfarin with a higher international normalized ratio (coagulation index) target. Angiotensin-converting enzyme (ACE) inhibitors have been suggested to reduce endothelial proliferation, and prostaglandin to improve microvascular perfusion. Successful intravenous systemic fibrinolysis with tissue plasminogen activator (tpA) has been reported in acute ischemic stroke. While the use of immunosuppressive therapy (azathioprine, cyclophosphamide) doesn't seem effective, there are data indicating that rituximab may be effective in aPL-positive patients.
Prognosis
SS is a chronic, intermittent or progressive disease leading to major morbidity. Dementia occurs in 50% of patients resulting in early retirement.

                            Last update:
                            March 2015

                            - Expert reviewer(s):
                            Pr Peter BERLIT


Snowflake vitreoretinal degeneration (SVD) is characterised by the presence of small granular-like deposits resembling snowflakes in the retina, fibrillary vitreous degeneration and cataract. The prevalence is unknown but the disorder has been described in several families. Transmission is autosomal dominant and the causative gene has been localised to a small region on chromosome 2q36.


A rare photodermatosis characterized by an abrupt onset of transient erythema, wheals, and pruritus appearing within minutes of exposure to light.

Summary:
Epidemiology
Exact, prevalence and incidence of solar urticaria are not known. It is reported as representing only 4-8% of all photodermatosis presentations and estimated to account for only 0.4% of all urticarias. To date, more than 650 cases have been described worldwide. Females are predominantly affected.
Clinical description
Wheal formation and pruritus are characteristic, but other manifestations have been reported such as headaches, general malaise, increased heart rate, low blood pressure and syncope. Symptoms almost always clear within 24 hours. The disease can initially appear in all age groups, although it most commonly presents during the third or fourth decade of life. It is a chronic disease requiring long-term treatment. However, some patients (up to 15%) experience spontaneous remissions.
Etiology
The etiology and pathophysiology are not clearly defined; however, the disease may be caused by an antigen-antibody reaction. There are two possible mechanisms, antibodies are either targeted against an abnormal photoallergen which is generated only in patients with SU, or they are targeted against a normal photoallergen generated both in patients and in normal individuals. The immune response involves a photoallergic reaction resulting in histamine release by mast cells.
Diagnostic methods
Phototesting is an important tool for confirming the diagnosis, to assess the responsible wavelengths, the minimal whealing (urticaria) dose (MUD) and the response to therapy.
Differential diagnosis
The major differential diagnoses to be considered include polymorphic light eruption (which generally appears only 2-3 days after sun exposure and lasts more than 24 hours), lupus erythematosus tumidus (which typically occurs more than a week after sun exposure) and erythropoietic protoporphyria, (an inherited disease that may have similar clinical manifestations).
Management and treatment
Treatment is difficult and referral to a specialist is recommended. Treatment recommendations are based on retrospective studies and small case series. They include broad‐spectrum sunscreens, antihistamines, leucotriene receptor antagonist (LRA), UV phototherapy (hardening), azathioprine, ciclosporin, intravenous immunoglobulins and omalizumab. The European consensus is first-line treatment with non-sedative anti-histamines. If the disease is inadequately controlled, treatment is stepwise with increased dose, followed by omalizumab and then ciclosporin.
Prognosis
Therapeutic intervention can significantly improve the quality of life but response is variable. Spontaneous resolution of symptoms may occur in 15% of patients within 10 years. Some patients have to avoid outdoor activities completely, severely impacting their quality of life.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr Claes ENK  - Dr Assi LEVI  - Dr Igor SNAST


Solid pseudopapillary carcinoma of pancreas

A rare carcinoma of the pancreas characterized by a variable combination of nonspecific signs and symptoms, such as abdominal pain, jaundice, abdominal fullness, anorexia, nausea, vomiting, and weight loss. One-third of the patients are asymptomatic. The tumor has low malignant potential, but can invade locally.


A benign non-epithelial bone cavity that is asymptomatic and that is found most commonly in the second decade of life by chance. The long bones are most often affected, but cases involving the jaw bone have been reported.


A rare soft tissue tumor characterized by a well-circumscribed mass potentially occurring at any anatomical site, histopathologically showing spindled to ovoid cells arranged around a branching and hyalinized vasculature and variable stromal collagen deposition. Immunohistochemistry reveals CD34 and/or STAT6 expression. NAB2-STAT6 gene fusions are pathognomonic for this tumor, which may be malignant or benign. Clinically, most patients present with a slow-growing, painless mass. Large tumors may cause paraneoplastic syndromes such as Doege-Potter syndrome, with the induction of severe hypoglycemia or acromegaloid features.


A rare nonmalignant hepatic lesion characterized by a mass with a completely necrotic core often partially calcified, surrounded by a dense hyalinized fibrous capsule containing elastin fibers. Patients are usually asymptomatic but some may suffer from intermittent abdominal pain or discomfort.


Solitary rectal ulcer syndrome (SRUS) is a rare rectal disease characterized by rectal bleeding, abdominal pain, passage of mucus, sensation of incomplete evacuation, straining at defecation and rectal prolapsed, secondary to ischemic changes in the rectum.


A rare, mixed, functioning pituitary adenoma characterized by the cosecretion of growth hormone and prolactin, which manifests with signs and symptoms of both acromegaly and hyperprolactinemia.


Somatostatinoma (SSoma) is an extremely rare pancreatic neuroendocrine tumor or duodenal endocrine tumor (see these terms) that originates either in the pancreas (50%) or the gastrointestinal tract (50%) and mainly presents with non-specific symptoms of abdominal pain, weight loss, jaundice and diarrhea but, in approximately 20% of pancreatic cases, leads to a somatostatin hypersecretion syndrome (somatostatinoma syndrome) characterized by diabetes mellitus, cholelithiasis, steatorrhea and hypochlorhydria.

Summary:
Epidemiology
The estimated incidence is of 1/40,000,000. Approximately 80 cases of pancreatic SSoma have been reported to date but this is probably an underestimate.
Clinical description
SSomas usually range in size from 3-11cm. Most SSomas present with non-specific symptoms of abdominal pain, weight loss, painless obstructive jaundice and diarrhea. Somatostatinoma syndrome occurs in those with a functioning pancreatic SSoma with manifestations including diabetes mellitus, cholelithiasis, diarrhea, weight loss, steatorrhea and hypochlorhydria. More than half of all SSomas are malignant and they have often metastasized at the time of diagnosis. Duodenal somatostatinoma is often associated with neurofibromatosis type 1 (NF1; see this term).
Etiology
Some SSomas are components of familial endocrine tumor syndromes. The cause of sporadic SSomas is not clear. SSoma hypersecretes stomatostatin, which inhibits the secretion of numerous gastrointestinal hormones (such as gastrin, secretin, insulin, glucagon, and cholecystokinin), resulting in somatostatinoma syndrome

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Run YU


Sorsby pseudoinflammatory fundus dystrophy

Sorsby's fundus dystrophy is a rare progressive autosomal dominant macular dystrophy, presenting between the third and sixth decades of life, characterized by retinal atrophy and retinal detachment and leading to loss of central vision, then peripheral vision, and eventually blindness.


A rare genetic overgrowth syndrome characterized by a typical facial appearance, overgrowth with macrocephaly and variable intellectual impairment.

Summary:
Epidemiology
Prevalence at birth is estimated at 1/14,000.
Clinical description
Excessive growth is evident across life, especially in childhood, and can manifest since fetal life, with final adult height beyond or in the upper part of the normal ranges. Macrocephaly is usually striking and disproportioned with respect to height. The distinct facial appearance is most easily recognized in early childhood (long narrow face, flushed cheeks, prominent forehead with frontotemporal hair scarcity, down-slanting palpebral fissures, hypertelorism, a high arched palate, and pointed chin). Sotos syndrome is associated with mild to severe intellectual disability as well as a wide spectrum of behavioral disorders. Developmental milestones are commonly delayed. Additional features may include in the neonatal period hypotonia and poor feeding and subsequently advanced bone age, scoliosis, prognathia, premature dental eruption, large hands and feet. Seizures and electroencephalogram abnormalities are common. Less common features are conductive hearing loss, and cardiac and genitourinary anomalies. Cancer predisposition is debated: the increased risk, if any, appears to be low.
Etiology
Sotos syndrome is caused by mutations or microdeletions in the NSD1 gene (5q35) in more than 95% of cases. NSD1 is involved in normal growth and development. Biallelic mutations in the APC2 gene (19p13.3) have also been reported in a few cases.
Diagnostic methods
The diagnosis is based on the major clinical manifestations (characteristic facial features, learning disability, and overgrowth). It can be confirmed by molecular genetic testing of the causative genes. Overlap with other overgrowth syndromes may complicate diagnosis.
Differential diagnosis
The differential diagnosis should include Malan syndrome, Simpson-Golabi-Behmal syndrome, Weaver syndrome, Tatton-Brown-Rahman syndrome, Bannayan-Riley-Ruvalcaba syndrome, Fragile X syndrome and megalocephalic syndromes associated with mutations in the PI3K-AKT-mTOR pathway. A Sotos-like phenotype has been reported in patients with SETD2 mutations.
Antenatal diagnosis
Prenatal diagnosis is possible if the disease-causing mutation has been identified in the family or if there is the strong suspicion of the condition (e.g. macrocephaly).
Genetic counseling
Sotos syndrome follows an autosomal dominant pattern of inheritance in the rare familial cases associated with NSD1; genetic counseling should be offered to affected individuals informing them that, for every pregnancy, there is a 50% risk of transmitting the disorder to offspring. The vast majority of patients have de novo mutations. In these cases, risk of recurrence is very low.
Management and treatment
There is no specific treatment for the syndrome. Management of Sotos syndrome requires a multidisciplinary approach.
Prognosis
Sotos syndrome shows a wide spectrum of intellectual impairment, with functioning from fully independent to fully dependent. Affected individuals are generally healthy with few medical issues.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Alessandro MUSSA | ITHACA*

                                * European Reference Network


Southeast Asian ovalocytosis (SAO) is a rare hereditary red cell membrane defect characterized by the presence of oval-shaped erythrocytes and with most patients being asymptomatic or occasionally manifesting with mild symptoms such as pallor, jaundice, anemia and gallstones.

Summary:
Epidemiology
SAO is common in Southeast Asian and Western Pacific countries (i.e. Thailand, Malaysia, Indonesia, Philippines and Papua New Guinea). SAO is very common in malaria-endemic areas (prevalence 1/20-1/4) but in Europe it is very rare.
Clinical description
SAO can occur at any age. Newborns with SAO might be symptomatic with hemolysis at birth that leads to anemia, pallor or jaundice. Anemia and hyperbilirubinemia in neonates is common together with mild splenomegaly and gallstones. Hemolysis usually disappears in the first three years of life. Adults are asymptomatic or have only minimal hemolytic anemia. Resistance to malaria (see this term) is also noted.
Etiology
SAO results from a 27 bp deletion in the SLC4A1 gene, localized on chromosome 17q21.31 (SLC4A1del27 mutation). This gene codes for a band 3 anion transport protein which is the bicarbonate/chloride exchanger in red blood cell membranes and defects in this protein cause membrane rigidity. Heterozygous mutations for the deletion are found in almost all cases, as homozygosity is thought to be lethal to the developing embryo. A homozygous mutation was recently reported in one case of SAO as the primary cause of extremely severe dyserythropoietic anemia associated with distal renal tubular acidosis (see this term), and that which would have been lethal if the fetus had not been transfused in utero. The association of mutation SLC4A1del27 with other mutations in the SLC4A1 gene may result in distal renal tubular acidosis associated with SAO in some cases.
Diagnostic methods
Diagnosis is based on the presence on a peripheral blood smear of macro-ovalocytes, some of them stomatocytic with more than one stoma, in the absence of hemolysis. Genetic assays can also be used to identify the mutation in the SLC4A1 gene.
Differential diagnosis
Differential diagnosis includes all forms of hereditary elliptocytosis and hereditary spherocytosis, and dehydrated hereditary stomatocytosis (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible but not undertaken because of the benign nature of the disease.
Genetic counseling
SAO follows an autosomal dominant pattern of inheritance. Genetic counseling is possible.
Management and treatment
Most cases of SAO are asymptomatic and treatment is not necessary.
Prognosis
SAO is not life threatening.

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Dr Alberto ZANELLA


Spasmus nutans (SN) is a rare eye disease characterized by the clinical triad of asymmetric and pendular nystagmus, head nodding, and torticollis.

Summary:
Epidemiology
The prevalence of SN is unknown.
Clinical description
The age of disease onset ranges from 4-12 months and clinically, SN is characterized by a triad of signs which are nystagmus, head nodding, and abnormal head turn or tilt (torticollis). The nystagmus in SN is typically pendular, intermittent, of small-amplitude, high frequency oscillations (shimmering nystagmus) and is usually bilateral, but it can be monocular, asymmetric, and variable in different positions of gaze. Head nodding is not always present, and often follows the onset of nystagmus. It is usually intermittent and of lower frequency than the nystagmus. Both nystagmus and head nodding can occur in any plane (horizontal (more frequent), vertical, oblique, or torsional). Strabismus and amblyopia may be present while oscillopsia is absent. Optic nerve, retinal, or intracranial abnormalities are generally absent.
Etiology
SN is an idiopathic disorder. Head nodding suppresses nystagmus through the vestibular-ocular reflex and aids vision. Similarly, the torticollis has been observed clinically and by electrooculography (EOG) recordings to dampen nystagmus by a hypothesized vestibular mechanism. Low socioeconomic status represents a risk factor for the development of SN.
Diagnostic methods
The diagnosis relies on exclusion of neurological and ophthalmological diseases. Eye movement recordings reveal a fine, high frequency, pendular horizontal nystagmus, which cannot be seen superimposed upon the normal optokinetic response. Visual acuities are generally lower in the eye with the greater nystagmus and vary between 6/6 and 6/24. Optic disc examinations are usually normal. Visual electrophysiology (visual evoked potential (VEP) and electroretinograms (ERG)) should be performed to exclude retinal diseases which can mimic SN.
Differential diagnosis
Differential diagnosis includes SN-like nystagmus, which is defined as a condition where children have nystagmus, head nodding and abnormal head position similar to SN but symptoms are associated with low vision (for example optic nerve hypoplasia, achromatopsia, congenital stationary night blindness, Bardet-Biedl syndrome), neurologic diseases (optic pathway glioma (chiasmal), arachnoid cyst, opsoclonus-myoclonus syndrome, diencephalic syndrome, and Leigh syndrome (see these terms), or systemic abnormalities. Nystagmus may also be associated with idiopathic infantile nystagmus (see this term). SN may also be misdiagnosed as thalamic neoplasm and empty sella.
Genetic counseling
SN is generally sporadic but cases of SN occurring in monozygotic twins have been reported.
Management and treatment
No cure exists and treatment is mainly supportive. This includes treatment for strabismus, amblyopia and refractive errors.
Prognosis
SN is a benign eye motility disorder where patients are usually healthy. The nystagmus has a tendency to decrease in intensity with age and symptoms tend to spontaneously remit within 1 to 5 years of onset with fine, residual nystagmus detectable only on eye movement recording. However, in rare cases, the signs may persist for as long as 8 years.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Pr Irene GOTTLOB


Spastic ataxia with congenital miosis is a rare hereditary ataxia characterized by an apparently non-progressive or slowly progressive symmetrical ataxia of gait, pyramidal signs in the limbs, spasticity and hyperreflexia (especially in the lower limbs) together with dysarthria and impaired pupillary reaction to light, presenting as a fixed miosis (with pupils that seldom exceed 2 mm in diameter and dilate poorly with mydriatics). Nystagmus may also be present.


Spastic ataxia-corneal dystrophy syndrome

A rare, hereditary ataxia disorder characterized by the presence of spastic ataxia in association with bilateral congenital cataract, macular corneal dystrophy (stromal with deposition of mucoid material) and nonaxial myopia. Patients present normal intellectual development. There have been no further descriptions in the literature since 1986.


Spastic ataxia-dysarthria due to glutaminase deficiency

A rare genetic neurometabolic disease characterized by childhood onset of global developmental delay, progressive spastic ataxia leading to loss of independent ambulation, and elevated plasma levels of glutamine. Optic atrophy, tremor, and dysarthria have also been reported. Brain imaging may show cerebellar atrophy.


A rare neurologic disease characterized by spastic paraparesis presenting in late childhood and hearing loss. Additional features may include retinal anomalies, lenticular opacities, short stature, hypogonadism, sensory deficits, tremor, dysdiochokinesia, elevated cerebrospinal fluid protein, and absent or prolonged somatosensory evoked potentials. Plasma and fibroblast levels of saturated very long-chain fatty acids are normal. There have been no further descriptions in the literature since 1986.


A rare, X-linked leukodystrophy characterized primarily by spastic gait and autonomic dysfunction. When additional central nervous system (CNS) signs, such as intellectual deficit, ataxia, or extrapyramidal signs, are present, the syndrome is referred to as complicated SPG.

Summary:
Epidemiology
The prevalence and incidence of SPG2 have not been reported, but as part of the Pelizaeus-Merzbacher (PMD; see this term) spectrum, SPG2 roughly accounts for about 20 % of cases. There have been approximately 20 cases published on SPG2. SPG2 affects males but some female heterozygotes presenting in adulthood with a milder phenotype have also been reported.
Clinical description
SPG2 spans a continuum of phenotypes that goes from pure to complicated SPG2. Pure SPG2 manifests as early as infancy or early childhood (<5 years) but may be delayed until early adulthood. It presents with weakness, hyperreflexia, Babinski sign and spastic gait due to spastic paraparesis. Autonomic dysfunction (spastic urinary bladder and possibly bowel, with increased urinary and fecal frequency and incontinence) is frequent. Patients are able to walk and their speech is normal. There is no CNS involvement and no cognitive decline. Complicated SPG2 shares the same features as SPG2 but also shows additional CNS involvement like nystagmus, and ataxia that present in the first years of life. Optic atrophy may be present. Patients can also show a mild intellectual deficit.
Etiology
SPG2 is due to missense substitutions affecting the PLP1 gene. PLP1 encodes the proteolipid protein (PLP), the most abundant protein of the myelin sheath in the central nervous system, and its alternatively spliced isoform (DM20). SPG2 is allelic to Pelizaeus-Merzbacher disease (PMD; see this term) that is also due to PLP1 mutations.
Diagnostic methods
Diagnosis is based on clinical, electrophysiologic, and neuroradiological findings. White matter N-acetyl aspartate levels are reduced. Brain magnetic resonance imaging (MRI) reveals patchy or diffuse hypomyelination on T2-weighted images. Patients with pure SPG2 can have very subtle T2 hyperintensity. Other MR techniques, including MR spectroscopy and diffusion tensor imaging are useful in the diagnosis of the disease. Molecular genetic testing of PLP1 confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes other forms of hereditary spastic paraplegia (see this tem). Complicated SPG2 is not clearly distinguishable from mild Pelizaeus-Merzbacher disease (PMD) and null syndrome (see these terms).
Antenatal diagnosis
Prenatal genetic testing is possible when a family's underlying PLP1 mutation has been identified.
Genetic counseling
Transmission is X-linked recessive.
Management and treatment
A son born to a female carrier has a 50% risk of inheriting the mutation and developing the disease, while a daughter has a 50% risk of being a carrier. All daughters of an affected male will be carriers but none of his sons will be affected. Management is multidisciplinary and involves neurologists, physical therapists, and orthopedic doctors. Treatment may include antiepileptic drugs for seizures, and physical therapy with antispasticity drugs (baclofen, diazepam, tizanidine, botulinum toxin, dantrolene) for spasticity. Regular surveillance is necessary.
Prognosis
Pure SPG2 patients show a normal life expectancy. In complicated SPG2 cases, patients deteriorate neurologically leading to a shorter life expectancy (between the fourth and seventh decade) typically from aspiration pneumonia, pulmonary embolism and other complications of generalized weakness.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr James GARBERN


A form of hereditary spastic ataxia characterized by an onset usually in adulthood (but ranging from 10-72 years) of progressive bilateral lower limb weakness and spasticity and sometimes predominant cerebellar ataxia. In addition to frequent sphincter dysfunction and decreased vibratory sense at the ankles, manifestations may include optical neuropathy, nystagmus, blepharoptosis, ophthalmoplegia, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, muscle atrophy, parkinsonism, and dystonia.

Summary:
Epidemiology
The worldwide prevalence of autosomal dominant and autosomal recessive spastic paraplegia (SPG) combined is about 1.8 /100.000, the prevalence of SPG type 7 is unknown.
Clinical description
The disease onset is typically between the third and fifth decade, even though earlier or later onset are reported (10-72 years). The clinical presentation can be a pure spastic paraplegia (pyramidal syndrome, sphincter dysfunction, lower limbs weakness, diminished vibration sense, pes cavus) mostly associated with, cerebellar ataxia. Optic atrophy, ptosis and oculomotor abnormalities (nystagmus, progressive external ophthalmoplegia, saccadic pursuit) are frequently associated. Additional neurological signs are spastic dysarthria, dysphagia, parkinsonism, dystonia, scoliosis, hearing loss, and cognitive impairment. Brain magnetic resonance imaging nearly always shows a cerebellar atrophy and electromyography can detect a motor and sensory neuropathy.
Etiology
The disease is due to biallelic pathogenic variants in the SPG7 gene (chromosome 16q24.3) coding for paraplegin protein.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by genetic testing (panel sequencing of hereditary spastic paraplegia genes, exome or genome analysis).
Differential diagnosis
The differential diagnosis includes autosomal dominant and recessive spastic paraplegias, spinocerebellar ataxias (e.g. Spinocerebellar ataxia type 28), adrenomyeloneuropathy and other leukodystrophies, amyotrophic lateral sclerosis, and primary progressive multiple sclerosis.
Antenatal diagnosis
Prenatal diagnosis is possible if the pathogenic variants are known and present in at risk couples (where both parents are heterozygous carriers).
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. Few cases of dominant transmission are reported, individuals carrying one pathogenic variant could present signs (e. g. mild cerebellar atrophy, peripheral neuropathy) or symptoms (e. g. cerebellar ataxia, brisk deep tendon reflexes).
Management and treatment
The treatment is symptomatic, including myorelaxants (oral or intrathecal baclofen, dantrolene, intramuscular botulinum toxin, etc.), bladder control medications, anti-parkinsonian drugs (L-Dopa, dopamine-agonists). Physical, occupational, and speech therapy should be proposed in association with medication.
Prognosis
The disease course is variable but often the walking autonomy is decreased requiring the use of a wheelchair. The disease strongly affects the quality of life.

                            Last update:
                            November 2021

                            - Expert reviewer(s):
                            Dr Giulia COARELLI | ERN-RND* - Pr Alexandra DURR | ERN-RND*

                                * European Reference Network


Spastic paraplegia-facial-cutaneous lesions syndrome

A complex form of hereditary spastic paraplegia characterized by delays in motor development followed by a slowly progressive spastic paraplegia (affecting mainly lower extremities) associated with a desquamating facial rash with butterfly distribution (presenting at around two months of age) and dysarthria. There have been no further descriptions in the literature since 1982.


Spastic paraplegia-glaucoma-intellectual disability syndrome is characterized by progressive spastic paraplegia, glaucoma and intellectual deficit. It has been described in two families. The second described sibship was born to consanguineous parents. The mode of inheritance is autosomal recessive.


Spastic paraplegia-intellectual disability-nystagmus-obesity syndrome

A rare genetic neurological disorder characterized by the association of congenital spastic paraplegia with global developmental delay and intellectual disability, ophthalmologic abnormalities (including nystagmus, reduced visual acuity, or hypermetropia), and obesity. Additional manifestations are brachyplagiocephaly and dysmorphic facial features. Brain imaging may show dilated ventricles, abnormal myelination, and mild generalized atrophy. Homozygous loss-of-function variants of KIDINS220 associated with a fetal lethal phenotype with ventriculomegaly and limb contractures have been reported.


Spastic paraplegia-nephritis-deafness syndrome is a complex form of hereditary spastic paraplegia characterized by progressive, variable spastic paraplegia associated with bilateral sensorineural deafness, intellectual disability, and progressive nephropathy. There have been no further descriptions in the literature since 1988.


A complex form of hereditary spastic paraplegia characterized by spastic paraplegia, demyelinating peripheral sensorimotor neuropathy, poikiloderma (manifesting with loss of eyebrows and eyelashes in childhood in addition to delicate, smooth, and wasted skin) and distal amyotrophy (presenting after puberty). There have been no further descriptions in the literature since 1992.


Spastic paraplegia-optic atrophy-neuropathy and spastic paraplegia-optic atrophy-neuropathy-related disorder

A group of rare, genetic, neurodegenerative diseases characterized by an infancy- to childhood-onset of progressive spastic paraplegia (with delayed motor milestones, gait disturbances, hyperreflexia and extensor plantar responses), optic atrophy (which may be accompanied by nystagmus and visual loss) and progressive peripheral neuropathy (with sensory impairment and distal muscle weakness/atrophy in upper and lower extremities). Additional signs may include foot deformities, spinal defects (scoliosis, kyphosis), joint contractures, exaggerated startle response, speech disorders, hyperhidrosis, extrapyramidal signs and intellectual disability. In very rare cases, a variant phenotype with less prominent or absent optic atrophy and/or neuropathy may be observed.


Spastic paraplegia-optic atrophy-neuropathy syndrome

A rare, complex type of hereditary spastic paraplegia characterized by early-onset progressive spastic paraplegia presenting in infancy, associated with optic atrophy, fixation nystagmus, polyneuropathy occurring in late childhood/early adolescence leading to severe motor disability and progressive joint contractures and scoliosis.


Spastic paraplegia-Paget disease of bone syndrome is an extremely rare, complex form of hereditary spastic paraplegia characterized by a slowly progressive spastic paraplegia (with increased muscle tone, decreased strength in the anterior tibial muscles and hyperreflexia in the lower extremities with Babinski sign) presenting in adulthood, associated with Paget disease of the bone. Cognitive decline, dementia and myopathic changes at muscle biopsy have not been reported.


Spastic paraplegia-precocious puberty syndrome is a complex form of hereditary spastic paraplegia characterized by the onset of progressive spastic paraplegia associated with precocious puberty (due to Leydig cell hyperplasia) in childhood (at the age of 2 years). Moderate intellectual disability was also reported. There have been no further descriptions in the literature since 1983.


Spastic paraplegia-severe developmental delay-epilepsy syndrome is a rare, genetic, complex spastic paraplegia disorder characterized by an infantile-onset of psychomotor developmental delay with severe intellectual disability and poor speech acquisition, associated with seizures (mostly myoclonic), muscular hypotonia which may be noted at birth, and slowly progressive spasticity in the lower limbs leading to severe gait disturbances. Ocular abnormalities and incontinence are commonly associated. Other symptoms may include verbal dyspraxia, hypogenitalism, macrocephaly and sensorineural hearing loss, as well as dystonic movements and ataxia with upper limb involvement.


Spastic tetraplegia-retinitis pigmentosa-intellectual disability syndrome

A rare, genetic, syndromic intellectual disability disorder characterized by the association of nonprogressive spastic quadriparesis, retinitis pigmentosa, intellectual disability, and variable deafness. There have been no further descriptions in the literature since 1976.


Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome

A rare neurometabolic disorder due to serine deficiency characterized by neonatal to infantile onset of global developmental delay, postnatal microcephaly and intellectual disability, which may be associated with slowly progressive spastic tetraplegia mainly affecting the lower extremities, seizures, and brain MRI findings including thin corpus callosum, delayed myelination and cerebral atrophy. Additional symptoms include brisk deep tendon reflexes, extensor plantar responses, behavioral abnormalities (such as irritability, hyperactivity, sleep disorder), abnormal hand movements and stereotypy.


A rare autosomal dominant malformation syndrome characterized by hypertelorism, omphalocoele, cleft lip, ear pits, uterine malformation (bicornuate uterus), and more variably by diaphragmatic hernia and congenital heart defects.

Summary:
Epidemiology
Unknown. Less than 40 patients reported with genetic confirmation. The clinical diagnostic is unreliable in older literature due to phenotypic confusion.
Clinical description
Presentation is typically with characteristic facial dysmorphism: prominent forehead, hypertelorism (>95%) and telecanthus, cleft lip/palate (25%), slightly downslanting palpebral fissures, long philtrum prominent nasal root, and a large nose with a large tip. Malformations include omphalocoele (50%), uterine malformations (>25%), congenital heart malformations (20%), ear pits (30%), dysphagia, reflux and other esophageal problems (30%) and, less commonly, diaphragmatic herniae (10%), inguinal herniae, aortic root dilation, and rarely CNS anomalies (ventriculomegaly, agenesis of the corpus callosum) and craniosynostosis. Learning disability affects 20% of patients, and intellectual disability (ID) is present in 10%.
Etiology
The disorder is due to heterozygous gain of function variants in SPECC1L (Sperm antigen with calponin homology and Coiled-Coil domains 1 Like) located in 22q11.23. The SPECC1L protein is a cytoskeletal protein that associates with both actin and microtubules to affect larger cytoskeletal function. It is involved in cell adhesion, actin cytoskeleton organization, microtubule stabilization, spindle organization and cytokinesis. Of note, heterozygous loss of function of SPECC1L causes Tessier IV oblique facial cleft.
Diagnostic methods
SPECC1L-related hypertelorism syndrome is suspected on clinical findings : ocular hypertelorism and at least one other of the characterstic findings (omphalocoele or diaphragmatic hernia, bicornuate uterus, ear pits). Diagnosis is confirmed by identification of a SPECC1L variant.
Differential diagnosis
Opitz GBBB syndrome is the main differential diagnosis of SPECC1L-related hypertelorism syndrome. Opitz GBBB syndrome has strikingly overlapping craniofacial phenotype, leading to confusion in the past literature between MID1-confirmed Opitz GBBG and various overlapping conditions. Earpits, uterine malformations, omphalocoele, diaphragmatic herniae are specific to SPECC1L, whereas laryngeal and anorectal defects are specific to Optiz GBBB. ID is more common in the latter. Baraitser-Winter cerebrofrontofacial syndrome (ACTB and ACTG1), craniofrontonasal dysplasia (EFNB1), frontonasal dysplasia and Aarskog syndrome (FGD1) share marked hypertelorism.
Antenatal diagnosis
Prenatal testing is possible for at-risk pregnancies if a SPECC1L mutation has been previously identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal dominant and genetic counseling is recommended for young adults who are affected. The offspring of an affect individual have a 50% risk of also being affected.
Management and treatment
Multidisciplinary medical support with pediatricians, craniofacial, ENT (ear, nose and throat) and abdominal surgeons, cardiologists, and a medical geneticist is required. Neurodevelopmental support and speech therapy may be necessary. Uterine anomalies may cause fertility issues.
Prognosis
Prognosis is variable but usually favorable, depending on the severity of malformations and associated ID.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Alain VERLOES | ITHACA*

                                * European Reference Network


Spectrin-associated autosomal recessive cerebellar ataxia is a rare, genetic neurological disease, due to SPTBN2 mutations, characterized by global development delay in infancy, followed by childhood-onset gait ataxia with limb dysmetria and dysdiadochokinesia, mild to severe intellectual disability, development of cerebellar atrophy, and abnormal eye movements (including a convergent squint, hypometric saccades, jerky pursuit movements and incomplete range of movement).


Spermatocytic seminoma (SS) is an extremely rare form of testicular cancer distinguished from testicular seminomatous germ cell tumors (see this term) by a very low rate of metastasis and lack of an ovarian equivalent.

Summary:
Epidemiology
SS accounts for around 1- 2% of all cases of testicular germ cell tumors (see this term). Annual incidence in Europe is 1/3,300,000.
Clinical description
SS presents in males in their fifth to sixth decade of life. A painless mass in the scrotum or an interscrotal mass are indicative of disease. A long-standing hydrocele may be noted causing a feeling of heaviness in the testicle. Gynecomastia and back and flank pain are symptoms that are seen in some patients. The invasion of seminoma into the blood vessels, tunica albuginea and epididymus is rarely seen. In extremely rare instances a sarcomatous transformation can occur which causes the tumor size to rapidly increase along with its propensity for metastasis. In the very few cases that metastasis occurs, this aggressive form of tumor is referred to as metastatic spermatocytic seminoma.
Etiology
The etiology of SS is unknown. It is thought to originate from a premeiotic germ cell.
Diagnostic methods
Clinical findings orientate the diagnosis and measurement of tumor marker levels (alpha-fetoprotein) help in the precision of SS diagnosis. Testicular sonogram is also performed while bone scan and magnetic resonance imaging (MRI) of the central nervous system is only needed when symptoms of involvement in those areas are seen. Histopathological examination of the testicular mass biopsy confirms SS with the presence of three characteristic cell types: small cells (7-8 µm) with dark nuclei, medium sized cells (15 µm) with granular chromatin and eosinophilic cytoplasm in round nuclei and large multinucleated cells (up to 100 µm).
Differential diagnosis
Differential diagnoses include testicular seminomatous germ cell tumors and all types of lymphoma (see these terms).
Management and treatment
Treatment of SS is similar to that of testicular seminomatous germ cell tumors which involves an orchidectomy. As this form of seminoma rarely metastasizes there is usually no further treatment needed but surveillance following surgery is necessary. Patients with the rare metastatic form are given additional chemotherapy (carboplatin) and radiotherapy but no specific treatment regimen has yet been established. Due to cosmetic and psychological reasons, patients may be offered testicular prostheses after an orchidectomy.
Prognosis
The prognosis for SS is very good as once an orchidectomy is performed most patients are cured.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Pr Hans-Joachim SCHMOLL


Spheroid body myopathy is a rare form of myofibrillar myopathy characterized by predominantly proximal muscle weakness (that could be either non- or slowly progressive), associated with spheroid body inclusions (composed of myofilamentous material within individual muscle fibers) in skeletal muscle biopsy. Presentation is varied and may range from asymptomatic to severe muscle weakness that manifests with absent Achilles reflexes, gait abnormality and/or other motor incapacitations.


Spigelian hernia-cryptorchidism syndrome is a rare developmental defect during embryogenesis characterized by a ventral, uni- or bilateral protrusion of extraperitoneal fat, peritoneum and/or intra-abdominal organs through a defect in the spigelian fascia (Spigelian hernia), associated with ipsi- or bilateral undescended testis (usually found within or just beneath the hernial sac) in male neonates. The gubernaculum and/or inguinal canal may be absent.


Spina bifida and other spinal dysraphisms

A group of rare neural tube defect disorders characterized by improper closure of the spinal column during embryonal development that is usually not associated with other major congenital malformations but may include ventriculomegaly. The extent of the closure defect may vary, ranging from spina bifida occulta, in which the site of the lesion is not exposed (e.g. an isolated posterior vertebral arch defect), to spina bifida aperta, in which the lesion may be conformed of proturding spinal cord and meninges (myelomeningocele) or meninges exposure only (meningocele), with or without a proturding sac at the site of the lesion, to the most severe defect which includes total exposure of the spinal cord along its full length (rachischisis). Depending on the type, size and site of the defect, severe morbidity, typically inlcuding motor, sensory and sphincter dysfunction, and mortality may be associated. Spina bifida occulta may be asymptomatic.


Spina bifida-hypospadias syndrome is a rare developmental defect during embryogenesis disorder characterized by the specific association of glandular hypospadias and lumbo-sacral spina bifida. Affected individuals may or may not present additional congenital anomalies, such as hydrocephaly, microstomia, patent ductus arteriosus, cryptorchidism, intestinal malrotation, rocker-bottom feet, and hypertrichosis.


Cobb syndrome is defined by the association of vascular cutaneous (venous or arteriovenous), muscular (arteriovenous), osseous (arteriovenous) and medullary (arteriovenous) lesions at the same metamere or spinal segment. This segmental distribution may involve one or many of the 31 metameres present in humans. Only 16% of the medullary lesions are multiple and have a clearly metameric distribution.

Summary:
Epidemiology
Less than 100 cases of Cobb syndrome have been reported in the literature. There is no sex predilection. Cobb syndrome represents less than 15% of cases of spinal cord arteriovenous malformations.
Clinical description
The neurological symptomatology is comparable to that observed with acute haemorrhagic accidents or with chronic venous congestion of the spinal cord. The extent of the associated deficit depends on the localisation (cervical, thoracic, lumbar or sacral). These manifestations most often involve the lower limbs and are characterised by bilateral motor or sensory asymmetric deficits associated with sphincter anomalies. The morphological manifestations may be partial (appearing incomplete) in cases were some of the localisations at the same metamere are absent. The cutaneous manifestations of the syndrome are most often flat vascular lesions (port-wine stains) but angiokeratomas, angiolipomas and lymphangiomas have been reported. The medullary lesions are arteriovenous malformations. The muscular and osseous lesions may cause nonmechanical localised pain but are often asymptomatic.
Etiology
The syndrome is not familial or hereditary and no chromosomal anomaly has been described. The primitive events causing the disorder occur during early embryogenesis and involve a group of precursor vascular cells before the stage of migration to their definitive cell territories (skin, bone, peripheral nerve or spinal cord). Two consecutive territories may be affected resulting in multimetameric forms of the disease. Recent analysis of Cobb syndrome has led to use of the term Spinal Arteriovenous Metameric Syndrome 1-31 (SAMS 1-31), by analogy with the Cerebrofacial Arteriovenous Metameric Syndromes (CAMS 1-3) and the Cerebrofacial venous metameric syndromes (CVMS1-3).
Diagnostic methods
Diagnosis is made by MRI, supplemented by medullary angiography.
Management and treatment
Treatment of the osteomuscular malformations involves embolisation (endovascular navigation and occlusion of the arteries feeding the malformation using a biological glue) and/or surgery. Laser treatment is used for associated superficial cutaneous lesions. Radicular or medullary malformations are treated by embolisation. Indications for classic surgery are restricted to certain localisations and superficial lesions, epidural and paraspinal injections can be used if the endovascular approach fails. Radiotherapy is not indicated. Early diagnosis reduces the extent of the neurological deterioration, in particular paralysis.
Prognosis
The disease course is unpredictable and the lesions may remain asymptomatic for long periods of time.

                            Last update:
                            March 2007

                            - Expert reviewer(s):
                            Dr Hortensia ALVAREZ  - Pr Pierre LASJAUNIAS


Spinal atrophy-ophthalmoplegia-pyramidal syndrome is a rare, bulbospinal muscular atrophy characterized by generalized neonatal hypotonia, progressive pontobulbar and spinal palsy, pyramidal signs, and deafness. External ophthalmoplegia and bilateral mydriasis are typical signs. There have been no further descriptions in the literature since 1994.


Spinal dysraphism with a posterior meningocele

A rare spinal dysraphism characterized by the presence of a posteriorly located sac containing cerebrospinal fluid.


Spinal muscular atrophy with respiratory distress type 1 is a rare genetic motor neuron disease characterized by severe respiratory distress/respiratory failure in association with diaphragmatic eventration and palsy, as well as progressive, symmetrical, distal-to-proximal muscle weakness and atrophy (in lower limbs especially). Patients typically have a history of intrauterine growth retardation, low birth weight, feeble cry, weak suck and failure to thrive and present with inspiratory stridor, recurrent episodes of dyspnea or apnea, cyanosis and absent deep tendon reflexes. Kyphosis/scoliosis, foot deformities and joint contractures are frequently associated features.


Spinal muscular atrophy with respiratory distress type 2 is a rare, genetic, motor neuron disease characterized by progressive early respiratory failure associated with diaphragm paralysis, distal muscular weakness, joint contractures, and axial hypotonia with preserved antigravity limb movements. Phenotype overlaps considerably with SMARD type 1 but is differentiated by a mutation in a different gene.


Spinal muscular atrophy-Dandy-Walker malformation-cataracts syndrome

A rare neurologic disease characterized by bilateral cataract, Dandy-Walker malformation, and childhood onset of distal spinal muscular atrophy. Patients present with progressively deteriorating symmetrical distal muscle weakness and atrophy of the lower limbs (and, to a much lesser degree, also the upper limbs) and decreased tendon reflexes in the lower and upper limbs.


Spinal muscular atrophy-progressive myoclonic epilepsy syndrome is characterized by hereditary myoclonus and progressive distal muscular atrophy. Less than 10 cases have been reported. Treatment with clonazepam results in complete and lasting improvement of the myoclonus.


Spindle cell hemangioma (SCH), also known as spindle cell hemangioendothelioma, is a rare benign vascular tumor either solitary or multiple, characterized by cavernous blood vessels separated by spindle cells reminiscent of those in Kaposis sarcoma and located in the dermis and subcutis.


Spinocerebellar ataxia type 1 (SCA1) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term) characterized by dysarthria, writing difficulties, limb ataxia, and commonly nystagmus and saccadic abnormalities.

Summary:
Epidemiology
Prevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations.
Clinical description
The disease typically presents in the 4th decade (age range = 4-74 years). Ataxia gradually progresses and additional features may emerge including proprioceptive loss, hypoactive reflexes, ophthalmoparesis, and mild optic neuropathy. Initial presentation with blepharospasm, oromandibular dystonia, and retrocollis preceding ataxia has been reported. Cognition is relatively spared early on; however, executive dysfunction and impaired verbal memory may develop in later stages.
Etiology
SCA1 is caused by CAG repeat expansions in the ATXN1 gene region on chromosome 6p23.
Prognosis
Prognosis is poor. In the late stages of the disease, usually 10 to 15 years following onset, bulbar dysfunction secondary to affection of lower medullary nuclei results in aspiration which is life-threatening.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 10 (SCA10) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by slowly progressive cerebellar syndrome and epilepsy, sometimes mild pyramidal signs, peripheral neuropathy and neuropsychological disturbances.

Summary:
Epidemiology
Prevalence is unknown. Many kindreds have been found in Mexican and Brazilian populations. SCA10 is the second most common inherited ataxia in these two countries.
Clinical description
Age of onset ranges from 18 to 45 years (mean age = 32.2 years). The most common type of epilepsy is generalized motor seizures, but partial motor or partial complex seizures can occur.
Etiology
SCA10 is caused by an ATTCT pentanucleotide repeat expansion in intron 9 of the ATXN10 gene (22q13). Exact pathogenesis has not been determined but RNA processing may be involved.
Prognosis
Prognosis is poor, especially for patients with refractory epilepsy. Exact disease duration is unknown. However, the mean disease duration can be estimated to be about 13 years.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


A rare neurologic disease that is characterized by the early-onset of cerebellar signs, eye movement abnormalities and pyramidal signs.

Summary:
Epidemiology
Spinocerebellar ataxia type 11 (SCA11) prevalence is unknown but SCA11 is thought to account for 2% of ADCA type III cases. More than sixty clinically affected members from six families (of British, Pakistani, Danish, Chinese, German and French descent) have been reported to date.
Clinical description
SCA11 presents between the ages of 11-70 years with a mean age of onset of 25 years. It presents with the cerebellar signs such as dysarthria and progressive ataxia, eventually leading to difficulty walking and loss of balance as well as eye movement abnormalities (jerky pursuit, horizontal and vertical nystagmus and ophthalmoplegia). Pyramidal signs such as hyperreflexia mainly in the lower limbs, with positive Babinski sign are occasionally present. Rarely, dystonia and peripheral neuropathy have been reported. The disease is slowly progressive with dysphagia occurring later in the disease course. Patients usually become wheelchair bound 16 years after the onset of disease symptoms.
Etiology
SCA11 is due to mutations in the tau tubulin kinase 2 TTBK2 gene (15q15.2). This gene encodes TTBK2, which is found throughout the brain, and that is essential in stabilizing Purkinje cells and phosphorylating tau protein.
Diagnostic methods
Diagnosis is based on the clinical findings of pure cerebellar ataxia as well as molecular findings. Head magnetic resonance imaging (MRI) usually demonstrates the presence of cerebellar atrophy and is helpful in excluding other causes of ataxia. Molecular genetic testing identifies a mutation in the TTBK2  gene, confirming a diagnosis of SCA11.
Differential diagnosis
Differential diagnoses include other forms of ADCA type III, in particular SCA5, SCA6, SCA26, SCA30 and SCA31.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known disease causing mutation.
Genetic counseling
SCA11 is inherited autosomal dominantly and genetic counseling is possible. The disease shows full penetrance. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA11 and treatment is supportive. Language and speech therapy can help patients with dysarthria. Physiotherapy and the use of canes, walkers and wheelchairs can help patients remain mobile. Consultation with an ophthalmologist is recommended and prism glasses can help those with nystagmus. Neurological follow-up is recommended to monitor the progression of ataxia.
Prognosis
The prognosis is fair since the disease progresses very slowly (with disease duration of up to 20 years) and usually does not decrease life expectancy. Quality of life, however, is greatly affected.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 12 (SCA12) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by the presence of action tremor associated with relatively mild cerebellar ataxia. Associated pyramidal and extrapyramidal signs and dementia have been reported.

Summary:
Epidemiology
Prevalence is unknown. Approximately 40 families have been reported.
Clinical description
The age of symptomatic onset ranges from 8 to 55 years with most patients presenting in the 4th decade.
Etiology
Like SCA8 the pathogenesis of SCA12 seems to be related to a toxic effect at the RNA level as it is caused by a CAG expansion at the 5' end of the PPP2R2B gene on chromosome 5q31-5q32.
Prognosis
Prognosis is essentially good. In many cases progression of the illness is slow and in general life expectancy is not affected.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 13 (SCA13) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by onset in childhood marked by delayed motor and cognitive development followed by mild progression of cerebellar ataxia.

Summary:
Epidemiology
Prevalence is unknown. Fewer than 20 cases have been reported to date.
Clinical description
SCA13 is primarily a cerebellar syndrome, but dysphagia, urinary urgency, and bradykinesia have been described in affected patients older than 50.
Etiology
Etiology SCA13 has been mapped to chromosome 19q13.3-q13.4 and is known to be associated with two missense mutations in the KCNC3 gene.
Prognosis
Prognosis is relatively good. Many patients live beyond 70 years of age.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 14 (SCA14) is a rare mild subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by slowly progressive ataxia, dysarthria and nystagmus.

Summary:
Epidemiology
The disease has been reported in more than twenty families from Europe, the United States, and Australia.
Clinical description
Onset is usually in early adulthood while symptomatic disease onset may be from 10 to 70 years (mean = 33.9 years). In addition to cerebellar signs, hyperreflexia and decreased vibration sense are frequently observed. Some patients have cognitive impairment, parkinsonism characterized by rigidity, as well as focal dystonia, axial myoclonus, facial myokymia, choreic movement of hands and epilepsy.
Etiology
SCA14 is caused by missense mutations in the PRKCG gene (19q13.4) encoding protein kinase C gamma (PKC-gamma).
Prognosis
Prognosis is good. Some patients need supportive devices such as a cane or wheelchair for gait impairment. However, several affected patients have lived beyond 80 years of age.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 15/16 (SCA15/16) is a rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by cerebellar ataxia, tremor and cognitive impairment.

Summary:
Epidemiology
Prevalence is unknown. Fewer than 80 patients affected by the disease have been identified to date.
Clinical description
Age of onset is from 20 to 66 years (mean age = 39.6 years).
Etiology
Genetic testing has shown that patients originally classified under SCA15 and SCA16 have the same subtype caused by a deletion in the inositol 1,4,5-triphosphate receptor 1 ITPR1 gene (3p26.1).
Prognosis
Prognosis is generally good and life-shortening events do not usually occur. Some patients live beyond 80 years of age.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 17 (SCA17) is a rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by a variable clinical picture which can include dementia, psychiatric disorders, parkinsonism, dystonia, chorea, spasticity, and epilepsy.

Summary:
Epidemiology
Worldwide prevalence is unknown. Local prevalence is 0.47 per 1,000,000 in the Japanese population and 0.16 per 100,000 in North-East England. Fewer than 100 families have been reported to date.
Clinical description
Clinical features overlap with many neurodegenerative syndromes and specifically, Huntington disease (see this term).
Etiology
SCA17 is caused by a CAG repeat expansion in the TATA box-binding protein gene TBP (6q27).
Prognosis
Prognosis is poor. More than 60% of patients present with dysphagia which frequently results in aspiration and death. Mean disease duration is less than 18 years and a few patients live beyond 60 years of age.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 18 (SCA18) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by sensory neuropathy and cerebellar ataxia.

Summary:
Epidemiology
Prevalence is unknown. Only 26 cases in a 5-generation American family of Irish ancestry have been reported to date.
Clinical description
Onset is in the 2nd and 3rd decades of life with symptomatic onset ranging from 13 to 27 years. Patients initially present with axonal sensory neuropathy, while cerebellar ataxia and motor neuron dysfunction develop later.
Etiology
SCA18 has been linked to chromosome 7q22-q23 but the responsible gene mutation has not yet been identified.
Differential diagnosis
Both SCA3 and SCA4 are also associated with a peripheral neuropathy and should be taken into account in the differential diagnosis.
Prognosis
Prognosis is unclear. However, mean disease duration from age at onset of illness to age at last examination is about 24 years in the reported cases.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 19 (SCA19) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by mild cerebellar ataxia, cognitive impairment, low scores on the Wisconsin Card Sorting Test measuring executive function, myoclonus, and postural tremor.

Summary:
Epidemiology
Prevalence is unknown. Only 12 cases in a 5-generation Dutch family have been reported to date.
Clinical description
SCA19 presents in the 3rd decade of life with symptomatic disease onset ranging from 10 to 46 years. Onset symptoms of SCA22 (see this term) overlap significantly with those of SCA19 but with a more narrow age range of 35 to 46 years.
Etiology
Linkage to locus 1p21-q21 has been proposed but the gene mutation has not been identified.
Prognosis
Prognosis is good. SCA19 does not impact life expectancy to any major extent, and some patients live to over 80 years of age.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 2 (SCA2) is a subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term) characterized by truncal ataxia, dysarthria, slowed saccades and less commonly ophthalmoparesis and chorea.

Summary:
Epidemiology
Prevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations.
Clinical description
SCA2 presents in the 3rd or 4th decade (average age = 30 years; age range = 2-65 years). Parkinsonism is also a less common but well-documented manifestation. There is no distinct clinical feature that reliably distinguishes SCA2 from SCA1 although tremor and autonomic dysfunction are more common in SCA2. Disease course is similar in both SCA1 and SCA2 (see this term).
Etiology
The disease is caused by mutations in the ataxin 2 gene ATXN2 (12q23-q24.1). The normal CAG repeat length is 15-24; repeats 35 and longer are associated with the clinical manifestations of SCA2.
Prognosis
Prognosis is relatively good in most cases. Cases with disease duration of longer than 20 years have been described. However, in some cases, especially those with younger age of symptomatic disease onset (under 20 years), progression may be rapid.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 20 (SCA20) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by cerebellar dysarthria as the initial typical manifestation.

Summary:
Epidemiology
Prevalence is unknown. Fewer than 20 cases in a 4-generation Australian family of Anglo-Celtic descent have been reported to date.
Clinical description
Age of symptomatic disease onset ranges from 19 to 64 years (mean age = 46.5 years). Most affected patients also exhibit palatal tremor and spasmodic dysphonia. Head computed tomography (CT) shows dentate calcifications.
Etiology
SCA20 has been linked to chromosome 11q12.2-11q12.3, overlapping with the locus for SCA5 (see this term), though clinical features differ. SCA5 belongs to type III ADCA (see this term) and represents a pure ataxia syndrome with on average earlier age of symptomatic disease onset ranging from 14 to 50 years. Since the causative gene is unknown, SCA20 and SCA5 may be proven genetically to be the same disorder.
Prognosis
Prognosis is relatively good. Most patients can walk with or without gait aids and many patients live to more than 60 years of age.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 21 (SCA21) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by slowly progressive cerebellar ataxia, mild cognitive impairment, postural and/or resting tremor, bradykinesia, and rigidity.

Summary:
Epidemiology
Prevalence is unknown. Fewer than 20 cases in a 4-generation French family have been reported to date.
Clinical description
Mean age of onset is 17.4 years and is relatively early compared to most type I ADCAs. Individuals in successive generations tend to have earlier ages of onset. Parkinsonism was not responsive to L-dopa and magnetic resonance imaging (MRI) revealed cerebellar and brainstem atrophy.
Etiology
SCA21 maps to chromosome 7p21.3-p15.1 but the gene and gene mutation have not been identified.
Prognosis
There is insufficient clinical data to draw conclusions concerning prognosis.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 23 (SCA23) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by gait ataxia, dysarthria, slowed saccades, ocular dysmetria, Babinski sign and hyperreflexia.

Summary:
Epidemiology
This subtype has only been described in 4 Dutch families. Age of onset is from 43 to 56 years.
Clinical description
The clinical features, head magnetic resonance imaging (MRI), and neuropathological findings are indistinguishable from other SCA subtypes.
Etiology
SCA23 maps to chromosome region 20p12.3-p13 and missense mutations in the prodynorphin PDYN gene appear to cause the disease.
Prognosis
Prognosis may be good in some cases. Disease progression can be slow. Wheelchair dependence can occur more than 20 years after symptomatic disease onset.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 25 (SCA25) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by cerebellar ataxia and prominent sensory neuropathy.

Summary:
Epidemiology
Fewer than 10 cases in a 4-generation French family have been reported to date.
Clinical description
Age of onset ranges from 1 to 39 years. The clinical features vary widely from sensory neuropathy with little cerebellar ataxia to cerebellar ataxia with little sensory neuropathy. Some patients exhibit gastrointestinal (GI) disorders such as vomiting and abdominal pain as initial symptoms. GI problems can persist. Scoliosis and urinary problems (nycturia or urinary urgency) are also observed. Head magnetic resonance imaging (MRI) shows severe global cerebellar atrophy like in SCA5 and SCA6 (see these terms).
Etiology
SCA25 maps to chromosome 2p15-p21. Repeat expansion detection failed to identify CAG repeat expansion.
Prognosis
There is insufficient clinical data to draw conclusions concerning prognosis.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


A very rare subtype of autosomal dominant cerebellar ataxia type III (ADCA type III) characterized by late-onset and slowly progressive cerebellar signs (gait ataxia) and eye movement abnormalities.

Summary:
Epidemiology
To date, only 23 affected patients have been described from one American family of Norwegian descent.
Clinical description
Spinocerebellar ataxia type 26 (SCA26) onset occurs between the ages of 26-60 with a mean age of onset of 42 years. Slowly progressive gait ataxia and dysarthria were reported in all patients. Nystagmus, impaired pursuit, and dysmetric saccades were described in majority of patitents. Left-sided pyramidal signs (hyperreflexia with positive Babinski sign) were reported in one patient. The disease duration is unknown.
Etiology
A candidate gene for SCA26 has recently been identified as the eukaryotic translation elongation factor 2 (EEF2) gene, located on chromosome 19p13.3. Further confirmatory studies are still required in order to determine if a mutation in this gene directly causes SCA26.
Diagnostic methods
Diagnosis is based on the clinical findings of pure cerebellar ataxia as well as molecular findings. Head magnetic resonance imaging (MRI) usually demonstrates the presence of atrophy of the cerebellum sparing the brainstem and is helpful in excluding other causes of ataxia. Molecular genetic testing identifies a mutation in the EEF2  gene, confirming a diagnosis of SCA26.
Differential diagnosis
Differential diagnoses include other forms of ADCA type III, in particular SCA5, SCA6, SCA11, SCA30 and SCA31.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known disease causing mutation.
Genetic counseling
SCA26 is inherited autosomal dominantly and genetic counseling is possible. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
There is no cure for SCA26 and treatment is supportive. Neurological follow-up is recommended to monitor the progression of ataxia.
Prognosis
Disease progression is very slow, but precise prognosis is unknown.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Yoshio TSUBOI  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 27 (SCA27) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by early-onset tremor, dyskinesia, and slowly progressive cerebellar ataxia.

Summary:
Epidemiology
Fewer than 30 cases have been reported to date.
Etiology
This subtype is caused by a mutation in the fibroblast growth factor 14 FGF14 gene (13q34).
Prognosis
Prognosis is relatively good. Patients can walk unassisted until the 7th decade of life. Life-threatening status epilepticus and intractable seizure or severe dysphagia are rare.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Spinocerebellar ataxia type 28 (SCA28) is a very rare subtype of type I autosomal dominant cerebellar ataxia (ADCA type I; see this term). It is characterized by juvenile onset, slowly progressive cerebellar ataxia due to Purkinje cell degeneration.

Summary:
Epidemiology
Prevalence is unknown. SCA28 accounts for approximately 1.5% of all European cases of ADCA.
Clinical description
The mean age of symptom onset was 19.5 years in the original kindred. Some patients show cognitive impairment. In more advanced stages of the disorder, ophthalmoparesis, slowed saccades, ptosis and pyramidal signs are reported. Patients can walk unassisted until the 7th decade of life. Life-threatening status epilepticus and intractable seizure or severe dysphagia are rare.
Etiology
SCA28 is caused by mutations in the AFG3L2 gene located to chromosome 18p11.21.
Genetic counseling
SCA28 is inherited autosomal dominantly and genetic counseling is possible.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK