A rare non-hereditary condition characterized by gastrointestinal stromal tumors (GIST, intramural mesenchymal tumors of the gastrointestinal tract with neuronal or neural crest cell origin), pulmonary chondromas and extraadrenal paragangliomas.

Summary:
Epidemiology
Less than 100 cases have been reported worldwide. Carney's triad primarily affects young women (mean age of onset 20 years).
Clinical description
Most patients initially present with two of the three tumors (incomplete Carney's triad). The main symptoms at presentation are gastrointestinal bleeding, epigastric pain, anemia and palpable abdominal mass. These symptoms are related to the GIST, which occur in 99% of cases. Additional features include headaches, fatigue, anorexia, hypertension and tachycardia. Pulmonary chondromas (well-differentiated benign cartilaginous tumors) occur in approximately 80% of cases. They are often asymptomatic and may be unilateral (83%) or bilateral (32%). Secreting paragangliomas (typically extraadrenal and most often mediastinal) occur in approximately 50% of patients.
Etiology
The etiology is not completely understood. Impaired succinate dehydrogenase (SDH) function resulting from chromosomal losses (but not mutations) has been detected in some patients with Carney's triad, while SDHD, SDHB or SDHC germline mutations have been found in some patients with Carney-Stratakis dyad (see this term).
Diagnostic methods
Gastroscopy, radiography and computing tomography are the main diagnostic methods. SDH genetic testing is available. The absence of a paraganglioma, which usually completes the triad after several years (median: 6 years), does not allow exclusion of the diagnosis of Carney's triad. Iodine 131-metoiodobenzylguanidine scintigraphy and Octrescan® may help to detect paragangliomas.
Differential diagnosis
The differential diagnosis should include Carney-Stratakis dyad.
Management and treatment
The treatment of choice for GIST and its metastases (overall rate: 50%) is surgical resection. GIST associated with Carney's triad are mostly indolent. Recurrence after surgery is found in approximately 50% of patients, with a mean interval after the initial presentation of 12 years. Imatinib mesylate, an effective agent in the treatment of GIST, is under investigation as an adjuvant treatment. Paragangliomas require surgical resection; chemotherapy and metabolic radiotherapy may be used in malignant cases (overall rate: 10%). Surgery for pulmonary chondromas is indicated only in case of impaired lung function. Approaches targeting SDH function may potentially be useful in treating patients with Carney's triad who show SDH deficiencies. However, at present, there is no drug that restores SDH function. Life-long follow-up should be offered to all patients with Carney's triad.

                            Last update:
                            September 2008

                            - Expert reviewer(s):
                            Pr Sebastiano FILETTI


Carney-Stratakis syndrome is a recently described familial syndrome characterized by gastrointestinal stromal tumors (GIST) and paragangliomas, often at multiple sites.

Summary:
Epidemiology
It is a very rare syndrome reported in less than 20 unrelated families to date. It presents at a young age (median age: 19 years) with an apparently equal ratio of male and female patients.
Clinical description
Patients with Carney-Stratakis syndrome have both GIST and paraganglioma. The gastric stromal sarcomas are multifocal and the paragangliomas are multicentric. The clinical spectrum of Carney-Stratakis syndrome varies widely, depending on the localization and the size of the tumors, and may include a palpable mass, dysphagia, abdominal pain, weight loss, hematemesis, melena, obstruction, perforation, cranial nerve palsies, tinnitus and hearing loss. GIST are intramural mesenchymal tumors of the gastrointestinal tract that originate from stem cells with characteristics of the interstitial cells of Cajal (the pacemaker cells which regulate peristalsis in the digestive tract). Paragangliomas are usually benign tumors that occur without clinical evidence of oversecretion and that arise within the sympathetic nervous system from cells of the paraganglia.
Etiology
The vast majority of Carney-Stratakis syndrome cases are due to germline mutations of the succinate dehydrogenase (SDH) subunit genes SDHB, SDHC and SDHD.
Diagnostic methods
Diagnosis is made by clinical and radiologic examination, and confirmed immunohistochemically. Genetic testing to determine if SDH defects may be contributing to tumor growth or recurrence should be offered to pediatric GIST patients.
Differential diagnosis
The main differential diagnosis includes Carney triad.
Genetic counseling
Predisposition to developing these tumors is inherited in an autosomal dominant manner with incomplete penetrance.
Management and treatment
Treatment modalities are surgery, embolization and radiotherapy. Chemotherapy with imatinib mesylate may be helpful for some patients with advanced-stage GIST. Targeting SDH function may potentiallybe useful in treating Carney-Stratakis syndrome patients but, at present, there are no drugs that restore SDH function. Life-long follow-up should be offered to patients with Carney-Stratakis syndrome.

                            Last update:
                            January 2008

                            - Expert reviewer(s):
                            Pr Philippe CHANSON


Carnitine palmitoyl transferase 1A deficiency

Carnitine palmitoyltransferase 1A (CPT-1A) deficiency is an inborn error of metabolism that affects mitochondrial oxidation of long chain fatty acids (LCFA) in the liver and kidneys, and is characterized by recurrent attacks of fasting-induced hypoketotic hypoglycemia and risk of liver failure.

Summary:
Epidemiology
Since the description of the disease in 1981, less than 50 cases have been reported.
Clinical description
CPT-1A deficiency manifests between birth and 18 months of age with recurrent attacks of hypoketotic hypoglycemia of varying severity, triggered by fasting or intercurrent illness, that can lead to severe neurological sequelae. CPT-1A-deficient patients can also present with hepatic encephalopathy with loss of consciousness, seizures, coma, or even sudden death. There may be a risk of progression to liver failure. Patients with severe CPT-1A deficiency may also have renal tubular acidosis.
Etiology
CPT-1A deficiency is due to mutations in the CPT1A gene that codes for the liver isoform of the CPT1 enzyme located within the external mitochondrial membrane and whose function is to conjugate LCFAs to carnitine. This allows the transfer of LCFAs from the cytosol to mitochondria where they will be oxidized. CPT1 enzyme has three isoforms with tissue-specific expression and encoded by different genes: the 'L' isoform, expressed in the liver and kidney by the CPT1A gene (11q13), the 'M' isoform, synthesized in the skeletal and cardiac muscle by the CPT1B gene (22qter), and the brain type isoform expressed by the CPT1C gene (19q13). No clinical cases of deficiency of the muscle or brain type isoform have been described. A genetic variant of CPT1A (which results in a P479L protein change) that is very common in individuals of Alaskan and Greenland Inuit origin and some Canadian Native Americans has been described. The significance of this variant is not yet established and the risk of severe disease association as a result of the variation is uncertain. A single case of an adult who was homozygous for the P479L variant presented with muscular symptoms (muscle cramps), but an association with the variant seems doubtful.
Diagnostic methods
During metabolic crisis, blood tests reveal hypoglycemia, elevated levels of plasma carnitine and liver transaminases, and mild hyperammonemia. Urine tests may show unusually low levels of ketones, and medium-chain dicarboxylic aciduria. When well, the total free carnitine level may still be elevated but all other metabolic tests will be normal. Molecular testing and evidence of enzyme deficiency by CPT-1A assay (reduction to 5-20% of normal CPT1 activity) in the liver, lymphocytes or cultured fibroblasts, confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes fatty acid and ketogenesis disorders such as medium-chain acyl-CoA dehydrogenase (MCAD deficiency; see this term), other long-chain fatty acid oxidation disorders such as carnitine palmitoyltransferase (CPT) 2 deficiency and Reye's syndrome (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible by mutational analysis if the mutations in a proband have been identified.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be proposed to parents of an affected individual informing them of the 25% risk the offspring has of inheriting the disease-causing mutations.
Management and treatment
Treatment consists primarily of avoidance of fasting. Additional measures may be considered, including nighttime feeds with uncooked cornstarch during childhood and/or a low-fat diet supplemented with medium chain triglycerides that can be metabolized by mitochondria independently from the carnitine cycle. Regular surveillance of liver enzymes and function is necessary.
Prognosis
With treatment, prognosis is good and neurological damage resulting from recurrent hypoglycemia may be prevented.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Pr Michael BENNETT  - Dr Charles STANLEY


Carnitine palmitoyl transferase II deficiency, myopathic form

The myopathic form of carnitine palmitoyltransferase II (CPT II) deficiency, an inherited metabolic disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA), is the most common and the least severe form of CPT II deficiency (see this term).

Summary:
Epidemiology
About 300 cases of the myopathic form have been reported in the literature, but this number may under-estimate the disease prevalence.
Clinical description
The age of onset varies between 1 and 61 years of age with 70% of cases first presenting in childhood. The disease is more common in men, probably reflecting an ascertainment bias related to exposure to prolonged exercise. The clinical manifestations are characterized by recurrent attacks of rhabdomyolysis, muscle pain, and weakness triggered usually by prolonged physical exercise and sometimes exacerbated by extremes in temperature; episodes may also be provoked or exacerbated by prolonged fasting, such as may occur with intercurrent viral illness. Episodes of rhabdomyolysis may be associated with extreme elevation of serum creatine phosphokinase (CPK) and myoglobinuria (75% of cases) and can lead to renal failure (in 8-25% of cases, but rarely requiring dialysis). Patients are asymptomatic between episodes of rhabdomyolysis.
Etiology
Several missense mutations in the CPT2 gene result in the myopathic form of CPT II deficiency. In Caucasians, the most frequent mutation (60%) is the p.Ser113Leu mutation, which impairs enzyme stability.
Diagnostic methods
The diagnosis is made by an initial tandem mass spectrometry of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPT2 enzyme activity in fresh circulating lymphocytes, muscle or fibroblasts.
Differential diagnosis
The differential diagnosis should include McArdle disease, Duchenne muscular dystrophy, cytochrome c oxidase deficiency (see these terms), complex II deficiency, complex III deficiency and rhabdomyolysis due to excessive exercise, infections, autoimmune reactions or drug-related neuroleptic syndrome among others.
Genetic counseling
Transmission is autosomal recessive. If the disease-causing mutations are identified in an affected individual, early diagnosis by molecular genetic testing can be offered to at-risk relatives to reduce morbidity and mortality.
Management and treatment
Treatment is based on avoidance of prolonged fasting (>12 hr) and a low-fat and high-carbohydrate diet combined with exercise restriction in order to avoid muscle pain and rhabdomyolysis. L-carnitine administration and anaplerotic diet therapy with triheptanoin have been suggested for treatment of the disease; however benefits have not been proven.
Prognosis
The myopathic form of CPT II has a good prognosis.

                            Last update:
                            May 2010

                            - Expert reviewer(s):
                            Pr Michael BENNETT  - Dr Charles STANLEY


Carnitine palmitoyl transferase II deficiency, neonatal form

The neonatal form of carnitine palmitoyltransferase II (CPT II) deficiency (see this term), an inherited disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA), is the lethal form of the disease which presents with multisystem failure.

Summary:
Epidemiology
It is a rare form of CPT II deficiency that has been reported in less than 20 families.
Clinical description
Affected infants experience hypoketotic hypoglycemia, liver and respiratory failure and can present with cardiomyopathy, muscle hypotonia, liver calcification, cystic dysplastic kidneys and malformations of the brain due to a neuronal migration defect. Seizures and coma can occur as well as cardiac arrhythmias that generally lead to cardiac arrest in the perinatal/ early infantile period. Death occurs within days to months.
Etiology
The severe neonatal CPT II deficiency is caused by homozygous or compound heterozygous CPT2 mutations that typically result in complete loss of activity of the CPT II enzyme.
Diagnostic methods
The diagnosis is made by an initial tandem mass spectrometry of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPTII enzyme activity in fresh circulating lymphocytes, muscle or skin fibroblasts.
Differential diagnosis
The differential diagnosis should include severe forms of carnitine-acylcarnitine translocase deficiency (CACT) and very-long-chain acyl-CoA dehydrogenase deficiency (see these terms).
Antenatal diagnosis
Prenatal diagnosis is available based on a combination of enzymatic and molecular testing (if mutations have been identified in the proband).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is only symptomatic.
Prognosis
Prognosis is poor. The neonatal form is almost always lethal during the first months of life.

                            Last update:
                            May 2010

                            - Expert reviewer(s):
                            Pr Michael BENNETT  - Dr Charles STANLEY


Carnitine palmitoyl transferase II deficiency, severe infantile form

The severe infantile form of carnitine palmitoyltransferase II (CPT II) deficiency (see this term), an inherited disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA), is the early-onset form of the disease.

Summary:
Epidemiology
It has been identified in approximately 30 families.
Clinical description
Presentation can be in the newborn period but most cases have an age of onset between 6 and 24 months. The disease is characterized by a severe fasting intolerance leading to metabolic derangements of hypoketotic hypoglycemia, resulting in coma and seizures, and hepatic encephalopathy leading to liver failure. There is associated skeletal muscle myopathy and cardiomyopathy which can lead to fatal paroxysmal cardiac arrhythmias.
Etiology
Missense mutations in the CPT2 gene result in the infantile form of CPT II deficiency. Contrary to the adult myopathic form (see this term), no S113L mutations have ever been detected in the infantile form.
Diagnostic methods
The diagnosis is made by an initial tandem mass spectrometric analysis of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPT2 enzyme activity in fresh circulating lymphocytes, muscle or skin fibroblasts.
Differential diagnosis
The differential diagnosis should include carnitine-acylcarnitine translocase deficiency (CACT) and very-long-chain acyl-CoA dehydrogenase deficiency (see these terms).
Antenatal diagnosis
Prenatal diagnosis is available using both molecular and enzymatic analysis.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is based on prevention of the fasting intolerance by providing carbohydrate calories during periods of febrile or gastrointestinal illness. When well, a low-fat and high-carbohydrate diet is initiated and for the most severe forms of the disease overnight feeding with a slow release carbohydrate such as corn starch can be implemented. Anaplerotic therapy with triheptanoin has also been suggested as a therapy. Plasma carnitine levels may be low in the disease and L-carnitine administration is also used in the treatment but this approach has not been validated in a controlled study.
Prognosis
The severe infantile form may lead to sudden death during infancy due, in general, to paroxysmal cardiac arrhythmias. This is particularly true for undiagnosed cases. Early diagnosis through newborn screening has identified cases pre-symptomatically and outcomes appear to be improving as a result.

                            Last update:
                            May 2010

                            - Expert reviewer(s):
                            Pr Michael BENNETT  - Dr Charles STANLEY


Carnitine palmitoyltransferase II deficiency

Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited metabolic disorder that affects mitochondrial oxidation of long chain fatty acids (LCFA). Three forms of CPT II deficiency have been described: a myopathic form, a severe infantile form and a neonatal form (see these terms).

Summary:
Epidemiology
More than 300 CPT II cases have been described with the myopathic form being the most common (myopathic form: 86%, severe infantile form: 8%, neonatal form: 6% of cases).
Clinical description
The myopathic form is the least severe and is characterized by recurrent attacks of rhabdomyolysis, muscle pain and weakness triggered by prolonged physical exercise, fasting, viral illness or extremes in temperature. The severe infantile form is characterized by a severe fasting intolerance leading to metabolic disorders such as hypoketotic hypoglycemia and hepatic encephalopathy. The lethal neonatal form includes symptoms of the infantile disease as well as dysmorphic features (e.g. cystic dysplastic kidneys).
Etiology
More than 60 mutations in the CPT2 gene, resulting in general in amino acid substitutions or small deletions, cause the CPT II deficiency.
Diagnostic methods
The diagnosis is made by an initial tandem mass spectrometry of serum/plasma acylcarnitines followed by mutation analysis and measurements of CPT2 enzyme activity in fresh circulating lymphocytes, muscle or fibroblasts.
Differential diagnosis
The differential diagnosis for the myopathic form should include McArdle disease, Duchenne muscular dystrophy, and cytochrome c oxidase deficiency (see these terms) among others, and carnitine-acylcarnitine translocase deficiency (CACT) and very-long-chain acyl-CoA dehydrogenase deficiency (see these terms) for the infantile and neonatal forms
Antenatal diagnosis
Prenatal diagnosis is available based on a combination of enzymatic and molecular testing.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is based on avoidance of prolonged fasting (>12 hr) and a low-fat and high-carbohydrate diet.
Prognosis
The myopathic form of CPT II has a good prognosis. The severe infantile form may lead to sudden death during infancy due, in general, to paroxysmal cardiac arrhythmias. The neonatal form is almost always lethal during the first months of life.

                            Last update:
                            April 2010

                            - Expert reviewer(s):
                            Pr Michael BENNETT  - Dr Charles STANLEY


Carnitine-acylcarnitine translocase (CACT) deficiency is a life-threatening, inherited disorder of fatty acid oxidation which usually presents in the neonatal period with severe hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy and/or arrhythmia, hepatic dysfunction, skeletal muscle weakness, and encephalopathy.

Summary:
Epidemiology
The prevalence is unknown. Less than 60 cases have been reported worldwide to date.
Clinical description
Most patients with CACT deficiency have a severe phenotype presenting within the first 48 hours of life as hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy and arrhythmias, skeletal muscle damage, liver dysfunction and hypothermia. Neurological involvement with encephalopathy, epilepsy and developmental delay are also noted. Some patients present as a sudden infant death. A rare milder phenotype presenting in infancy/early childhood is also described which manifests with episodes of hypoketotic hypoglycemia and hyperammonemia often precipitated by fasting and/or intercurrent illness.
Etiology
Mutations in the SLC25A20 gene (3p21.31) are responsible for CACT deficiency. CACT is located in the inner mitochondrial membrane and operates a carnitine/acylcarnitine exchange across this membrane. It is an essential component of the carnitine cycle that regulates the transport of long chain fatty acids into the mitochondria where fatty acid oxidation takes place. The milder phenotype results from significant mutant protein activity.
Diagnostic methods
Patients with CACT deficiency present with a non-specific dicarboxylic aciduria. Blood acylcarnitine analysis shows a very high acyl fraction with marked increase in C16, C18, and C18:1 species. Free carnitine is very low. Specific enzyme analysis in cultured fibroblasts or lymphocytes will confirm a diagnosis as will the demonstration of two pathogenic mutations in the  SLC25A20 gene. Newborn screening for CACT deficiency is available in Austria, Czech Republic, Germany, Hungary, Iceland, Portugal and Spain.
Differential diagnosis
The neonatal and severe infantile forms of carnitine palmitoyl transferase II (CPT II) deficiency (see this term) need to be excluded as they have an identical acylcarnitine profile to CACT. Clinically these two disorders are virtually indistinguishable, although congenital abnormalities are not reported in CACT and only sometimes in CPT II.
Antenatal diagnosis
Prenatal diagnosis is possible by mutation analysis of chorionic villus tissue when two pathogenic mutations have been established in a family. Specific enzyme analysis is also available for cultured chorionic villus cells.
Genetic counseling
CACT is an autosomal recessive condition and genetic counseling is available.
Management and treatment
Strict avoidance of fasting along with the institution of a low long-chain fat diet and medium chain triglyceride (MCT) supplementation is necessary. However, the MCT formula should be as low as possible in C10 and C12 fatty acids as high dietary intake of these can lead to decompensation. Carnitine supplementation is also recommended. During an acute episode, intravenous glucose is administered in order to inhibit lipolysis.
Prognosis
Severe CACT deficiency generally has a poor prognosis, with most patients dying before the age of 3 months, although a few infants treated early on in the neonatal period have had a favorable outcome in the medium term. Patients with a mild phenotype generally have a good prognosis given adherence to the treatment regimen.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Simon OLPIN


A rare inborn error of metabolism characterized by low serum carnosinase activity, persistent carnosinuria, and carnosinemia. The clinical phenotype is highly variable, with some patients remaining asymptomatic, while others have been reported to show severe developmental delay, intellectual disability, hypotonia, seizures, and other neurological signs and symptoms.


Caroli disease (CD) is a rare congenital liver disease characterized by non-obstructive cystic dilatations of the intra-hepatic and rarely extra-hepatic bile ducts.

Summary:
Epidemiology
Exact prevalence and annual incidence data are not available for CD, but the disease is known to be very rare. An estimated prevalence of 1/1,000,000 has been suggested. There is a slight female gender bias.
Clinical description
Caroli disease can present at any age. CD ranges from simple ectasias of the larger intra-hepatic bile ducts (in this less common form the name Caroli disease is used) to a syndromic form (Caroli syndrome) that is more common and includes congenital hepatic fibrosis. Some patients remain asymptomatic throughout the disease course. Some develop intra- or extra-hepatic calculi, leading to recurrent cholangitis (with bacteremia and sepsis), and acute pancreatitis. Manifestations are those of complications, mostly bacterial cholangitis, and include abdominal pain and biliary colic, fever with chills, and jaundice. Hepatomegaly, cirrhosis and portal hypertension (with splenomegaly) are also frequently reported to develop. Besides bacterial cholangitis, complications include liver abscess, biliary infection, and in late stages, cholangiocarcinoma. CS is often associated with recessive polycystic kidney disease (see these terms). The course is largely dependent on the associated disorders.
Etiology
CD and CS are strongly related to PKHD1 mutations. Abnormal development of the embryonic bile ducts at the stage of ductal plate has been suggested. Full characterization of genetic anomalies associated with CD or CS beyond PKHD1 has not yet been achieved.
Diagnostic methods
The diagnosis is suspected on clinical grounds and confirmed through detection of cystic dilatation in the biliary tree through imaging studies. The key diagnostic procedure is magnetic resonance cholangiography showing a characteristic aspect of abnormal bile ducts. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) should not be used for diagnosis because they are associated with an increased risk of bacterial cholangitis.
Differential diagnosis
The differential diagnosis should include primary sclerosing cholangitis, isolated polycystic liver disease, and hepatic cystic hamartoma (see these terms), as well as hepatic and choledochal cysts.
Antenatal diagnosis
Cases of prenatal diagnosis based on ultrasonographic findings have been reported.
Genetic counseling
Most cases of CD are sporadic. Syndromic cases (CS) share with congenital hepatic fibrosis and recessive polycystic kidney disease an autosomal recessive transmission.
Management and treatment
Management depends on the clinical presentation, localization and stage of the disease. Ursodeoxycholic acid may be used to prevent stone formation. Antibiotics are used for cholangitis. Radiological, endoscopic, and surgical intervention may be required for patients with biliary obstruction, abscess formation and liver or bile duct stones. Patients with severe disease may be candidates for liver transplantation.
Prognosis
Quality of life may be significantly affected by recurrent cholangitis. Prognosis depends on the clinical course and the risk of cholangiocarcinoma.

                            Last update:
                            November 2016

                            - Expert reviewer(s):
                            Pr Dominique VALLA


A rare genetic hepatic disease characterized by multiple segmental cystic dilatations of both central and smaller peripheral bile ducts associated with congenital hepatic fibrosis. Age of symptom onset is variable, as is disease progression. Patients present recurrent cholangitis, hepatolithiasis, and cholecystolithiasis. Portal hypertension may appear later in the disease course, and the risk of developing cholangiocarcinoma is increased significantly. The syndrome is often associated with autosomal recessive polycystic kidney disease.


A rare syndromic craniosynostosis with variable phenotypic expression characterized by craniosynostosis, intellectual disability, distinctive facies, abnormalities of the fingers and toes (brachydactyly, polydactyly and syndactyly), short stature, congenital heart disease, skeletal defects, obesity, genital abnormalities and umbilical hernia.

Summary:
Epidemiology
Over 70 cases have been described in the literature.
Clinical description
Presentation at birth is with macrosomia, umbilical hernia and craniosynostosis which ranges from cloverleaf configuration to predominant involvement of the metopic ridge to craniofacial asymmetry. Cranial anomalies may lead to raised intercranial pressure, difficulty in articulation, frequent otitis media and resultant hearing loss. Typical abnormalities of the digits include brachydactyly, cutaneous syndactyly, preaxial polydactyly in the toes and postaxial polydactlyly in the hands with broad thumbs and absent middle phalanges. Characteristic facial features may include flat nasal bridge with epicanthal folds, down-slanting palpebral fissures, corneal anomalies, low-set, posteriorly rotated malformed ears, and an underdeveloped maxilla and mandible. Congenital cardiac malformations are frequent and may include ventricular septal defect, patent ductus arteriosus, pulmonic stenosis, tetralogy of Fallot, and transposition of great vessels. Intellectual disability is common (affecting 63-75% of cases). Males often have genital abnormalities such as hypogonadism and cryptorchidism. Small primary dentition is usual, teeth are short, undersized and widely spaced, appearing as small buds worn to the gingival margins and often there is prolonged retention of primary teeth. Growth is either slightly delayed or normal and many individuals have short stature. Persistent obesity, particularly truncal obesity, beginning in childhood is common. Additional skeletal abnormalities such as deformed hips, kyphoscoliosis, and genu valgum frequently occur. Situs inversus, dextrocardia, and polysplenia has been observed in a few patients.
Etiology
The syndrome is caused by truncating, misssense and loss of function mutations in two different genes RAB23 gene (6p12.1) and less commonly MEGF8 gene (19q13.2). MEGF8 mutations are associated with defective lateralization and less severe craniosynostosis (usually involving only the metopic suture) in comparison with individuals with RAB23 gene mutations.
Diagnostic methods
Clinical diagnosis is suspected on clinical presentation and confirmed by diagnostic molecular genetic screening firstly of RAB23 and then MEGF8.
Differential diagnosis
Differential diagnosis includes other acrocephalosyndactyly disorders, as well as Gorlin syndrome, Apert syndrome and Greig cephalopolysyndactyly syndrome. Ciliopathy disorders also have overlapping features including the wide clinical variability and features such as obesity and polydactyly. Summitt syndrome and Goodman syndrome falls within the clinical spectrum of Carpenter syndrome.
Antenatal diagnosis
Genetic prenatal diagnosis to screen for the causative familial mutations is possible where the mutation has previously been identified in a family member. Ultrasound may detect abnormal head shape, short and bowed femurs, flattened face, proptosis, heart defect, heterotaxy and digit anomalies.
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 of the 25% risk of having an affected child at each pregnancy. Phenotypic expression varies considerably, even within the same family. Genetic counseling is recommended to affected families.
Management and treatment
Multidisciplinary management and treatment is required. Most patients with this syndrome will undergo early craniofacial reconstruction to improve appearance and prevent intellectual disability. Surgery may be required for congenital heart defects and shunting may be required if there is raised intercranial pressure.
Prognosis
The prognosis is highly variable depending on the severity of the malformations and the degree of intellectual disability; some children grow up to become independent adults and others require more support due to intellectual disability or physical challenges. Life expectancy is shortened, mainly due to heart defects.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Dr Corinne COLLET | ITHACA*

                                * European Reference Network


Carpotarsal osteochondromatosis is a very rare primary bone dysplasia disorder characterized by abnormal bone proliferation and osteochondromas in the upper and lower limbs.


Cartilage-hair hypoplasia is a disease affecting the bone metaphyses causing small stature from birth.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The disease is associated with fine, slow growing hair, and sometimes with immune deficiencies. Other symptoms include short hands and possibly short, deformed limbs (varus). X-ray reveals metaphyseal lesions, especially in the knees, and large, round epiphyses during childhood. Short stature is common and has very early onset but immune deficiency is not always present. The disease course is variable.
Etiology
Mutations in the RMRP (RNA component of mitochondrial RNA-processing endoribonuclease) gene, which maps to the 9p21-p12 locus, are responsible for the disease.
Diagnostic methods
The diagnosis is confirmed by direct sequencing of the RMRP gene.
Differential diagnosis
The differential diagnosis should include other forms of short-limb dwarfism.
Antenatal diagnosis
A recurrence risk of 25% justifies prenatal diagnosis, which is possible through molecular analysis if the causative mutation has already been identified in a proband. Micromelia may be detected early in pregnancy during ultrasound follow up, but is not specific.
Genetic counseling
Cartilage-hair hypoplasia is inherited in an autosomal recessive manner.
Management and treatment
Immunodeficiency, when severe, may require bone marrow transplantation but this does not have any effect on the growth deficiency.
Prognosis
The prognosis depends on the presence and severity of the immune deficiency and the possible association with Hirschsprung disease (see this term).

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


A rare genetic ectodermal dysplasia syndrome characterized by woolly hair (presenting at birth), palmoplantar keratoderma (developing in the first year of life) and dilated cardiomyopathy with predominant left ventricle involvement (developing in childhood) which can lead to life-threatening heart failure in childhood or adolescence.


A rare lymphoid hemopathy characterized by involvement of lymph nodes in any part of the body, most frequently the mediastinum, abdomen, neck, or spleen, and occurring as unicentric, idiopathic multicentric, or KSHV/HHV8-associated multicentric Castleman disease. Depending on the type, patients are most commonly asymptomatic or typically present with systemic symptoms.


Cat eye syndrome (CES) is a rare chromosomal disorder with a highly variable clinical presentation. Most patients have multiple malformations affecting the eyes (iris coloboma), ears (preauricular pits and/or tags), anal region (anal atresia), heart and kidneys. Intellectual disability is usually mild or borderline normal.

Summary:
Epidemiology
CES has an estimated prevalence of 1/50,000 to 1/150,000 live births. Males and females appear to be affected equally.
Clinical description
CES covers a very wide clinical spectrum in terms of features and severity, ranging from a normal phenotype to severe multisystemic disease. The 3 main visible characteristics are preauricular anomalies, anal atresia, and iris coloboma but none are found consistently. Preauricular skin tags and/or pits are the most consistent feature. The typical eye anomaly is absent in up to 50% of patients. Eye coloboma may involve the iris, the choroid and/or the retina. Less frequently, unilateral microphtalmia, aniridia, cornea clouding, cataract and/or Duane anomaly are observed. In addition to preauricular tags and/or pits, the external ears may be low-set and severely reduced with possible atresia of the external ear canal. Characteristic facial features are down-slanting palpebral fissures, inner epicanthic folds, hypertelorism, flat nasal bridge, and small mandible. Cleft lip/palate (see this term) is sometimes observed. In some individuals, the anal canal is narrow or absent with a fistula from the rectum into an abnormal location (the bladder, vagina or perineum). The most frequently reported congenital heart defect is congenital total pulmonary venous return anomaly and, less frequently, tetralogy of Fallot (see these terms). Congenital kidney abnormalities include absence of one or both kidneys, hydronephrosis, supernumerary kidneys, and/or renal hypoplasia. Skeletal abnormalities include spinal defects and limb malformations. Possible gastrointestinal malformations are biliary atresia, intestinal malrotation and/or Hirschsprung disease (see this term). Other variable features include hernias, cryptorchidism and hypospadias in males. Rarer malformations may affect almost every organ. Most patients have mild intellectual disability (although some moderate to severe) but a few have normal cognitive development. Short stature with growth hormone deficiency is possible in some cases.
Etiology
Most patients harbor a small supernumerary bisatellited marker chromosome (sSMC) that results in partial tetrasomy of 22pter-22q11. In one third of cases, this extra chromosome is present in a mosaic state. Other cytogenetic anomalies have been rarely reported, including partial trisomy of chromosome 22 and intrachromosomal triplication of the 22q11 region.
Diagnostic methods
The diagnosis, suspected on the basis of clinical manifestations, is based on cytogenetic testing showing the presence of extra material derived from chromosome 22q11. Fluorescence in situ hybridization (FISH) with specific probes is needed to detect a low level mosaicism.
Differential diagnosis
Differential diagnosis includes other chromosomal disorders with overlapping phenotypes such as CHARGE syndrome and VACTERL/VATER association (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible through karyotyping and FISH analysis of prenatal samples.
Genetic counseling
The extra chromosome usually arises de novo.
Management and treatment
Multidisciplinary management is necessary and depends on the specific symptoms that are apparent in each patient. Surgical correction is necessary for anal atresia and severe cardiac malformations. Bacterial infections should be anticipated and treated vigorously. Patients should be screened for visual and hearing impairment. Early intervention with educational support can be beneficial.
Prognosis
Some patients die from severe malformations in early infancy. Otherwise, life expectancy is generally not significantly reduced.

                            Last update:
                            January 2016

                            - Expert reviewer(s):
                            Dr Catherine TURLEAU


Cat-scratch disease is a rare infectious disease, caused by the Gram-negative bacteria Bartonella henselae, that is transmitted to humans via a scratch or bite of an infected cat and that has a variable clinical presentation but that usually manifests with an erythematous papule at the site of inoculation followed by chronic regional lymphadenopathy. Clinical course is usually self-limiting but disseminated illness with high fever, hepatosplenomegaly, granulomatous osteolytic lesions, encephalitis, retinitis, and atypical pneumonia can also occur. Cat-scratch disease can atypically present as parinaud oculoglandular syndrome (unilateral conjunctivitis and preauricular lymphadenopathy).


Cataract-aberrant oral frenula-growth delay syndrome is characterized by cataracts and short stature associated with variable anomalies, including aberrant oral frenula, a characteristic facial appearance (posteriorly angulated ears, upslanting palpebral fissures, small nose, ptosis and epicanthal folds) cavernous hemangiomas and hernias. It has been described in a mother and her two children. It is transmitted as an autosomal dominant trait.


A rare genetic disease characterized by mild intellectual deficit, congenital cataract, progressive sensorineural hearing impairment, ataxia, peripheral neuropathy, and short stature. There have been no further descriptions in the literature since 1991.


Cataract-congenital heart disease-neural tube defect syndrome is a multiple congenital anomaly syndrome characterized by sacral neural tube defects resulting in tethered cord, atrial and/or ventricular septal heart defects (that are detected in infancy), bilateral, symmetrical hyperopia, rapidly progressive early childhood cataracts, bilateral aphakic glaucoma, and abnormal facial features (low frontal hairline, small ears, short philtrum, prominent, widely spaced central incisors, and micrognathia). Hypotonia, growth and developmental delay, seizures, and joint limitation are also reported.


Cataract-deafness-hypogonadism syndrome is an extremely rare multiple congenital abnormality syndrome, described in only three brothers to date, that is characterized by the association of congenital cataract, sensorineural deafness, hypogonadism, mild intellectual deficit, hypertrichosis, and short stature. There have been no further descriptions in the literature since 1995.


Cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome

A rare mitochondrial disease characterized by a highly variable phenotypic spectrum comprising delayed motor development, peripheral neuropathy, cataract, short stature due to growth hormone deficiency, nystagmus, sensorineural hearing loss, dysmorphic facial features, and skeletal abnormalities consistent with spondyloepimetaphyseal dysplasia. Hyperextensible joints, achalasia, and telangiectasia have also been described. Cognition is normal. Atrophy of the pituitary gland has been observed in brain imaging.


Cataract-hypertrichosis-intellectual disability syndrome is characterized by congenital cataract, generalized hypertrichosis and intellectual deficit. It has been described in two Egyptian sibs born to consanguineous parents. It is transmitted as an autosomal recessive trait.


Cataract-intellectual disability-anal atresia-urinary defects syndrome is characterised by congenital cataracts with squint, intellectual deficit, anomalies of the genitourinary tract (rectovesical fistula, micropenis, undescended testis, and hypospadias), imperforate anus and other anomalies.

Summary:
Epidemiology
It has been described in three siblings born to nonconsanguineous parents.
Genetic counseling
It is likely to be transmitted as an autosomal recessive trait.
Management and treatment
The patients underwent surgery for imperforate anus and cataract.

                            Last update:
                            March 2007


This syndrome is characterized by the association of intellectual deficit, congenital cataract, and hypogonadotropic hypogonadism.

Summary:
Epidemiology
Less than 20 cases have been described in the literature so far.
Clinical description
Besides the three main features of the syndrome, other anomalies have been reported in some of the affected patients including short stature, minor digital abnormalities, microcephaly, cardiomyopathy, heart failure, and mild facial dysmorphism (micrognathia, maxilla hypoplasia, low posterior hairline and large ears).
Etiology
Mutations in the RAB3GAP2 gene have been identified in some patients.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            May 2009


A rare syndromic, genetic cataract characterized by the association of congenital cataract and microcornea without any other systemic anomaly or dysmorphism. Clinical findings include a decreased corneal diameter (inferior to 10 mm) in both meridians in an otherwise normal eye, and an inherited cataract, which is mostly bilateral posterior polar with opacification in the lens periphery that progresses to form a total cataract after visual maturity has been achieved. Association with other ocular manifestations, including myopia, iris coloboma, sclerocornea and Peters anomaly may be observed.


A rare lethal combination of manifestations including short stature, congenital cataracts, encephalopathy with epileptic fits, and postmortem confirmation of nephropathy (renal tubular necrosis). There have been no further descriptions in the literature since 1963.


A rare systemic autoimmune disease characterized by acute onset of life-threatening thromboses in three or more organs either simultaneously or within less than a week, in the presence of serum antiphospholipid antibodies (such as lupus anticoagulant, anticardiolipin antibodies, and anti-beta2-glycoprotein 1 antibodies), and with histopathological confirmation of small-vessel occlusion in at least one affected organ. The condition is often precipitated by infection, trauma, or surgery.


Catecholaminergic polymorphic ventricular tachycardia

A rare, severe genetic arrhythmogenic disorder of the structurally normal heart characterized by catecholamine-induced ventricular tachycardia (VT) manifesting as syncope and sudden death in young individuals.

Summary:
Epidemiology
The prevalence of catecholaminergic polymorphic ventricular tachycardia (CPVT) is estimated to be 1/10,000. Both sexes are equally affected.
Clinical description
Typical age of onset of CPVT is between 7 and 15 years of age. Exercise- or emotion-induced syncopal spells are frequently the first symptom. In a subset of patients (10-20%), the disease is clinically silent, presenting only in the event of sudden death. Up to one third of CPVT patients experience life-threatening arrhythmic events prior to starting treatment. The typical arrhythmias of CPVT are bidirectional VT, and, less frequently, supraventricular tachycardias.
Etiology
The disorder is genetically heterogeneous; in 70% of cases, the cardiac ryanodine receptor (RYR2, 1q43) gene is implicated with autosomal dominant inheritance. Mutations in the cardiac calsequestrin gene (CASQ2, 1p13.1) cause an autosomal recessive form of CPVT in 2% to 5% of patients, and in rare instances may cause autosomal dominant CPVT. Other, rarer genes causing CPVT include Trans-2,3-enoyl-CoA reductase-like (TECRL, 4q13.1), calmodulin-1 (CALM1, 14q32.11), and cardiac triadin (TRDN, 6q22.31).
Diagnostic methods
Subjects with a family history of CPVT, or emotion- or exercise-induced sudden death or syncope should undergo exercise stress test and Holter monitoring. Given the reproducibility of arrhythmias, graded exercise stress test is of utmost diagnostic importance. Holter monitoring is also indicated for the rarer cases where acute emotion represents a more powerful trigger. Resting electrocardiogram is usually unremarkable. Cardiac imaging (echocardiogram and MRI) is unremarkable.
Differential diagnosis
The principal differential diagnoses are long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy (ARVC), and Andersen-Tawil syndrome.
Antenatal diagnosis
Antenatal diagnosis can be performed in families with high penetrance and a highly lethal mutation.
Genetic counseling
Screening for the RYR2 mutation and CASQ2 mutation is indicated in all patients with confirmed or suspected CPVT. Screening forTECRL, CALM1, and TRDN mutations may be considered as a second-line analysis. According to the mutation identified, the appropriate genetic counseling should be offered to affected families.
Management and treatment
Lifestyle changes such as limitation of physical activity, avoidance of strong emotion and stressful environments should be recommended to all CPVT patients. Beta blockers (BB; particularly nadolol) are the first treatment option for patients with CPVT and the maximum tolerated dose should be administered to control arrhythmias. Flecainide, a sodium channel blocker, can be considered in patients with BB-resistant arrhythmias. Implantable cardioverter defibrillator (ICD) is recommended in CPVT patients who survived a cardiac arrest, and in those experiencing recurrent syncope or breakthrough arrhythmias despite compliance to an optimal medical treatment.
Prognosis
Although CPVT is a severe disease with high mortality if untreated, early diagnosis and adequate treatment can greatly increase life expectancy. Lifestyle modifications along with optimal medical therapy and ICD implantation in patients with recurrent symptoms portends a favorable prognosis.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Dr Deni KUKAVICA  - Pr Silvia PRIORI


Catel-Manzke syndrome is a rare bone disease characterized by bilateral hyperphalangy and clinodactyly of the index finger typically in association with Pierre Robin sequence (see this term) comprising micrognathia, cleft palate and glossoptosis.

Summary:
Epidemiology
Catel-Manzke syndrome has been described in more than 33 patients.
Clinical description
The key feature of Catel-Manzke syndrome is a bilateral hyperphalangy of the index finger in which there is an accessory ossification center at the metacarpophalangeal joint, resulting in radial deviation of the index finger. In 80% of cases, the digital abnormality is associated with Pierre Robin sequence which combines micrognathia, glossoptosis and cleft palate. Additional frequently reported congenital malformations include cardiac defects such as ventricular septal defect and interatrial communication (see these terms). Less frequent findings include iris coloboma, mild facial dysmorphism (hypertelorism, short palpebral fissures, full cheeks, low-set or posteriorly rotated ears), pectus excavatum, pectus carinatum, scoliosis, bilateral brachydactyly, bilateral fifth finger clinodactyly, knee dislocation, talipes, short halluces, failure to thrive and an intellectual disability, ranging from mild to severe.
Etiology
Homozygous and compound heterozygous mutations in TGDS (13q32.1) have been implicated as causal in Catel-Manzke syndrome.
Diagnostic methods
The disease is diagnosed at birth due to the manifestions linked with Pierre Robin sequence and the abnormal index finger. Radiological findings confirm digital abnormalities including a supernumerary deltoid or trapezoid bone located ulnarwards between the slightly shortened second metacarpal and the significantly shortened corresponding proximal phalanx. On its ulnar side, or more unusually on its radial side, the accessory bone has a pin-shaped bone, possibly an epiphysis causing a broadening of the index finger at the level of the metacarpophalangeal joint. The supernumerary bone fuses with the first phalanx in later life which may cause subluxation at the metacarpo-phalangeal joint.
Differential diagnosis
Differential diagnoses related to the bone abnormalities may include Desbuquois syndrome, Temtamy preaxial brachydactyly syndrome and brachydactyly type C (see these terms).
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is recommended.
Management and treatment
Treatment for airway distress and/or feeding complications involves prone positioning for breathing and/or feeding and is effective for most neonates. The cleft palate is usually corrected by surgical intervention before the age of nine months. Long-term orthodontic care is required. However, follow-up by a multidisciplinary team (pediatrician, craniofacial surgeon, cardiologist, ear, nose and throat specialist and speech therapist) is recommended. The infant continues to need feeding and speech assessments and breathing capacity needs to be monitored.
Prognosis
Prognosis is good with appropriate early treatment and successful management of clinical manifestations during the first year of life.

                            Last update:
                            December 2015

                            - Expert reviewer(s):
                            Dr Almuth CALIEBE


A rare genetic cerebral small vessel disease characterized by an adult-onset primary microangiopathy with severe atherosclerosis of arterioles and secondary leukoencephalopathy. Patients may present with migraine, transient ischemic attacks, stroke with central facial palsy, cognitive dysfunction with impaired concentration, dementia, depression, movement disorder, vertigo, dysphagia, dysarthria, sicca syndrome, impaired REM sleep, and therapy-resistant hypertension, among others. Brain MRI typically shows a leukoencephalopathy that is disproportionately severe and extensive compared to the clinical disease.


Caudal appendage-deafness syndrome is characterized by caudal appendage, short terminal phalanges, deafness, cryptorchidism, intellectual deficit, short stature and dysmorphism. It has been described in monozygotic twin boys.


Caudal duplication (CD) is a rare developmental anomaly in which structures derived from the embryonic cloaca and notochord are duplicated to varying extents.


A rare congenital malformation of the lower spinal segments characterized by a high truncated conus with either aplasia or hypoplasia of the sacrum and lumbar spine. Coexisting malformations of gastrointestinal, genitourinary, skeletal, nervous system are commonly described.

Summary:
Epidemiology
Whilst the exact prevalence at birth is unknown, the incidence of caudal regression syndrome (CRS) is estimated between 1/20,000-100,000 pregnancies. Maternal diabetes is a major risk factor for developing CRS, and the disorder is up to 200 fold more frequent in this group of patients than in the general population.
Clinical description
The spectrum of anomalies affecting the caudal end of the trunk vary from isolated partial agenesis of the sacrococcygeal spine to more severe deformities. The caudal malformation can result in deformities of the pelvis (typically fusion of the iliac wings), anomalies of the lower extremities (i.e. flexion of the knees, varus position of the feet) and motor and neurological deficits of varying degrees of severity (i.e. spontaneous motor activity and impaired deep tendon reflexes of lower limbs). Additional complications of the genitourinary, gastrointestinal and respiratory systems may occur. Genitourinary anomalies can involve unilateral or bilateral renal agenesis, renal ectopia and fused ureters, and generally lead to urinary obstruction, neurogenic bladder, enuresis, or vesicoureteral reflux. Gastrointestinal anomalies can involve inability to control bowel movements (incontinence, encopresis) and an imperforate anus. Congenital heart anomalies are frequently observed. Cases with Chiari I malformation, holoprosencephaly, chronic hypertension and cleft lip and palate have also been reported.
Etiology
The malformations are believed to result from impaired development of the mesoderm prior to 4 weeks gestation. However, vascular steal or hypoperfusion with fetal hypoxemia is also hypothesized due to a few descriptions of a single umbilical cord. Several etiologic factors have been suggested and include maternal diabetes, hypoperfusion, as well as a genetic predisposition (for example mutation in VANGL1 gene (1p13.1), CELSR1 (22q13.31) and, FUZ gene (19q13.33).
Diagnostic methods
Diagnosis is based on antenatal ultrasound examination in the first trimester of pregnancy in the most severe cases. The severity of the disease is determined by examination of the newborn by means of postnatal ultrasonographic and nuclear magnetic resonance imaging (MRI) examination.
Differential diagnosis
The main differential diagnosis is sirenomelia. CRS has also been associated with the VACTERL syndrome, and Currarino syndrome is a form of caudal regression syndrome characterized by the classic triad of presacral mass, sacral bone defect and anorectal malformation. Due to the similarity between sirenomelia, VACTERL and CRS, the distinction between these defects is debated.
Antenatal diagnosis
In severe forms, diagnosis is easier in the first trimester and more difficult later in pregnancy due to oligohydramnios. Sacrococcygeal dysgenesis, abrupt termination of spinal cord, and other anomalies (cardiac, renal, gastrointestinal, lower limbs) can be diagnosed in the second or third trimester. Fetal MRI can be useful in difficult cases or to better define anomalies.
Genetic counseling
The most severe cases of CRS appear to be sporadic but the milder forms appear to be inherited in an autosomal dominant manner with variable phenotypes.
Management and treatment
Treatment and management is supportive and requires a multidisciplinary approach by neurosurgeons, orthopedics, urologists, nephrologists, physical therapists, and psychologists. Neurogenic bladder is commonly described and clean intermittent catheterization and/or anticholinergic drug administration are generally required to treat urological disorders. Surgical interventions such as vesicoureteral reimplantation, cystostomy, Mitrofanoff are commonly performed in order to improve quality of life, urinary continence, and preserve renal function. Surgical reconstruction (Pena Procedure) can be required for imperforate anus, although colostomy may be required in some cases. Depending on the severity of the syndrome, orthopedic interventions may also be required.
Prognosis
Prognosis is poor and is mainly related to urological and cardiac malformations. Early neonatal death in the severe forms occurs from cardiac, renal and respiratory complications. Surviving infants usually have normal cognitive function.

                            Last update:
                            April 2022

                            - Expert reviewer(s):
                            Dr Giovanni MOSIELLO | EUROGEN* - Dr Emmanuelle SAMSON

                                * European Reference Network


A group of rare genetic developmental defect during embryogenesis disorders characterized by varying degrees of caudal abdomen, pelvic, renal, anorectal, urogenital and/or lumbosacral spine malformations, with or without lower limb fusion. Phenotype is highly variable ranging from minor forms with isolated coccygeal agenesis to severe forms presenting with a single rudimentary limb. Central nervous system anomalies have also been reported.


Cavitary myiasis is a rare parasitic disease characterized by the infestation of natural body cavities (e.g. aural, nasal, oral, urogenital myiasis) and internal organs (e.g. cerebral myiasis, ophthalmomyiasis, intestinal and tracheopulmonary myiasis) with dipteran larvae. Clinical presentation is variable depending on the affected site(s) and degree of infestation and include foreign-body sensation (with or without movement sensation), hemorrhage, pain, edema, sensory loss, malodor, and pruritus, among others. Neurological features (e.g. motor deficits, seizures, reduced mental status, extrapyramidal signs) have been reported in cerebral myiasis.


A rare congenital disorder of glycosylation characterized by infantile onset of hepatosplenomegaly, progressive liver failure, hypotonia, and global developmental delay. Mild dysmorphic features and seizures have also been reported. Laboratory abnormalities include elevated liver enzymes, mild hypercholesterolemia, and low serum ceruloplasmin.


A rare genetic neurodevelopmental disorder characterized by early-onset drug-resistant seizures and severe neurodevelopmental impairment with major motor development delay.

Summary:
Epidemiology
CDKL5-related epileptic encephalopathy has an estimated birth prevalence of 1/42,400 in the UK (Scotland). It affects predominantly females with a sex ratio of 12:1
Clinical description
Presentation is of severe seizures with onset in the first six months of life (often within the first 3 months or even the first few weeks after birth), hypotonia, poor eye contact and poor neurocognitive development. Severe hypotonia can be present before seizure onset, as well as irritability, excessive crying, drowsiness, and poor sucking. Seizures are usually difficult and include epileptic spasms, myoclonic seizures, tonic seizures and tonic-clonic seizures. At the beginning EEG might not reveal significant epileptiform abnormalities, however over time abundant and multifocal epileptiform discharges are evident. During the disease course a seizure free period might be observed, this is also reported as ''honey-moon period''. The neurological outcome is poor as most affected individuals cannot walk and many are confined to a wheelchair. Communication strategies are restricted to elementary non-verbal communication. Patients do not develop autonomy to feed themselves. Subtle dysmorphic facial features include a prominent/broad forehead, deep-set eyes, a well-defined philtrum, and everted lower lip, possibly associated with tapered fingers and hallux valgus. Stereotypies are common. Some may have scoliosis, visual impairment, gastrointestinal difficulties, and sleep problems. Epilepsy is drug-resistant and most of patients continue with active epilepsy.
Etiology
The disorder is caused by mutations or deletions in the cyclin-dependent kinase-like 5 (CDKL5, Xp22.13) gene situated in the X chromosome. CDKL5 is a kinase predominantly expressed in the brain. Deficiency in CDKL5 leads to neurodevelopmental alterations.
Diagnostic methods
Diagnosis is suspected in patients with early onset epilepsy with a severe developmental delay and with a poor response to anti-epileptic drugs. Genetic identification of CDKL5 alterations confirms diagnosis.
Differential diagnosis
Differential diagnosis includes developmental epileptic encephalopathies (DEE) with early onset seizures and West syndrome. Molecular testing of the CDKL5 gene should be considered in cases DEE, West syndrome.
Genetic counseling
The pattern of inheritance is X-linked. The risk of recurrence in affected families is low since the pathogenic mutations occur de novo in most cases; however, some cases of parental mosaicism have been reported.
Management and treatment
There is no medication currently approved for the specific treatment of this disorder. Management is symptom-based and requires a multidisciplinary approach. Anticonvulsant medications and ketogenic diet is used for the management of seizures. Non-pharmacological management includes physical, occupational, visual and speech therapy.
Prognosis
Life expectancy is unknown due to underdiagnosis in adults, but adult patients are known. Prognosis is poor with severe psychomotor deficits and intractable seizures remaining into adulthood. Autonomy is never reached.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Pr Helen CROSS | EpiCARE* - Pr Reetta KÄLVIÄINEN | EpiCARE* - Pr Rima NABBOUT | EpiCARE* - Pr Nicola SPECCHIO | EpiCARE*

                                * European Reference Network


CEBPE-associated autoinflammation-immunodeficiency-neutrophil dysfunction syndrome

A rare genetic autoinflammatory syndrome with immune deficiency characterized by a combination of autoinflammation, immunodeficiency, and neutrophil dysfunction, as well as mild bleeding diathesis. Patients present recurrent attacks of abdominal pain, high fever, and systemic inflammation lasting four to five days and occurring every few weeks. Attacks may be accompanied by nailbed, tongue, submandibular, and gluteal abscesses, intra-abdominal granulomas, pyoderma gangrenosum, and buccal ulcerations. Frequent episodes of purulent paronychia, superficial skin and mucosal infections, and purulent upper respiratory tract infections have also been reported.


A rare, genetic, neurocutaneous disease characterized by severe developmental abnormalities of the nervous system and aberrant differentiation of the epidermis. Patients present with a unique constellation of clinical signs described with the acronym CEDNIK: CErebral Dysgenesis, Neuropathy, Ichthyosis, and palmoplantar Keratoderma.


A rare disease caused by compression of the celiac axis by an abnormally shaped arcuate ligament (the part of the diaphragm in which both pillars join in the midline around the aorta). Patients have recurrent abdominal pain, anorexia and weight loss. The pain is epigastric, and diarrhea or constipation may be present as well. Onset of pain will usually, although not always, be after food intake, and may be associated with nausea and emesis. Other symptoms may include lassitude, exercise intolerance and vomiting. Occasionally, a patient may show an abdominal murmur upon auscultation.


Celiac disease-epilepsy-cerebral calcification syndrome

Celiac disease, epilepsy and cerebral calcification syndrome (CEC) is a rare disorder characterized by the combination of auto-immune intestinal disease, epileptic seizures and cerebral calcifications.

Summary:
Epidemiology
CEC was first described in 1992 and fewer than 200 cases have been reported so far.
Clinical description
Celiac disease (CD, see this term) and epilepsy manifest at a variable age, and CD is frequently diagnosed in late childhood, when specific investigations are performed secondary to observation of epileptic seizures and cerebral calcifications (CC). CD can present in a typical form characterized by onset in the first 2 years of life, chronic diarrhea, weight loss, short stature, anorexia, and, in some cases, irritability and vomiting. CD may also present in silent or latent forms, which are characterized - in the absence of gastrointestinal symptoms - by dermatitis herpetiformis, dental enamel defects or autoimmune thyroiditis. In CEC patients, CD usually evolves into latent, silent or paucisymptomatic forms. Epilepsy onset is between infancy and adulthood; most cases occur in early childhood. Most patients present with occipital epileptic seizures, the course being highly variable, with benign, drug-resistant, or epileptic encephalopathy forms. In the latter, severe mental deterioration and/or learning disorders have been reported while a mild mental deterioration is observed in only one third of all CEC cases. CCs are seen in subcortical parieto-occipital regions. CC size does not change significantly over time, but in several cases, new CCs appeared in other regions. Patients with CCs and CD without epilepsy are considered as having an incomplete form of CEC. Some patients with epilepsy and CC without CD are considered to have a CEC with latent CD.
Etiology
Etiology of CEC is unclear. It is not known if epilepsy and/or CC are a consequence of CD. CD is an immune auto-inflammatory reaction occurring in predisposed gluten-intolerant individuals. It originates from the jejunal mucosa and spreads to the lamina propria, leading to the observed histopathological features (crypt hyperplasia, jejunal villous atrophy and inflammatory infiltrate in the lamina propria). CD may induce autoimmune responses outside the gastrointestinal tract. Circulating activated T cells may cross the blood-brain barrier and be toxic to myelin or myelin-producing cells. As for isolated CD, CEC is associated with the HLA-DQ2 and HLA-DQ8 genes.
Diagnostic methods
Diagnosis relies on anamnestic investigation and EEG to characterize epileptic seizures. Computed tomography (CT) imaging reveals CC. Laboratory findings (antiendomisium antibodies, antigliadin antibodies, anti-tissue-transglutaminase type 2 antibodies, HLA phenotype), and histopathological analysis of small bowel biopsy (jejunal mucosa villous atrophy) enable identification of silent or latent CD in a patient with epileptic seizures and CC.
Differential diagnosis
Differential diagnosis of CEC includes Sturge-Weber syndrome (see this term) without nevus flammeus and other conditions such as congenital folate malabsorption or adverse effects of methotrexate, antifolate agents and radiotherapy of leukemic children.
Management and treatment
CD requires life-long observance of a gluten-free diet (GFD), leading to clinical and histopathological resolution of symptoms. A study has revealed that early CD diagnosis and treatment by GFD could prevent or reverse the epileptic disorder.
Prognosis
Early diagnosis and good compliance of GFD greatly improve outcome. On the contrary, if treatment is delayed, epilepsy may be more severe and epileptic encephalopathy may develop.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Giuseppe GOBBI


CELSR1-related late-onset primary lymphedema

A rare genetic primary lymphedema characterized by unilateral or bilateral lower limb lymphedema of variable severity. The condition shows almost complete penetrance with onset in childhood or adolescence in females, whereas in males it shows incomplete penetrance with later onset of disease. Lymphoscintigraphy in more severely affected individuals reveals lymphatic abnormalities consistent with lymphangiectasia, valve dysfunction, and thoracic duct reflux.


Cenani-Lenz syndrome (CLS) is a congenital malformation syndrome that associates a complex syndactyly of the hands with malformations of the forearm bones and similar manifestations in the lower limbs.

Summary:
Epidemiology
Fewer than 30 cases have been described and the exact incidence has not been evaluated. The majority of cases occurred in related families.
Clinical description
Classical CLS is characterized by the almost symmetrical presence of a total fusion of fingers and synostosis of the hand bones, giving the hands a mitten-like appearance. A variant of the syndrome, with oligodactyly and partial syndactyly, has been reported. The following features characterize the syndrome: carpal, metacarpal and digital synostoses, disorganization of the carpal bones, numeric reduction of the digital rays and toe syndactyly. Other features are radioulnar synostosis with shortening of the radius and ulna, brachymesomelia, radius head dislocation and metatarsal synostoses. The syndrome affects both the upper and lower limbs but, in general, the latter are less severely affected. Associated malformations (renal hypoplasia and vertebral and hemivertebral anomalies) have occasionally been reported. A few publications associate CLS with other, more frequent, forms of syndactyly. Mild facial dysmorphism (ptosis, high-arched palate, high, broad and prominent forehead, hypertelorism, flat nasal bridge, down slanting palpebral fissures, short nose, short prominent philtrum and malar hypoplasia) has been described in isolated cases.
Etiology
The disease is transmitted as an autosomal recessive trait. Homozygous or compound heterozygous mutations of the LRP4 gene (11p12-p11.2) have been identified. A heterozygous duplication of 1.7 Mb covering the GREM1 and FMN1 genes has also been reported in a CLS-like form of the syndrome.
Diagnostic methods
Diagnosis is essentially clinical.
Differential diagnosis
CLS can be distinguished clinically from other limb malformations.
Antenatal diagnosis
Diagnosis can be suspected antenatally by ultrasonography.
Genetic counseling
As an autosomal recessive syndrome, recurrence risk for CLS is 25% for a subsequent pregnancy.
Management and treatment
Surgical treatment with reconstruction of an individualized finger is recommended but the functional results of syndactyly release may be unsatisfactory.
Prognosis
Functional prognosis depends on the specific limb anomalies of the patient.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Pr Didier LACOMBE


A hereditary macular disorder, usually presenting between the ages of 30-60, characterized by a large area of atrophy in the centre of the macula and the loss or absence of photoreceptors, retinal pigment epithelium and choriocapillaris in this area, resulting in a progressive decrease in visual acuity.


Central cloudy dystrophy of François is a very rare form of stromal corneal dystrophy (see this term) characterized by polygonal or rounded stromal opacities surrounded by clear tissue, and generally no effect on vision.

Summary:
Epidemiology
The prevalence of this form of corneal dystrophy is unknown.
Clinical description
Lesions generally appear in the first decade of life; subjects with the condition are mostly asymptomatic. The course of the disease is non-progressive.
Etiology
Etiology is unknown.
Differential diagnosis
Corneal changes are very similar to Vogt posterior crocodile shagreen, a corneal degenerative disease.
Genetic counseling
Autosomal dominant inheritance has been reported.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Central or secondary congenital hypothyroidism is a type of permanent congenital hypothyroidism (see this term) characterized by permanent thyroid hormone deficiency that is present from birth and secondary to a disorder in the thyroid-stimulating hormone (TSH) - thyrotropin-releasing hormone (TRH) system.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Goiter is always absent. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment central hypothyroidism results in intellectual deficit and short stature.
Etiology
Central hypothyroidism usually results from defects of TSH production and is often part of a disorder causing congenital hypopituitarism (see this term), in which case the clinical signs may also include septo-optic dysplasia or cleft lip and/or palate as well as other signs of hypopituitarism, or part of a larger genetic syndrome such as pituitary stalk interruption syndrome (see this term). Mutations in genes regulating pituitary gland development including HESX1, LHX3, LHX4, POU1F1 and PROP1 (3p21.2-p21.1, 9q34.3, 1q25, 3p11 and 5q) may also cause central hypothyroidism. Central hypothyroidism may also result from isolated TSH deficiency (see this term), which is transmitted in an autosomal recessive manner and is caused by mutations in the TSHB subunit gene (1p13), or from TRH resistance (see this term) caused by mutations in the TRH receptor gene (TRHR; 8q23).

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI


Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness, pronounced in the hip girdle. Orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication.
Etiology
CCD and MHS are allelic conditions, both caused by (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes in the RyR protein are considered to be the main pathogenetic mechanism(s).
Diagnostic methods
The diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy. Muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis.
Management and treatment
Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment.
Prognosis
In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.

                            Last update:
                            May 2007

                            - Expert reviewer(s):
                            Dr Heinz JUNGBLUTH


Central neurocytoma is a very rare brain tumor of young adults (over 100 cases reported worldwide). It is typically found in the lateral ventricles and occasionally in the third ventricle. Symptoms are those of increased intracranial pressure: headache, nausea and vomiting, drowsiness, vision problems and mental changes. Total removal of the tumor is the therapy of choice. Post-operative prognosis is generally good.


A rare congenital limb malformation characterized by complete or partial duplication of one of the three middle digits in a hand or foot. It most commonly affects the fourth digit. The malformation may be unilateral or bilateral and can occur as an isolated defect or in association with other anomalies.


A rare retinal vasculopathy characterized by impaired venous return from the retinal circulation due to an occlusion occurring within or posterior to the optic nerve head. The clinical presentation is variable and may range from asymptomatic to an abrupt and profound loss of vision. Complications causing visual loss include macular edema, macular ischemia, optic neuropathy, vitreous hemorrhage, tractional retinal detachment, and in more severe cases extensive capillary non-perfusion with a high risk of neovascular glaucoma.


A rare, acquired, choroidal disorder characterized by subretinal detachment in the macular área and leakage of fluid under the retina that accumulates under the central macula. Symptoms tend to include blurred or distorted vision (metamorphopsia), moderate dyschromatopsia, relative central scotoma, hypermetropization, micropsia and reduced contrast sensitivity. A blurred or gray spot in the central visual field is common when the retina is detached.


Centrifugal lipodystrophy is a rare, acquired, localized lipodistrophy characterized by single or, occasionally, multiple, centrifugally progressive, asymptomatic to sometimes mildly tender, hypopigmented, lipoatrophic skin depressions with weakly erymatheous inflammatory borders, typically associated with regional ipsilateral lymph nodes swelling. Lesions typically occur on lower trunk (in particular groin and abdomen region), followed by upper trunk (axilla and neighboring regions) and, rarely, neck and head. It is usually not associated with systemic disease and is typically self-resolving.


A rare group of inherited neuromuscular disorders characterized by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy. The clinical picture and other histologic features varies according to gene involved and mode of inheritance.

Summary:
Epidemiology
The exact prevalence and incidence of this group of diseases are unknown. For the X-linked form (XLMTM1) the incidence is estimated at 1/50,000 male birth.
Clinical description
These congenital myopathies are characterized by generalized muscle weakness that can range from mild to severe. Symptoms are often present at birth in the severe forms, but may first develop at any point during life, although onset in adulthood is unusual. In the severe forms the common symptoms include hypotonia, feeding difficulties and respiratory distress. Extraocular muscle involvement is also common in all forms. Other common signs and symptoms include delayed motor milestones, facial weakness and ptosis.
Etiology
Centronuclear myopathies (CNMs) are genetically widely heterogeneous and have been attributed mainly to X-linked recessive mutations in MTM1 (Xq28), encoding myotubularin 1 (X-linked centronuclear myopathy), autosomal-dominant mutations in DNM2( 19p13.2), encoding dynamin-2, autosomal dominant or recessive mutations in BIN1 (2q14.3), encoding myc box-dependent-interacting protein 1, and autosomal-recessive mutations in RYR1 (19q13.2), encoding the skeletal muscle ryanodine receptor, and in TTN (2q31.2), encoding titin. More recently, there have also been reports on peculiar CNM phenotypes related to autosomal recessive mutations in SPEG (2q35), encoding the striated muscle preferentially expressed protein kinase, and mutations in CCDC78 (16p13.3), encoding the coiled-coil domain-containing protein-78.
Diagnostic methods
Diagnosis is based on typical histological findings of central nuclei, hypotrophy and predominance of type I fibers.
Differential diagnosis
The main differential diagnoses include other forms of congenital myopathies or other neuromuscular conditions with severe neonatal hypotonia.
Antenatal diagnosis
In familial cases, prenatal diagnosis can be performed if the genetic background is known.
Genetic counseling
Genetic counseling should be offered to all patients and families in whom a diagnosis of CNM has been made.
Management and treatment
Management of CNM requires a multidisciplinary approach. No specific therapy exists yet but different therapeutic strategies are under investigation.
Prognosis
The prognosis of this group of disease is variable. Whereas the XLMTM1 is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with a globally more favourable prognosis.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Enrico BERTINI  - Dr Adele D'AMICO  - Pr Fabiana FATTORI


Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

A rare slowly progressive autosomal recessive syndromic cerebellar ataxia characterized by late-onset cerebellar dysfunction (including gait and limb ataxia, nystagmus, and dysarthria), bilateral vestibulopathy (abnormal vestibulo-ocular reflex), and axonal sensory neuropathy. Variable features may include chronic cough and autonomic dysfunction. Brain imaging usually shows cerebellar atrophy.


A rare, autosomal recessive, congenital, cerebellar ataxia disorder characterized by hypotonia from birth, marked psychomotor delay and prominent cerebellar dysfunction (manifesting with nystagmus, intention tremor, dysarthria, ataxic gait and truncal ataxia), described in an isolated population of the Grand Cayman Island. Cerebellar hypoplasia, observed on CT scan, may be associated.


Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

A rare autosomal dominant neurological disorder characterized by early onset cerebellar ataxia, associated with areflexia, progressive optic atrophy, sensorineural deafness, a pes cavus deformity, and abnormal eye movements.


Cerebellar ataxia-ectodermal dysplasia syndrome

A rare syndromic cerebellar ataxia characterized by hypodontia and sparse hair in combination with cerebellar ataxia and normal intelligence. Imaging demonstrates a cerebellar atrophy.


Cerebellar ataxia-hypogonadism syndrome is a very rare autosomal recessive neurodegenerative disorder characterized by the combination of progressive cerebellar ataxia with onset from early childhood to the fourth decade, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). Cerebellar ataxia-hypogonadism syndrome belongs to a clinical continuum of neurodegenerative disorders along with clinically overlapping disorders such as ataxia-hypogonadism-choroidal dystrophy syndrome (see this term).


Cerebellar hypoplasia-tapetoretinal degeneration syndrome is a rare syndrome with a cerebellar malformation as a major feature characterized by cerebellar hypoplasia, bilateral retinal pigmentary changes, intellectual disability that can range from mild to moderate and pronounced language development delay. It presents with early developmental delay, central and peripheral non-progressive visual impairment or asymptomatic retinal changes, hypotonia, non-progressive ataxia and nystagmus.


Cerebellar liponeurocytoma (cLPN) is a rare slow growing neuronal tumor seen more frequently in females than males, occurring most commonly in the cerebellum but occasionally in the supratentorial compartment or the fourth ventricle and presenting in the 4th to 6th decade of life with symptoms of dizziness, headache and gait instability. It often has a high rate of local recurrence.


A rare, autosomal recessive, multiple congenital anomalies/dysmorphic syndrome characterized mainly by developmental delay, variable intellectual disability, microcephaly, cerebellar hypoplasia, dysmorphic features (central incisors macrodontia and slender fingers), short stature and variable congenital anomalies.

Summary:
Epidemiology
To date, ten patients carrying biallelic BRF1 variants have been reported in the literature.
Clinical description
The clinical features of the syndrome include developmental delay and intellectual disability. Congenital microcephaly is present in all patients with occipital frontal circumference recorded and with progressive deceleration. Postnatal growth retardation occurred in all patients with height last evaluation between -2.5 and -5 SD. The most constant dysmorphic features include central incisors macrodontia and slender fingers. Laryngomalacia, tracheomalacia, congenital heart defect, sensorineural hearing impairment and inner ear malformation have been reported. Brain malformations, as detected on magnetic resonance imaging, may include cerebellar hypoplasia, corpus callosum hypoplasia and, more variably, enlarged cisterna magna and enlarged lateral ventricles.
Etiology
The disorder is due to biallelic variants in the BRF1 (14q32.33) gene; the pathogenic variants reported are missense variants, with only one frameshift mutation identified. All variants affect protein residues located within the cyclin 2 protein domain.
Diagnostic methods
All patients reported had been diagnosed by next generation sequencing.
Differential diagnosis
The disorder is distinguished from other intellectual disability syndromes mainly by short stature and progressive microcephaly. Prominent upper incisors is a remarkable sign.
Antenatal diagnosis
Where the mutation has been identified previously in a proband, prenatal molecular genetic testing could be offered.
Genetic counseling
The pattern of inheritance is autosomal recessive. Families with an affected child should be counselled that there is a recurrence risk of 25% for each pregnancy.
Management and treatment
Standard management is indicated for intellectual disability and postnatal growth retardation. Echocardiography, abdominal ultrasound and hearing evaluation is recommended at birth. Surveillance should include frequent monitoring of growth and development. Regular ophthalmological follow up is recommended.
Prognosis
Patients reported with poor prognosis are related to complex heart defects.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Irene VALENZUELA PALAFOLL | ITHACA*

                                * European Reference Network


A rare genetic cerebral small vessel disease characterized by amyloid deposition in the cerebral blood vessels leading to predominantly hemorrhagic strokes, focal neurological deficits, and progressive cognitive decline eventually leading to dementia.

Summary:
Epidemiology
The prevalence is unknown. HCHWA has been described in several families from all over the world. The estimated number of affected patients is between 300 and 400.
Clinical description
Unlike sporadic forms of cerebral amyloid angiopathy (CAA), HCHWA usually presents in younger patients (<55 years of age) and has more severe manifestations. Clinical features depend on the HCHWA disease type, with 7 discovered to date: Icelandic, Dutch, Arctic, Piedmont, Iowa, Flemish and Italian (see these terms). In general, patients present with either a stroke (with headache, nausea, vomiting, focal neurological deficits, and alterations in consciousness) or progressive dementia of the Alzheimer type. Transient neurological symptoms lasting a few minutes to a few hours, and seizures can also occur. Microbleeds and hemorrhages can occur throughout the brain, and are caused by involvement of the vessels in the cerebral cortex and the meninges. Hemorrhages tend to recur. Cognitive decline is progressive and can lead to dementia, either in a stepwise fashion or slowly progressive as in Alzheimer's disease.
Etiology
Most forms of HCHWA (Dutch, Arctic, Piedmont, Iowa, Flemish and Italian) are due to a point-mutation in the APP gene on chromosome 21q21.2, which encodes the beta-amyloid precursor protein. This mutation causes increased accumulation of amyloid-beta protein in the walls of cerebral arteries and capillaries. This can lead to rupture or narrowing of the blood vessels, leading to hemorrhagic or non-hemorrhagic stroke. Sometimes the affected blood vessels show signs of inflammation (CAA-angiitis). Only one form of HCHWA, Icelandic type, is due to a mutation in the CST3 gene on chromosome 20p11.2, encoding the precursor protein cystatin C.
Diagnostic methods
For a probable diagnosis of HCHWA a detailed family history, and (preferably) a magnetic resonance imaging (MRI) scan should be performed. Typically, the MRI shows multiple lobar (cortical, subcortical) hemorrhages and leukoencephalopathy. In the presence of otherwise unexplained lobar hemorrhages and a typical family history, the finding of a causative mutation is sufficient for a definite diagnosis of HCHWA in vivo. At postmortem examination severe CAA, and cortical, lobar or subcortical hemorrhages are found.
Differential diagnosis
Differential diagnoses include all other conditions that could cause lobar intracerebral hemorrhage such as coagulopathies, vasculitis, intravascular large B-cell lymphoma (see these terms), CNS neoplasms, cavernous malformations, cerebral vascular malformation and antecedent trauma
Antenatal diagnosis
Antenatal diagnosis is possible but is rarely performed.
Genetic counseling
The presently known types of HCHWA are inherited in an autosomal dominant manner. Screening of family members of patients with HCHWA is recommended, because of the possibility of genetic counseling. Presymptomatic genetic testing is offered.
Management and treatment
There is no known acute or preventive treatment for cerebral hemorrhages in HCHWA. Antihypertensive therapy is recommended, even in cases of mild to moderate hypertension, but its efficacy is not evidence-based. Corticosteroids can ameliorate symptoms caused by CAA-related inflammation. Patients experiencing seizures should be given antiepileptic drugs. Surgical hematoma evacuation is rarely performed for HCHWA because of the poor outcome associated with severe neurological deficits.
Prognosis
The prognosis is often poor.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Joost HAAN  - Pr G.M. [Gisela] TERWINDT


Cerebral arteriovenous malformation (AVM) is a congenital malformative communication between the veins and the arteries in the brain in the form of a nidus, an anatomical structure composed of dilated and tangled supplying arterioles and drainage veins with no intervening capillary bed, that can be asymptomatic or cause, depending on the location and the size of the AVM, headaches of varying severity, generalized or focal seizures, focalneurological defects (weakness, numbness, speech difficulties, vision loss) or potentially fatal intracranial hemorrhage in case the AVM ruptures.


Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary cerebrovascular disorder characterized by mid-adult onset of recurrent subcortical ischemic stroke and cognitive impairment progressing to dementia in addition to migraines with aura and mood disturbances seen in about a third of patients.

Summary:
Epidemiology
In Europe, the prevalence of CADASIL has been estimated to range between 1/50 000- 1/25 000.
Clinical description
The first manifestation of the disease occurs at a mean age of 45-50, usually in the form of ischemic stroke or cognitive decline. The disease onset and course is variable, but more than two thirds of patients suffer from (recurrent) stroke or dementia. Migraine, usually with aura, occurs in about a third of patients and often precedes stroke and dementia symptoms, with a mean age of onset of about 30 years. Psychiatric disorders are also common and include depression, apathy and personality changes. Less common signs include reversible acute encephalopathy (accompanied by headache, confusion, and seizures), epilepsy and subclinical peripheral neuropathy. The most common cause of death is pneumonia, followed by sudden unexpected death and asphyxia.
Etiology
CADASIL is caused by mutations in the NOTCH3 gene (>95% of cases), located to 19p13.2-p13.1, which encodes transmembrane receptor NOTCH3, mainly expressed in vascular smooth muscle cells. More than 90% are missense mutations which lead to a numerical cysteine alteration in one of the epidermal growth factor receptor (EGFR) encoding exons of NOTCH3 (exons 2-23). The mutated EGFR contains 5 or 7 cysteine residues, rather than the usual 6. This leads to increased multimerisation of the mutated protein and accumulation of mutated NOTCH3 in the vascular wall.
Diagnostic methods
The diagnosis of CADASIL should be considered in patients with young onset stroke or cognitive decline, ischemic changes on MRI (such as symmetrical white matter hyperintensities, subcortical infarctions, microbleeds) and a positive family history for stroke or dementia. Diagnosis can be confirmed through molecular analysis, by the identification of a typical cysteine altering NOTCH3 mutation. Alternatively, electron microscopy of a skin biopsy can be used to reveal characteristic granular deposits in the vessel wall, or immunohistochemical analysis can show positive NOTCH3 staining of the vessel wall.
Differential diagnosis
Differential diagnoses include Binswanger disease, primary angiitis of the central nervous system and multiple sclerosis as well as other genetic disorders such as CARASIL, MELAS syndrome, Fabry disease and small-vessel diseases associated with COL4A1 mutations (e.g. familial porencephaly) (see these terms).
Antenatal diagnosis
Antenatal diagnosis and pre-implantation genetic diagnosis is possible if a disease-causing mutation in the family is known.
Genetic counseling
Due to the autosomal dominant inheritance and the generally severe progression, patients and family members should always be offered genetic counseling.
Management and treatment
There is no cure for CADASIL. Antiplatelet therapy is often used but it has not yet been proven as an effective treatment. Symptomatic treatment can be offered to patients to treat migraines and potential concomitant vascular risk factors (hypertension, hypercholesterolemia and diabetes). Psychological counseling should be offered to patients and their families in order to give them emotional support. Smoking, angiography, anticoagulants and thrombolytic therapy are all to be avoided by those with CADASIL as they increase the risk of cerebrovascular manifestations.
Prognosis
The prognosis is poor with most patients eventually becoming bed-ridden and dement and requiring constant nursing care. The median age at death is 68 years.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Dr S.A.J. [Saskia] LESNIK OBERSTEIN  - Pr G.M. [Gisela] TERWINDT