Drug-induced autoimmune hemolytic anemia is a type of autoimmune hemolytic anemia (AIHA; see this term) that occurs as a reaction to therapeutic drugs, and can be due to various mechanisms.

Summary:
Epidemiology
Drug-induced AIHA is rare; annual incidence is estimated at about 1/1,000,000. It is more common in adults and is very rare in children, although some fatal cases in children have been reported.
Clinical description
The disease presents with anemia linked to hemolysis, and physical examination may show an enlarged spleen.
Etiology
To date about 100 drugs have been implicated in drug-induced AIHA, including: cephalosporins (primarily cefotetan and ceftriaxone), levodopa, methyldopa, penicillin and its derivatives, quinidine and some nonsteroidal anti-inflammatory drugs.
Diagnostic methods
It is important to consider drug-induced AIHA when a patient serologically presents as either warm- or cold-type AIHA (see these terms) to avoid erroneous diagnosis.
Management and treatment
Stopping the drug that is causing the problem may relieve or control the symptoms. Patients may also be given IV immunoglobulin and prednisone to reduce the immune response. Blood transfusion may be needed in severe cases.
Prognosis
The prognosis is good if the causative drug is identified and the patient stops taking it. Death is a rare outcome, but has been reported particularly in children with AIHA caused by cefotetan and ceftriaxone.

                            Last update:
                            August 2010

                            - Expert reviewer(s):
                            Pr Marc MICHEL


Drug-induced localized lipodystrophy is a rare, acquired, localized lipodystrophy characterized by the appearance of asymptomatic, well-demarcated, variably sized, depressed, lipoatrophic lesions secondary to subcutaneous, intradermic or intramuscular drug injection, including corticosteroids, insulin, human growth hormone and antibiotics. Skin coloration may vary from white or hypopigmented to reddish, pinkish or violaceous. Epidermal atrophy may be also present.


A rare, systemic disease with skin involvement characterized by the onset of idiopathic lupus erythematosus-like signs and symptoms resulting from continuous drug intake (>1 month), which resolve when treatment is discontinued, in persons with no history of autoimmune disease. Manifestations are variable and may be systemic (e.g. arthralgia, myalgia, fever, fatigue, serositis, pleuritis, pericarditis), subacute cutaneous (incl. photosensitive, non-scarring, annular, polycyclic or papulosquamous lesions, malar erythema, vasculitis, bullous lesions, erythema multiforme-like changes), and/or chronic cutaneous (typically discoid lesions in sun-exposed areas). Procainamide and hydralazine are the drugs most frequently implicated.


A rare secondary vasculitis characterized by inflammation of blood vessels caused by various drugs, including antibiotics, anti-tumor necrosis factor-alpha agents, immunotherapeutic drugs, and psychoactive agents, among others. The skin is most commonly affected, but other tissues and organs, such as the subcutis, kidneys, or lungs, may also be involved. Systemic disease develops only in a minority of patients, typically when treated with the causative drug over a prolonged period of time. Presenting signs and symptoms include skin rash, myalgia, arthralgia, fever, and malaise.

Summary:
Epidemiology
The incidence and prevalence of drug-induced vasculitis remains unknown. No population-based study has been performed.
Clinical description
Drug-induced vasculitis typically presents with a petechial rash, purpura and skin necrosis. Symptoms are usually mild and localized. Rarely, systemic involvement of the lungs, kidneys, central nervous system, and/or liver can occur; this can be severe and potentially life-threating. Clinical features include rash, fever, malaise and myalgia, with a temporal relationship with drug administration.
Etiology
The etiology of drug-induced vasculitis (DIV) is incompletely understood, however, aberrant NETosis, breakdown in immune tolerance and epitope spreading, implicated in the development of autoimmunity, have been identified as potential etiological mechanisms.
Diagnostic methods
Drug-induced vasculitis is a diagnosis of exclusion. There is no laboratory diagnostic tool for drug-induced vasculitis. Eosinophil count may be raised; this is seen more frequently in the case of systemic involvement. A comprehensive drug history of prescribed and over-the-counter medicines is paramount. Tissue biopsy can be beneficial in confirming the diagnosis.
Differential diagnosis
Differential diagnosis includes systemic lupus erythematosus, other non-drug-induced ANCA-vasculitis, infections, and malignancies.
Management and treatment
Treatment is focused on stopping administration of the offending agent, and is enough to induce remission in mild cases. In addition, short-course and low-dose steroids therapy can be beneficial. For severe presentations, higher doses of steroids for longer durations may be required. In severe systemic presentations patients can be treated according to ANCA-vasculitis flare protocols. Plasma exchange can also be considered. Relapse is likely upon reintroduction of the offending drug.
Prognosis
Most cases are mild and resolve with cessation of the offending drug without any long-term sequelae. However, in cases with severe systemic involvement, drug-induced vasculitis can result in critical illness and death.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Dr Eithne NIC AN RÍOGH


A rare genetic disease characterized by bilateral Duane retraction syndrome type 3 (consisting of severe limitation of abduction, restriction of adduction, retraction of the globe, and narrowing of the palpebral fissure) and congenital myopathy manifesting as mild non-progressive hypotonia without muscular weakness, as well as delayed motor milestones, severe early-onset scoliosis, and short stature. Intelligence is normal.


Duane retraction syndrome with congenital deafness

A rare neurologic disease characterized by the presence of Duane retraction syndrome (i. e. a congenital cranial dysinnervation disorder with unilateral or bilateral limitation of abduction and/or adduction of the eye, as well as globe retraction and palpebral fissure narrowing on attempted adduction) in combination with congenital unilateral or bilateral hearing loss. The sidedness of hearing loss corresponds to the sidedness of the retraction syndrome.


A rare, ocular congenital cranial dysinnervation disorder characterized by limited horizontal eye movement accompanied by globe retraction and palpebral fissure narrowing on attempted adduction.

Summary:
Epidemiology
Duane retraction syndrome (DRS) prevalence is estimated at between 1/1000 and 1/10,000 in the general population, representing approximately 1-5% of all strabismus cases. Females are more frequently affected than males.
Clinical description
DRS is a congenital disorder, characterized by non-progressive horizontal ophthalmoplegia without ptosis. Vertical eye movement abnormalities may be observed, including upshoot or downshoot on adduction. Isolated, simplex DRS is usually unilateral and the left eye is more commonly affected. At birth, affected infants have restricted abduction and/or adduction, though it may not be appreciated immediately. Most individuals with DRS have strabismus in primary gaze but can use a compensatory head position to align the eyes, avoiding diplopia. Development of amblyopia is possible. The majority of DRS cases (70%) are not associated with other anomalies. DRS can be classified based on the extent of abduction and adduction: limited or absent abduction with normal or slightly limited adduction (type I) , normal or mildly restricted abduction with limited or absent adduction (type II), absent or limited abduction and adduction (type III). In all types, there is globe retraction with narrowing of palpebral fissure on attempted adduction.
Etiology
DRS results from abnormal development of the pontine abducens nucleus or nerve, unilaterally or bilaterally, leading to failure of the normal innervation of the lateral rectus muscle on the affected side. This results in limited abduction and horizontal gaze palsy. Globe retraction and fissure narrowing are due to co-contraction of the medial and lateral rectus muscles on attempted adduction, which is itself secondary to aberrant innervation of the lateral rectus by the oculomotor nerve. Identified genetic pathogenic variants include CHN1 or MAFB and rarely, SALL4.
Diagnostic methods
Diagnosis of DRS is based on clinical features. Magnetic resonance imaging of the brainstem reveals small or absent abducens nerves (CNVI). In individuals with DRS due to CHN1 mutations, the optic (CNII), oculomotor (CNIII) and/or trochlear (CNIV) nerves may also be hypoplastic.
Differential diagnosis
Differential diagnosis of isolated DRS includes syndromic forms of DRS such as Duane-radial ray syndrome (Okihiro syndrome), Townes-Brocks syndrome, acro-renal-ocular syndrome, Bosley-Salih-Alorainy and Athabaskan brainstem dysgenesis-related disorders, Wildervanck syndrome, and oculo-auriculo-vertebral spectrum. Syndromic DRS can also arise from chromosomal anomalies and copy number variants, primarily on chromosome 8. Differential diagnosis of DRS also includes Moebius syndrome, congenital fibrosis of extraocular muscles, and isolated horizontal gaze palsy without globe retraction with or without progressive scoliosis (HGPPS).
Antenatal diagnosis
Prenatal and preimplantation genetic testing for at-risk pregnancies is possible if a pathogenic variant has been identified in a family.
Genetic counseling
Most cases are sporadic, but up to 10% of patients have affected relatives. When inherited, isolated DRS most commonly segregates in families as an autosomal dominant trait but autosomal recessive inheritance is also possible. In familial forms, DRS is often bilateral; however, incomplete penetrance and variable expressivity can complicate assessments.
Management and treatment
Management of DRS is mainly supportive and involves wearing spectacles or contact lenses to correct refractive errors, occlusion or penalization of the better-seeing eye for treatment of amblyopia, or prisms to correct for abnormal head posture. Eye muscle surgery may be indicated to correct abnormal head position, to align the eyes in primary gaze, or to correct for upshoot or downshoot on adduction. However, surgery does not restore full normal eye movements. Surveillance is necessary to detect and prevent amblyopia. Vision therapy is advised for secondary convergence insufficiency.
Prognosis
Isolated DRS is a benign disorder that, if managed appropriately, results in excellent long-term prognosis for vision. In some cases, amblyopia or loss of binocular single vision might develop.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                             Brenda BARRY  - Dr Elizabeth ENGLE


Dubin-Johnson syndrome (DJS) is a benign, inherited liver disorder characterized clinically by chronic, predominantly conjugated, hyperbilirubinemia and histopathologically by black-brown pigment deposition in parenchymal liver cells.

Summary:
Epidemiology
Prevalence in the general population is unknown. DJS affects individuals of all ethnic origins but is most common among Iranian or Moroccan Jews, in which, due to founder mutations, it has been reported to occur in up to 1/1,300 individuals.
Clinical description
Patients usually present during adolescence or young adulthood with mild to moderate, recurrent jaundice without pruritus, often triggered by intercurrent illness, pregnancy, oral contraceptives or drugs. Abdominal pain and fatigue are sometimes observed during outbreaks and hepatosplenomegaly may be present in rare cases. Total serum bilirubin (mainly in the conjugated form: the proportion of conjugated to total serum bilirubin is 50-80%) is elevated, usually between 2 and 5 mg/dl (very rarely up to 20 mg/dl). Liver enzyme activities (i.e. aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase), total bile acid concentration, albumin level and prothrombin time are normal. An association with clotting factor VII deficiency (see this term) can be observed, especially in Iranian and Moroccan Jews. Histological studies reveal a typical black-brown granular pigment deposition in the cytosol of hepatocytes, mostly in the centrilobular area, without other histological abnormalities.
Etiology
DJS is inherited in an autosomal recessive manner and is caused by homozygous mutations in the ABCC2 gene. ABCC2 encodes an ATP-dependent apical membrane transporter that mediates the efflux of bilirubin-glucuronides and other conjugated organic anions from the hepatocyte into bile.
Diagnostic methods
Diagnosis should be suspected in patients exhibiting isolated conjugated hyperbilirubinemia (i.e. without changes in liver enzyme activities) in the absence of any septic condition, ultrasound anomaly of the liver or potentially interfering drug. In this context, the characteristic urinary coproporphyrin excretion pattern (i.e. an elevated proportion of coproporphyrin I (over 80%) with a normal total coproporphyrin level) is usually diagnostic for DJS. 99mTc-HIDA cholescintigraphy, showing delayed or non-visualization of the gallbladder and bile ducts and prolonged visualization of the liver may also be useful. Definitive diagnosis can be obtained through molecular analysis of the ABCC2 gene. Although histological studies also allow a definitive diagnosis, liver biopsy is not systematically performed considering the invasive nature of the procedure together with the benign prognosis of the disease.
Differential diagnosis
The main differential diagnosis is another form of mainly conjugated hyperbilirubinemia, Rotor syndrome (RT; see this term).
Management and treatment
There is no curative treatment for DJS, even though short-term administration of phenobarbital has been reported to reduce serum bilirubin level in some cases.
Prognosis
DJS is a benign disorder and the prognosis for patients is good, highlighting the need for correct diagnosis to avoid unnecessary diagnostic procedures, treatment and follow-up. Progression to liver failure, cirrhosis or hepatic fibrosis is not observed.

                            Last update:
                            January 2010

                            - Expert reviewer(s):
                            Dr Véronique BARBU  - Dr Christophe CORPECHOT


Dubowitz syndrome (DS) is a rare multiple congenital syndrome characterized primarly by growth retardation, microcephaly, distinctive facial dysmorphism, cutaneous eczema, a mild to severe intellectual deficit and genital abnormalities.

Summary:
Epidemiology
The total birth prevalence in Europe has been estimated at 1/500,000. Over 150 cases have been described to date.
Clinical description
Newborns often have a low birth weight with a small head and body size. Facial appearance is characteristic with narrow or triangular shaped head and high or sloping forehead, flat supraorbital ridge, scanty lateral eyebrows, short palpebral fissures, blepharophimosis, ptosis, abnormally modeled ears, broad and flat nasal bridge, micrognathia and unusual configuration of the mouth. Sumucous cleft palate is common. Other findings include cutaneous ezema, high-pitched or hoarse voice, hypospadias and cryptorchidism. Skeletal abnormalities in DS include sacral dimple, and clinodactyly (5th fingers), with cutaneous syndactyly of toes or fingers. Intellectual deficit is mostly mild to moderate. Furthermore a variety of ocular and dental abnormalities, such as hyperopia, cataracts, tapetoretinal degeneration, strabismus and taurodontia, anodontia/hypodontia or hyperdontia have been reported. Behavioral characteristics may include hyperactivity with short attention span, impulsivity and shyness. The spectrum of manifestations of Dubowitz syndrome may also comprise: hematological (aplastic anemia) and congenital heart defects, frequent infections, chromosomal instability and developement of malignancies (acute lymphoblastic leukemia or neuroblastoma; see these terms).
Etiology
The etiology of Dubowitz syndrome has not been evidently elucidated. Two causal genes have been put forward in separate isolated cases and include NSUN2 and LIG4. However due to the large phenotypic overlap of Dubowitz syndrome with other clinical entities, there remains uncertainty on the etiology.
Diagnostic methods
Diagnosis is based on the multiple clinical manifestations and is commonly made in early childhood.
Differential diagnosis
Differential diagnosis includes fetal alcohol syndrome, Bloom syndrome, LIG4 syndrome and Fanconi anemia (see these terms).
Antenatal diagnosis
Prenatal growth retardation may be observed on ultrasound but does not lead to a reliable prenatal diagnosis.
Genetic counseling
In some families, Dubowitz syndrome appears to have an autosomal recessive transmission. However, it has been suggested recently that Dubowitz syndrome is a microdeletion/microduplication syndrome rather than an autosomal disorder.
Management and treatment
Growth, dental speech, behavioral and intellectual development and a general health status check should be monitored regularly and treated appropriately. Eczema and recurrent infections require conservative treatment. Surgical intervention might be necessary for certain cardiovascular, urogenital, craniofacial or limb anomalies. Surveillance of hematological and malignant disorders is recommended.
Prognosis
The prognosis is very variable depending on the severity and types of congenital anomalies present and the long-term outcome still remains elusive, as no data is available after puberty.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Chantal FARRA


A group of rare, genetic, progressive muscular dystrophies, including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and a symptomatic form in female carriers. The diseases represent a spectrum of severity ranging from progressive skeletal and cardiac muscle wasting and weakness (DMD, BMD) to less severe muscle weakness or isolated cardiomyopathy affecting carrier females.

Summary:
Epidemiology
The prevalence of DMD ranges between 1/3,500-1/ 9,300 male births. The prevalence of BMD varies from 1/16,700 to 1/18,500 male births. The prevalence of symptomatic female carriers is unknown.
Clinical description
Dystrophinopathies present with a spectrum of severity whereby BMD is at the mildest end and DMD the most severe, there is an intermediate phenotype in between. At the mildest end of the spectrum exercise-induced muscle cramps and myoglobinuria may be the only feature while at the severe end, there may be complete loss of muscle function, cardiomyopathy and respiratory failure. DMD presents in early childhood, motor milestones are delayed. Brain involvement leads to cognitive impairment (affecting about a third of patients) and/or pervasive behavioral disorders such as ADHD (attention deficit hyperactivity disorder), autism, anxiety and obsessive compulsive disorder. Muscle hypertrophy is evident, especially in the calf muscles. Progression is rapid, such that by the age of 5 there is likely to be a waddling gait and positive Gowers' sign. In untreated boys, walking is lost by 13 years of age (mean 9.5 years). Following loss of ambulation, scoliosis, respiratory failure and cardiomyopathy develop. BMD presents a broad spectrum of clinical severity, with onset of symptoms occurring from early childhood to as late as the sixth decade. Manifesting carriers of DMD and BMD may present with varying degrees of cardiomyopathy and muscle weakness. X-linked dilated cardiomyopathy (XLDCM), which may be caused by mutations in the dystrophin gene, presents with very severe, rapidly progressive, dilated cardiomyopathy.
Etiology
Dystrophinopathies are allelic conditions caused by deletions, duplications and mutations in the DMD gene, located on the X chromosome (Xp21.2). DMD genetic variants are frame-shift, while BMD variants are in-frame.
Diagnostic methods
The clinical diagnosis can be confirmed by several methods. Creatine Kinase (CK) is very raised. Molecular genetic analysis by MLPA (multiplex ligation-dependent probe amplification) will show a deletion in 60%; full gene sequencing is necessary to identify small deletions, duplications and nonsense mutations. Muscle biopsy for dystrophin analysis which is absent in DMD and reduced in BMD.
Differential diagnosis
The differential diagnosis includes LGMD and, in adults, other muscle disorders presenting with a raised CK.
Antenatal diagnosis
Prenatal diagnosis requires the most precise molecular diagnosis possible in the index case.
Genetic counseling
The pattern of inheritance is X-linked recessive. Genetic counselling of affected families is recommended and screening of women carriers in the family is important.
Management and treatment
There is no known cure for this group of dystrophinopathies. In DMD, treatment with corticosteroids stabilizes motor function and delays loss of ambulation and respiratory failure by several years. Physiotherapy and orthotics delay the onset of joint contractures. Non-invasive ventilation (NIV) to treat respiratory failure prolongs life expectancy. Regular cardiac monitoring from diagnosis with early treatment using ACE (angiotensin-converting enzyme) inhibitors and beta blockers stabilizes cardiomyopathy. For XLDCM, cardiac transplantation is the treatment of choice.
Prognosis
Life expectancy is shortened by cardiac and respiratory involvement, but can be substantially improved with regular monitoring and pro-active management.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Shpresa PULA  - Pr Rosaline QUINLIVAN


A rare, genetic, muscular dystrophy characterized by rapidly progressive muscle weakness and wasting due to degeneration of skeletal, smooth and cardiac muscle.

Summary:
Epidemiology
DMD primarily affects males with an estimated male birth prevalence of 1/3,500-1/9,300.
Clinical description
Onset occurs in early childhood, and affected boys may show a delay in walking (after 18 months of age) accompanied with speech and/or global developmental delay. Autism and behavioral problems, such as ADHD (attention deficit hyperactivity disorder), anxiety, obsessive compulsive disorder, are relatively common. Untreated children with DMD rarely achieve the ability to run or jump. The condition progresses rapidly and the child develops a waddling gait and a positive Gowers' sign. Climbing stairs becomes difficult and the child falls frequently. Loss of independent ambulation occurs between the ages of 6 and 13 years, the average being 9.5 years in non-steroid treated patients. Once ambulation is lost, joint contractures and scoliosis develop rapidly. Untreated patients die during late teens to early twenties from respiratory failure and or cardiomyopathy
Etiology
Muscle damage is caused by the complete absence of the sarcolemmal protein dystrophin as a result of variants in the DMD gene (Xp21.2).
Diagnostic methods
Diagnosis is suspected on the basis of the clinical picture, family history and laboratory findings (serum creatine kinase (CK) is 100-200 times the normal level). Genetic testing is the gold standard and involves multiplex-ligation dependent probe amplification (MLPA) for detection of deletions and duplications of exon (s) and full gene sequencing for detecting small deletions and duplications and non-sense or point mutations. Given the value of information provided by genetic analysis muscle biopsy is now recommended when genetic analysis in inconclusive. Genetic testing is therefore a critical tool in the accurate diagnosis of DMD and helps avoid missing the opportunity for personalized treatment.
Differential diagnosis
Differential diagnoses include severe Becker muscular dystrophy and limb girdle muscular dystrophy.
Antenatal diagnosis
Antenatal diagnosis is possible for families in which the diagnosis has been confirmed by molecular testing.
Genetic counseling
DMD is an X-linked recessive disease. Genetic counseling is very important: the risk of recurrence is 50% for male siblings of a proband. Female siblings have a 50% risk of being carriers and are usually asymptomatic but a small percentage manifest milder forms of the disease (symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers).
Management and treatment
International standards of care recommend a multidisciplinary approach. Physiotherapy includes passive stretching and night time ankle-foot orthoses (AFO) to reduce tendo-Achilles contractures. Treatment with corticosteroids (prednisolone, prednisone or deflazacort) is the gold standard. Corticosteroids should be introduced early or when the child's motor skills plateau, usually around 4-5 years of age. Complications of corticosteroid therapy must be managed and include: weight management, gastric protection, monitoring and treatment of osteoporosis, ophthalmic assessment for cataracts and glaucoma. Ataluren (authorized in Europe) is the only disease-modifying drug for use in ambulatory patients older than 5 years of age and where DMD is caused by non-sense mutations. Cardiac management includes regular monitoring (echo and/or MRI) and prophylactic treatment with ACE inhibitors and/or beta inhibitors to maintain cardiac function. Respiratory management includes monitoring respiratory function, assessment for sleep hypoventilation and timely introduction of BiPAP (bilevel positive airway pressure). In older patients cough augmentation and pneumococcal and flu vaccines are recommended. Surgery may be required for correction of scoliosis.
Prognosis
DMD has a severe prognosis and life expectancy is significantly reduced with death occurring in the third to fifth decades, although this is improving with advancements in management and treatment.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Shpresa PULA  - Pr Rosaline QUINLIVAN


A rare, non-syndromic intestinal malformation characterized by a complete but short segment obliteration of the duodenal lumen.

Summary:
Epidemiology
The prevalence at birth of duodenal atresia is estimated at 1/11,000 in Europe, with an approximately equal male to female ratio.
Clinical description
Duodenal atresia is classified into three types: type I (duodenal diaphragm) is linked to the presence of a mucosal diaphragmatic membrane with an intact muscle wall; type II (complete duodenal atresia) characterized by a short fibrous cord connecting the two ends or pouches of the duodenum; and type III (also complete duodenal atresia) which corresponds to a complete separation of the two ends of the duodenum, sometimes together with annular pancreas. Clinical presentation is similar irrespective of the type of atresia with repeated vomiting after feeding during the first day first or second day of life. The vomit is often without bile stain, as most atresias are located above the papilla of Vater. Weight loss, dehydration, and hypochloremic metabolic alkalosis are the most common accompanying symptoms. In rare cases with a membranous atresia, there may by a small opening in the mucosal membrane and less severe obstructions may manifest several months, or even several years, after birth; intermittent vomiting without abdominal distention may be the only presentation.
Etiology
Vascular anomalies, abnormalities in neural cell migration and failure of recanalization of the duodenal lumen may play a causative role, although the exact cause remains unknown.
Diagnostic methods
The clinical diagnosis is confirmed by abdominal radiography that shows a characteristic 'double bubble'' appearance with air trapped in the first portion of the duodenum (bulb) and stomach. The membranous type with a small luminal opening is diagnosed by endoscopy.
Differential diagnosis
In 30-52% of infants it is an isolated anomaly, but it is often associated with other congenital abnormalities. Approximately 20 to 30% of infants with duodenal atresia are carriers of trisomy 21, and about 20 to 25% have cardiac anomalies. Other frequently described associated malformations include duodenal growth failure, annular pancreas, which are particular clinical forms of duodenal atresia, and anomalies of the biliopancreatic tract or choledochal cysts. Other differential diagnoses include late appearing pyloric stenosis in cases of incomplete mucosal diaphragm, and other forms of intestinal atresia, small intestinal volvulus due to malrotation, duodenal duplication and duodenal stenosis.
Antenatal diagnosis
The malformation may be diagnosed at prenatal ultrasound from week 16-20 by the appearance of dilatated stomach and duodenal bulb associated with increased amounts of amniotic fluid.
Genetic counseling
Genetic counseling should be offered at prenatal diagnosis with special emphasis on the risk of trisomy 21. Whilst different mutations have been associated with duodenal atresia in a few instances, no specific genetic mapping in association with isolated duodenal atresia has been reported.
Management and treatment
Management involves neonatal resuscitation and surgical correction in the neonatal period. Post-operative complications are rare, but late complications (megaduodenum, blind loop syndrome, duodenogastric reflux, esophagitis, pancreatitis, cholecystitis and cholelithiasis) occur in very rare cases.
Prognosis
The prognosis with early surgical intervention is excellent.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Pr Niels QVIST | ERNICA*

                                * European Reference Network


A rare midline cerebral malformation characterized by duplicated pituitary stalks and/or glands within duplicated sella. Patients may present various degrees of facial dysmorphism and endocrine abnormalities, including precocious puberty, hypogonadism, hypothyroidism and/or hyperprolactinemia, as well as associated congenital anomalies, such as clift lip/palate, bifid nasal bridge/tongue/uvula, hypothalamic enlargement with or without hamartoma, nasopharyngeal tumors, corpus callosum agenesis/hypoplasia, basilar artery duplication, and/or vertebral defects (in particular, duplication of the odontoid process).


A rare congenital genitourinary anomaly, encompassing a wide spectrum of anatomic variants in which the urethra is partially or totally duplicated, which may be asymptomatic or cause symptoms such as incontinence, recurrent urinary infections and difficulty urinating.


A rare neurovascular malformation characterized by massive dilation of one or more dural sinuses typically associated with arteriovenous shunts. Anatomic types are the lateral type involving the jugular bulb, which presents with minimal symptoms, and the usually symptomatic midline type involving the confluens sinuum (torcular Herophili) and adjacent posterior sinuses. Complications include sinus thrombosis, venous infarction, and cerebral hemorrhage, as well as cardiac failure, macrocrania, and hydrocephalus. Spontaneous regression of the malformation may occur.


A rare, genetic primary bone dysplasia of the spondylo-epi-metaphyseal dysplasia (SEMD) group characterized by progressive short-trunked dwarfism, protruding sternum, microcephaly, intellectual disability and pathognomonic radiological findings (generalized platyspondyly with double-humped end plates, irregularly ossified femoral heads, a hypoplastic odontoid, and a lace-like appearance of iliac crests)

Summary:
Epidemiology
To date approximately 100 cases have been reported worldwide.
Clinical description
Clinically, Dyggve-Melchior-Clausen disease (DMC) is characterized by progressive dwarfism with short trunk, protruding sternum, rhizomelic limb shortening, postnatal microcephaly with facial dysmorphism, coarse face and intellectual disability varying from moderate to severe. Physical measurements at birth are typically normal, with patients clinically presenting with short stature within the first two years of life along with progressive appearance of the skeletal deformities of the thorax, spine, pelvis, hands and knees. Orthopedic complications usually occur during childhood almost constantly including bilateral hip subluxation, deformations of the knees, lumbar lordosis, scoliosis and thoracic kyphosis. Radiological features include progressive flattened vertebral bodies (platyspondyly) with a double-humped shape clearly visible by 3-4 years of age, misaligned spine, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small pelvis with thickened and scalloped iliac crests. This specific aspect of iliac crests becomes clearly visible around 4 years of age, broadens through adolescence and persists into adulthood. Hands are generally short and broad with irregular shape of metacarpal bones and phalanges.
Etiology
The disease is caused by mutations of the DYM gene (18q21.1). The large majority of mutations identified in the gene predict a loss of function of its product. DYM is expressed in the majority of tissue and codes for dymeclin, a protein which interacts with membranes of the Golgi apparatus, and has a role in the regulation of Golgi homeostasis and membrane trafficking
Diagnostic methods
Diagnosis is based on radiological evidence revealing platyspondyly with double vertebral humps, epiphyseal and metaphyseal dysplasia and scalloped iliac crests.
Differential diagnosis
Differential diagnoses include Smith-McCort syndrome, which presents with the same clinical and radiological features as DMC but without intellectual deficiency, and mucopolysaccharidosis type 4 which is clinically similar but has specific radiological and enzymatic signs.
Genetic counseling
Transmission is autosomal recessive. There is a 25% risk of disease transmission where both parents are unaffected carriers.
Management and treatment
Management requires both a multidisciplinary approach and a long-term follow-up as the disease is progressive. Preventive or corrective orthopedic surgery may be an option to manage lower limb deformities. However, due to the poor quality of osseous tissue, minimal-invasive surgery such as guided growth may be preferable
Prognosis
The disease often progresses towards orthopedic complications which can include lumbar lordosis, thoracic kyphosis, hip luxation, deformation of the knees and spinal cord compression secondary to instability of the atlas-axis.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Vincent EL GHOUZZI  - Pr Alain VERLOES | ITHACA*

                                * European Reference Network


DYRK1A-related intellectual disability syndrome due to 21q22.13q22.2 microdeletion

A rare, syndromic intellectual disability characterized by global developmental delay including severely delayed or absent speech, moderate to severe intellectual disability, behavioral issues, stereotypic behavior, febrile seizures and epilepsy, abnormal gait, vision defects, and characteristic facial features. Intrauterine growth restriction and feeding difficulties are frequently present.


A rare genetic syndromic intellectual disability characterized by microcephaly, global developmental delay, mild to severe intellectual disability, impairment of speech, feeding problems, behavior problems (often autism spectrum disorder) and dysmorphic facial features (such as prominent ears, deep-set eyes, a short nose with a broad nasal tip, and retrognathia with a broad chin). Other, more variable manifestations include seizures, short stature, ocular anomalies, cardiac anomalies, urogenital anomalies and musculoskeletal defects.

Summary:
Epidemiology
DYRK1A-related intellectual disability syndrome (DYRK1A syndrome) accounts for 0.1%-0.5% of individuals with intellectual disability and/or autism.
Clinical description
Developmental delay is observed at a young age and, usually, mild to severe intellectual disability later in life. An apparent speech/language delay is typical with understanding seemingly greater than verbal expression. Neonatal feeding problems (reflux, suck or swallowing problems) may occur and may persist into adulthood, warranting tube feeding in some individuals. Low weight and a slender build are common in later in life. Children have delayed motor development but most children learn to walk, sometimes with a broader gait. The motor skills may be hampered by hypertonia and, later in life the, occurrence of contractures. Many individuals have autism spectrum disorder and other behavior disorders (anxiety, hyperactivity or sleeping problems) are possible. Febrile seizures may develop during infancy and epilepsy may ensue thereafter. Eye abnormalities mainly include strabismus, astigmatism, and hypermetropia; other ocular anomalies have also been reported. More variable anomalies include cardiac defects (septal defects, hypoplastic left heart, valve abnormalities, aortic stenosis, and patent ductus arteriosus), urogenital anomalies (undescended testes, hypoplastic scrotum, shawl scrotum, micropenis, hypospadias, inguinal hernia, frequent urinary infections, vesicoureteral reflux, and unilateral renal agenesis) and, less frequently, dental anomalies. Most children have overlapping physical characteristics such as short stature, microcephaly, prominent ears, deep-set eyes, a short nose with a broad nasal tip, and retrognathia with a broad chin. Brain imaging may be indicative of global cerebral underdevelopment or hypomyelination.
Etiology
DYRK1A syndrome can be caused by a single nucleotide variant in the DYRK1A gene (21q22.13) or due to a chromosome 22q22.13 (micro)deletion including the DYRK1A gene.
Diagnostic methods
The disorder may be suspected on clinical presentation and diagnosed with molecular genetic testing. Chromosomal microarray analysis may detect chromosome 21q22.13 deletions including DYRK1A. Pathogenic DYRK1A single nucleotide variants may be detected by sequencing of the DYRK1A gene (most often by a multigene panel using whole exome sequencing or genome sequencing).
Differential diagnosis
There is a broad differential diagnosis including syndromes with primary microcephaly and absence/delay of speech development.
Antenatal diagnosis
Signs and symptoms of DYRK1A syndrome may be visible during the third trimester of pregnancy showing urogenital anomalies, cardiac anomalies and/or microcephaly. However, the absence of ultrasound anomalies does not exclude this disorder. Genetic antenatal testing is not applicable as mutations occur de novo.
Genetic counseling
To date, all reported cases, whose parents have undergone genetic testing, have occurred de novo suggesting a low recurrence risk (<1% due to risk of germline mosaicism). Penetrance is likely to be 100%. The course of the syndrome is similar in males and females.
Management and treatment
Regular follow-up is recommended by a pediatrician or a doctor specialized in the care for people with an intellectual disability, preferably in consultation with other specialties in a multidisciplinary setting. These may include a speech therapist, rehabilitation doctor, physiotherapist, occupational therapist and/or dietician. In case of epilepsy, the referral to a neurologist is required. After diagnosis, cardiac evaluation and periodical ophthalmological check-ups are required. In case of behavioral problems, a (child) psychiatrist can be involved in the treatment.
Prognosis
Based on current data, life expectancy is not limited in affected individuals as several adults have been reported. Data on possible progression of behavior abnormalities or neurologic findings are still limited.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr B.M.W. [Bregje] VAN BON | ITHACA*

                                * European Reference Network


A rare combined hyperlipidemia (HLP type 3) characterized by high levels of cholesterol and triglycerides, transported by intermediate density lipoproteins (IDLs), and a high risk of progressive atherosclerosis and premature cardiovascular disease.

Summary:
Epidemiology
Dysbetalipoproteinemia prevalence is estimated at 1/10,000 in the general population. Men are predominantly affected (male-female ratio about 2:1). The disease very rarely occurs before adulthood or in premenopausal women.
Clinical description
Most patients are asymptomatic. Clinical signs that may appear during adulthood are xanthomas of the eyelids (i.e. xanthelasma), transient xanthomas on palms (i.e. planar palmar xanthomas) or tuberous xanthomas over elbows or knees. Sensitive hepatomegaly may be observed. Patients develop highly progressive atherosclerosis that can lead to premature cardiovascular disease (stroke, coronary and peripheral artery disease. Patients expressing major hypertriglyceridemia may also develop acute pancreatitis.
Etiology
The disease results from mutations in the APOE gene (19q13.31) encoding apolipoprotein E, a protein mediating the cellular uptake of triglyceride-rich lipoprotein remnants (i.e., IDLs with roughly equal amounts of cholesterol and triglycerides) with anti-oxidant and anti-inflammatory properties. Dietary, metabolic, hormonal factors may aggravate the disease, as well as chronic inflammation, xenobiotics (e.g. immune suppressants, retinoids, antidepressants) or other genetic cofactors (e.g. APOA5, APOC3, LIPC, LPL variants).
Diagnostic methods
Diagnosis is based on the evidence of an abnormal lipoprotein profile with increased fasting serum concentrations of total cholesterol, triglycerides and Apolipoprotein B, and lowered plasma high-density lipoprotein (HDL) cholesterol (<40 mg/dL). Genetic testing confirms the diagnosis. In young adults, signs of silent atherosclerosis may be observed with arterial imaging.
Differential diagnosis
Differential diagnosis includes all other forms of atherogenic hyperlipidemias such as familial hypercholesterolemia, and familial hypertriglyceridemia.
Genetic counseling
In most cases associated with the APOE ''E2'' genotype, inheritance is semi-dominant or conditionally recessive. Carriers of this genotype exhibit the phenotype of HLP type 3 only when other metabolic, exogenous or genetic factors are present. Some patients however, carry heterozygous or compound heterozygous rare APOE variants that are sufficient for the development of the disease; in these cases, transmission is autosomal dominant or semi-dominant.
Management and treatment
Treatment includes a diet poor in carbohydrates and saturated fat, exercise, and lipid-lowering drugs (e.g. fibrates, statins) and is usually sufficient for complete regression of the disease within a few months. In severe cases with overt cardiovascular and/or pancreatic manifestations, intensive therapies (e.g. proprotein convertase subtilisin kexin type 9 (PCSK9), ApoC3 or microsomal triglyceride transfer protein (MTP) inhibitors, LDL apheresis) may be proposed.
Prognosis
Without treatment, patients have a 5-10 times higher risk of premature and recurrent atherothrombotic events than the general population.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Pascale BENLIAN


A rare genodermatosis characterized by the presence of the mixture of hyperpigmented and hypopigmented macules of approximately 5mm in diameter, principally located on the extremities.

Summary:
Epidemiology
DSH has been reported mainly in eastern Asia including Japan, although genetically confirmed DSH cases have also been reported in Thai, Indian, European, and Hispanic populations. The prevalence of DSH in Japan is estimated to be approximately 1/67,000 people. There does not appear to be male or female predominance. Pathogenic ADAR was also observed in the American population based on a genetic mutation database which implies that DSH patients might be found in the United States.
Clinical description
The first manifestations of the disease generally appear during early childhood and 70% of patients show eruptions until the age of 7. The eruptions might be exacerbated until the age of 20. Skin manifestations on the hands of DSH patients tend to worsen in summer. Quantitative analysis of seasonal changes in DSH severity revealed that sun exposure is only a transiently aggravating factor.
Etiology
The disease is caused by monoallelic mutations in double-stranded RNA-specific adenosine deaminase 1 (ADAR1) gene. Biallelic ADAR1 mutations may also cause a form of Aicardi-Goutières syndrome (a severe genetic inflammatory disease in childhood that affects the brain and the skin, and mimics viral infection) or bilateral striatal necrosis (affecting the central nervous system).
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by genetic testing. Although DSH shows autosomal dominant inheritance with nearly complete penetrance, intrafamilial variation of severity of skin manifestation can be seen. Thus, ultraviolet light examination can be useful to check the slight skin manifestation.
Differential diagnosis
The differential diagnosis includes xeroderma pigmentosum, dyschromatosis universalis hereditaria, reticulate acropigmentation of Kitamura and Aicardi-Goutières syndrome caused by ADAR1 mutations.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disorder is autosomal dominant; some cases occur sporadically. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. The genetic penetrance is almost 100%.
Management and treatment
There is no curative treatment. Topical sunscreen and sun-protective clothing can help to control the skin lesions.
Prognosis
DSH patient usually have a normal life expectancy.

                            Last update:
                            June 2023

                            - Expert reviewer(s):
                            Pr Michihiro KONO


A rare, genetic, pigmentation anomaly of the skin characterized by generalized, irregularly shaped, asymptomatic, hyper- and hypopigmented macules distributed in a reticular pattern involving the trunk, limbs, and sometimes the face. The palms, soles and mucosa are usually not affected. Systemic abnormalities have been rarely reported.


A rare mixed neuronal-glial tumor characterized by a benign, usually supratentorial lesion with predominantly cortical location and multinodular architecture. The tumor typically becomes symptomatic in the second or third decade of life with drug-resistant partial seizures. Histological hallmark is the specific glioneuronal element, columns oriented perpendicularly to the cortical surface, formed by bundles of axons attached to oligodendroglia-like cells, while neurons appear to float in an abundant eosinophilic matrix.


Dysequilibrium syndrome (DES) is a non-progressive cerebellar disorder characterized by ataxia associated with an intellectual disability, delayed ambulation and cerebellar hypoplasia.

Summary:
Epidemiology
To date, more than 50 individuals have been reported in the world literature.
Clinical description
DES is a congenital disorder characterized by nonprogressive cerebellar ataxia, associated with a moderate to profound intellectual disability and delayed ambulation. Gait can be either bipedal or quadrupedal. Additional features include hypotonia, lack of coordination, delayed motor development, seizures, dysarthria, strabismus, short stature and pes planus.
Etiology
Etiological subtypes of DES have been reported and include type 1 (CAMRQ1), 2 (CAMRQ2), 3 (CAMRQ3) and 4 (CAMRQ4) which are attributed to mutations in VLDLR (9p24), CA8 (8q12.1), WDR81 (17p13.3) and ATP8A2 (13q12) genes, respectively. VLDLR encodes the very low density lipoprotein receptor (VLDLR) which is involved in neuronal migration in the cerebral cortex and cerebellum. CA8 encodes a carbonic-anhydrase related protein, whose biological function is not yet fully understood. The function of WDR81 is still unknown. ATP8A2 encodes an ATPase which is mainly expressed in brain tissue, with the highest levels found in the cerebellum, and that may be critical for the developmental processes of the central nervous system.
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.

                            Last update:
                            March 2016

                            - Expert reviewer(s):
                            Pr Kym BOYCOTT


Dysferlin-related limb-girdle muscular dystrophy R2

A subtype of autosomal recessive limb-girdle muscular dystrophy characterized by an onset in late adolescence or early adulthood of slowly progressive, proximal weakness and atrophy of shoulder and pelvic girdle muscles. Cardiac and respiratory muscles are not involved. Hypertrophy of the calf muscles and highly elevated serum creatine kinase levels are frequently observed.


A rare ectodermal dysplasia syndrome that often presents with the classic triad of nail dysplasia, skin pigmentary changes, and oral leukoplakia associated with a high risk of bone marrow failure (BMF) and cancer.

Summary:
Epidemiology
Dyskeratosis congenita (DC) prevalence is unknown. More than 400 families are reported in the world.
Clinical description
DC has a wide phenotypic spectrum and age onset. It classically manifests during childhood with the triad of dysplastic nails, lacy reticular pigmentation and atrophy of the skin at the level of the neck and upper chest, and oral leukoplakia. Patients are at high risk of progressive BMF and may develop myelodysplastic syndrome or acute myelogenous leukemia at any age (the risk increasing with age). There is also an increased risk for solid tumors, typically squamous cell carcinoma of head and neck or anogenital cancer. Additional clinical findings have been reported and may include: developmental delay, short stature, microcephaly, blepharitis, epiphora, periodontal disease, taurodontism, decreased teeth/root ratio, esophageal stenosis, urethral stenosis, osteoporosis, avascular necrosis of femur and/or humerus, premature hair greying/alopecia, or abnormal eyelashes. Patients with DC may also develop pulmonary fibrosis, pulmonary arteriovenous malformations, gastrointestinal telangiectasias, and liver disease. It is important to note that the clinical features of DC progress over time and that all features, including the mucocutaneous triad, may not be present.
Etiology
DC is caused by germline mutations in genes important in telomere biology. De novo cases also occur. X-linked recessive DC is due to mutations in DKC1 (Xq28). The autosomal dominant genes associated with DC are TERC (3q26.2), TERT (5p15.33), TINF2 (14q12), RTEL1 (20q13.3), PARN (16p13.12), and ACD (16q22.1). Autosomal recessive genes include TERT (5p15.33), NHP2 (5q35.3), NOP10 (15q14-q15), RTEL1 (20q13.3), WRAP53 (17p13.1), ACD (16q22.1). Mutations in CTC1 (17p13.1), POT1 (7q31.33) and STN1 (10q24.33) are rare causes of DC.
Diagnostic methods
Diagnosis should be considered if at least 2 characteristics of the triad are present or one feature in addition to two other primary clinical findings. Clinical diagnosis may be confirmed by telomere length testing by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH), and genetic testing.
Differential diagnosis
Differential diagnosis includes palmoplantar keratoderma-spastic paralysis syndrome, nail-patella syndrome, autosomal dominant nail dysplasia, poikiloderma with netropenia, Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond Anemia, idiopathic aplastic anemia, idiopathic pulmonary fibrosis, Coats plus syndrome.
Antenatal diagnosis
In case of family history, prenatal genetic diagnosis by chorionic villus sampling or preimplantation genetic diagnosis may be available.
Genetic counseling
The disorder may be inherited in X-linked recessive (XLR), autosomal dominant (AD), or autosomal recessive (AR) patterns.
Management and treatment
Management includes regular complete clinical examinations. To date hematopoietic stem cell transplantation (HSCT) is the only cure for BMF. Androgen therapy may be considered first when no related donor is available. Treatment of cancer uses individualized chemotherapy and radiotherapy regimens.
Prognosis
Life expectancy ranges from infancy to well into the 7th decade. Up to 40% of patients will have BMF by the age of 40. Major causes of morbidity include BMF, cancer and pulmonary complications.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Sharon SAVAGE


Dysmorphism-cleft palate-loose skin syndrome is a rare, genetic developmental defect during embryogenesis characterized by severe psychomotor delay, intellectual disability, congenital, symmetrical circumferential skin creases of arms and legs, cleft palate, and facial dysmorphism (incl. elongated face, high forehead, blepharophimosis, short palpebral fissures, microphthalmia, microcornea, epicanthic folds, telecanthus, microtia, posteriorly angulated ears, broad nasal bridge, microstomia and micrognathia). Additional features reported include short stature, microcephaly, hypotonia, pectus excavatum, severe scoliosis, hypoplastic scrotum, and mixed hearing loss.


Dysmorphism-conductive hearing loss-heart defect syndrome is a rare, multiple congenital anomalies syndrome characterized by a distinctive facial appearance (low frontal hairline, bilateral ptosis, prominent eyes, flat midface, broad, ﬂat nares, Cupid's bow upper lip vermilion, and small, low-set, posteriorly rotated ears), in addition to cleft palate, conductive hearing loss, heart defects (atrial or ventricular septal defect) and mild developmental delay/intellectual disability.


Dysmorphism-pectus carinatum-joint laxity syndrome is characterised by joint laxity, pectus carinatum and facial dysmorphism (mild frontal bossing, a beaked nose with a low nasal bridge, malar hypoplasia, chubby cheeks, a striking philtrum and arched upper lips). It has been described in two siblings. The mode of transmission is unknown.


Dysmorphism-short stature-deafness-difference of sex development syndrome

Dysmorphism-short stature-deafness-disorder of sex development syndrome is characterized by dysmorphism (including facial asymmetry, arched eyebrows, hypertelorism, broad and flat nasal bridge, microtia, small nose with anteverted nostrils, micrognathia), deafness, cleft palate, male pseudohermaphroditism, and growth and psychomotor retardation. It has been described in two siblings. It is transmitted as an autosomal recessive trait.


A rare genetic primary bone dysplasia disease characterized by progressive osteosclerosis and platyspondyly.

Summary:
Epidemiology
Less than 30 cases of Dysosteosclerosis have been reported in the literature to date.
Clinical description
The disease is characterized by sclerosis of the skull base, ribs, clavicles, scapulae, mid-diaphyses and increased bone fragility. Patients have a prominent forehead, narrow midface, flattening of the vertebral bodies and dental anomalies. Short stature, optic atrophy, hearing impairment, epilepsy, skin changes, and progressive psychomotor deficit are frequent.
Etiology
The disease is caused by mutations in SLC29A3. This gene encodes a nucleoside transporter. Mutations in this gene may also cause Faisalabad histiocytosis, Rosai-Dorfman disease, H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome. Parental consanguinity has been noted in some cases. Mutations in osteopetrosis genes TNFRSF11A and TCIRG1 can also cause dysosteosclerosis.
Diagnostic methods
Sequencing combined by deletion and duplication analysis is possible.
Differential diagnosis
Osteopetrosis is more common than dysosteosclerosis and distinguishing features are the presence of sclerotic platyspondyly as well as widened and relatively radiolucent sub-metaphyseal regions of long tubular bones with sclerotic diaphysis. Responsible genes include OSTM1, SNX10, CA2, TCIRG1, TNFSF11, CLCN7, PLEKHM1, TNFRSF11A, and LRP5. In Pyle disease, there is important metaphyseal expansion with cortical thinning of the tubular bones well into the diaphyses. There can be mild platyspondyly and skull sclerosis but not as much as in dysosteosclerosis. Genu valgum is a key clinical feature. The responsible gene is SFRP4. In BANDDOS (Brain abnormalities, neurodegeneration, and dysosteosclerosis), there are bone changes similar to dysosteosclerosis, osteopetrosis or Pyle disease, but there is also neurological disease of neonatal, childhood or adult onset. The responsible gene is CSF1R.
Genetic counseling
Dysosteosclerosis is inherited in an autosomal recessive manner for SLC29A3, TNFRSF11A and TCIRG1 mutation. An X-linked pedigree has also been reported.
Management and treatment
Management is mostly supportive, bone marrow transplantation was tried in one individual without success.
Prognosis
The overall prognosis is generally poor, although, as in osteopetrosis, there is a wide spectrum of severity.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Philippe CAMPEAU


Brachydactyly ('short digits') is a general term that refers to disproportionately short fingers and toes, and forms part of the group of limb malformations characterized by bone dysostosis.

Summary:
Epidemiology
The various types of isolated brachydactyly are rare, except for types A3 and D.
Clinical description
Brachydactyly can occur either as an isolated malformation or as part of a complex malformation syndrome. To date, many different forms of brachydactyly have been identified. Some forms also result in short stature. In isolated brachydactyly, subtle changes elsewhere may be present. Brachydactyly may also be accompanied by other hand malformations, such as syndactyly, polydactyly, reduction defects, or symphalangism.
Etiology
For the majority of isolated brachydactylies and some syndromic forms of brachydactyly, the causative gene defect has been identified. In isolated brachydactyly, the inheritance is mostly autosomal dominant with variable expressivity and penetrance.
Diagnostic methods
Diagnosis is clinical, anthropometric and radiological.
Antenatal diagnosis
Prenatal diagnosis is usually not indicated for isolated forms of brachydactyly, but may be appropriate in syndromic forms. Molecular studies of chorionic villus samples at 11 weeks of gestation and by amniocentesis after the 14th week of gestation can provide antenatal diagnosis if the causative mutation in the family is known.
Genetic counseling
The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms.
Management and treatment
There is no specific management or treatment that is applicable to all forms of brachydactyly. Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed. Physical therapy and ergotherapy may ameliorate hand function.
Prognosis
Prognosis for the brachydactylies is strongly dependent on the nature of the brachydactyly, and may vary from excellent to severely influencing hand function. If brachydactyly forms part of a syndromic entity, prognosis often depends on the nature of the associated anomalies.

                            Last update:
                            June 2008

                            - Expert reviewer(s):
                            Dr Mona AGLAN  - Pr Samia TEMTAMY


A rare aortic arch defect characterized by variable degrees of dysphagia due to compression of the esophagus from an aberrant right subclavian artery (arteria lusoria), which arises as the fourth branch, distal to the left subclavian artery, from the aortic arch. In most cases, the aberrant vessel then passes posterior to the esophagus, less frequently between the trachea and esophagus, or anterior to the trachea. Children may also present with stridor and recurrent chest infections.


A rare bone development disorder characterized by localized, asymmetric osteochondral overgrowth affecting single or multiple epiphyses, most commonly the distal femur, proximal tibia, and talus. The lesions are typically restricted to one side of the epiphysis, with the medial side being affected twice as often as the lateral side. The condition is usually diagnosed in children, and three times more often in boys than in girls. Patients present with pain, limitation in range of motion, and deformity or swelling of the affected joint.


Meyer dysplasia of the femoral head is a mild localized form of skeletal dysplasia characterized by delayed, irregular ossification of femoral capital epiphysis.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The condition is often discovered incidentally during early childhood (during the second or third year of life). It is often bilateral, although severity may be asymmetric. Clinical manifestations may include a waddling gait, genu valgum, hip pain and restricted movement, although these manifestations are usually transient and the majority of patients are asymptomatic. Resolution without treatment by six years of age has been reported in some cases, however, permanent deformity (flattening) of the femoral head has also been described and could represent a mild form of multiple epiphyseal dysplasia (see this term).

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Dysplastic cortical hyperostosis, Kozlowski-Tsuruta type

Dysplastic cortical hyperostosis is an extremely rare primary bone dysplasia with increased bone density characterized by lethal neonatal dwarfism with hydrops, narrow chest and short limbs with extensive cortical thickening of all long bones, ribs, clavicles and scapulae, and coronal clefts in vertebral bodies.


Dysraphism-cleft lip/palate-limb reduction defects syndrome

A rare developmental defect during embryogenesis disorder characterized by spinal dysraphism, cleft lip and palate, limb reduction defects and anencephaly. There have been no further descriptions in the literature since 1994.


Dyssegmental dysplasia, Silverman-Handmaker type is a rare, genetic, primary bone dysplasia disorder, and lethal form of neonatal short-limbed dwarfism, characterized by anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (i.e. flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (e.g. joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities.


Dysspondyloenchondromatosis is a rare skeletal dysplasia characterized by anisospondyly and multiple enchondromas in vertebrae and the metaphyseal and diaphyseal parts of long tubular bones, leading to kyphoscoliosis and lower limb asymmetry.


Dystonia 16 (DYT16) is a very rare and newly discovered movement disorder which is characterized by early-onset progressive limb dystonia, laryngeal and oromandibular dystonia, and parkinsonism.

Summary:
Epidemiology
It has been described in 8 patients from three Brazilian families and one German family to date.
Clinical description
Disease presents in infancy to late childhood with one of two possible phenotypes: either generalized dystonia or dystonia-parkinsonism not responsive to L-Dopa. Dystonia usually starts in one limb, becomes generalized and mainly affects the trunk, neck and oromandibular muscles. Motor and speech developmental delays were also reported. The phenotypic spectrum of this disease is still being determined. Pharmacological therapy is ineffective.
Etiology
DYT16 is caused by mutations in the protein kinase, interferon-inducible double stranded RNA dependent activator (PRKRA) gene, located on chromosome 2q31.2.
Genetic counseling
DYT16 is inherited in an autosomal recessive manner, and genetic counseling is possible and recommended.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


A rare persistent combined dystonia characterized by childhood onset of progressive dystonia typically beginning in the lower limbs and eventually progressing to generalized dystonia with involvement of the upper limbs, trunk, face, and neck. Variable developmental delay and intellectual disability, as well as mild microcephaly, short stature, abnormal eye movements, and slightly dysmorphic facial features have been reported in association.


Dystonia-aphonia syndrome is a rare, genetic, persistent combined dystonia disorder characterized by slowly progressive, severe, caudo-rostrally spreading generalized dystonia with prominent facial and oro-mandibular involvement leading to severe anarthria and/or aphonia, swallowing difficulties, and gait disturbances. Additional manifestations include slowed horizontal saccades, subclinical epilepsy, photic myoclonus, oral hypertrophic changes (e.g. gingival or lingual hyperplasia), as well as delayed milestones and cognitive impairment.


A rare disorder of manganese transport characterized by progressive movement disorder and elevated blood manganese levels. Patients present in infancy or early childhood with loss of motor milestones, rapidly progressive dystonia, spasticity, bulbar dysfunction, and parkinsonism, resulting in loss of independent ambulation. Cognition may be impaired but is generally better preserved than motor function. Additional manifestations include abnormal head growth and skull deformities. Brain MRI shows abnormalities of the basal ganglia, variably also of other brain regions.


Dystrophic epidermolysis bullosa pruriginosa

A rare dystrophic epidermolysis bullosa (DEB) characterized by generalized or localized skin lesions associated with severe, if not intractable, pruritus.

Summary:
Epidemiology
Prevalence is unknown. Approximately 100 families or sporadic cases have been reported to date, but it might be underreported.
Clinical description
While skin fragility and blistering lesions usually manifest in infancy, which heal with atrophic scarring and milia formation, the onset of intense pruritus is frequently delayed until the adolescence or even adulthood. At the onset of pruritus, the clinical picture generally worsens with the development of papules, nodules, lichenoid and hypertrophic lesions in a linear distribution, preferentially on the extensor surfaces of the limbs. Nail dystrophy is usually present.
Etiology
DEB pruriginosa is caused by mutations within the type VII collagen gene (COL7A1/i>; 3p21.31). Mutations in this gene lead to an alteration in function or to reduced amounts of collagen VII. This impairs its assembly into anchoring fibrils that anchor the basement membrane to the underlying dermis.
Diagnostic methods
Transmission electron microscopy shows blister formation below the lamina densa and reduced number of anchoring fibrils in adjacent non-blistered skin. Immunofluorescence mapping shows dermal cleavage of the skin and reduced immunoreactivity for type VII collagen. The diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis includes nodular prurigo, lichen simplex, lichen planus, hypertrophic scarring and dermatitis artefacta.
Antenatal diagnosis
Antenatal diagnosis is not recommended.
Genetic counseling
The disorder is typically sporadic but autosomal dominant and recessive inheritance has also been reported. Genetic counselling should be offered to affected individuals informing them of risk of transmitting the pathogenic variant to offspring.
Management and treatment
Clinical management of DEB pruruginosa is often difficult, although generic measures reduce itching. Nevertheless, there are some reports of helpful interventions which include topical treatments (e.g. tacrolimus), systemic agents (e.g. ciclosporin or thalidomide), and cryotherapy. Recently, dupilumab has proven to be effective.
Prognosis
The condition is therapy resistant, but the overall course of the disease is mild to moderate and life expectancy is normal.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Cristina HAS | ERN-Skin* - Pr Carmen SALAVASTRU | ERN-Skin*

                                * European Reference Network


A group of inherited epidermolysis bullosa (EB) characterized by cutaneous and mucosal fragility resulting in blisters and superficial ulcerations that develop below the lamina densa of the cutaneous basement membrane and that heal with significant scarring and milia formation. Dystrophic epidermolysis bullosa (DEB) comprises four major and several rare sub-types with the three most common being intermediate dominant DEB, severe recessive DEB and intermediate recessive DEB.

Summary:
Epidemiology
DEB is the second most common form of EB, the first being EB simplex. Based on recent data, the prevalence in Europe ranges between 1/120,000-350,000.
Clinical description
The clinical picture varies widely, ranging from mild localized to severe generalized involvement. Onset is usually at birth but a delayed onset in infancy, childhood or adolescence can also be observed in milder subtypes. Skin lesions, forming spontaneously or in response to friction, may show a generalized or a localized distribution, particularly on the hands, feet or pretibial areas. Healing of blisters is associated with atrophic or, more rarely, hypertrophic scarring, albopapuloid lesions, milia formation and dystrophic nails. Excessive scarring can lead to highly disabling hand/foot deformities. Mucosal involvement is common and most frequently manifests with oral cavity lesions and esophageal strictures. The eyes and the genitourinary tract can also be affected. Skin and mucosal involvement can lead to anemia, iron deficiency, osteopenia/osteoporosis, growth delay and, rarely, renal failure. DEB patients are also at a higher risk of occurrence of squamous cell carcinomas (SCC).
Etiology
DEB is caused by mutations in the COL7A1 (3p21.31) gene encoding type VII collagen. Mutations are either autosomal dominant (dominant DEB) or recessive (recessive DEB), and alter the function or reduce or disrupt the production of collagen VII. This impairs its assembly into anchoring fibrils that anchor the basement membrane to the underlying dermis, resulting in a cleavage plane below the lamina densa, within the upper papillary dermis. In the case of severe recessive DEB there is no collagen VII production.
Diagnostic methods
Diagnosis is suspected at clinical examination. It is confirmed by biopsy of skin samples by immunofluorescence antigen mapping and/or transmission electron microscopy (showing a blister cleavage plane beneath the lamina densa of the cutaneous basement membrane zone), and by COL7A1 mutation screening.
Differential diagnosis
The differential diagnosis includes other forms of EB. During the neonatal period and infancy, it may also include aplasia cutis congenita, herpes simplex infection, epidermolytic ichthyosis, bullous impetigo, staphylococcal scalded skin syndrome, linear IgA bullous dermatosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis. For rare forms of DEB with a late onset, differential diagnosis includes acquired skin disorders such as lichen planus or autoimmune bullous diseases.
Antenatal diagnosis
Antenatal diagnosis should be offered to affect families with recessive severe DEB.
Genetic counseling
Genetic counseling should be offered to affect families and depends on the inheritance type and form of DEB.
Management and treatment
Management is preventive and symptomatic and requires an inter- and multidisciplinary approach. Protective padding of the skin and careful wound care reduces blistering, scarring and prevents secondary infection. Treatment of pain and itching is highly warranted but partly limited in effectiveness. Physiotherapy and occupational therapy are necessary to delay gradual loss of mobility and autonomy. Hand deformities can be treated surgically, but have a high recurrence. Nutritional requirements should be evaluated by a dietitian and gastrostomy feeding may be necessary. Esophageal strictures are treated by balloon dilatation with fluoroscopic guidance. Transfusions, iron supplementation, and erythropoietin administration improve anemia and iron deficiency. A regular follow-up with complete skin checks and biopsies is necessary for the surveillance of SCC development. Psychological support should be offered.
Prognosis
Prognosis depends on the subtype. Patients with dominant DEB usually have a normal life expectancy. Patients with severe recessive DEB are at high risk of mortality primarily from metastatic SCC, less frequently from chronic renal failure, sepsis and dilated cardiomyopathy.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Martin LAIMER | ERN-Skin*

                                * European Reference Network


A rare ophthalmic disorder characterized by 3 stages: vasculitis, occlusion, and retinal neovascularization, leading to recurrent vitreous hemorrhages and vision loss.

Summary:
Epidemiology
The prevalence is unknown. The disorder has been reported worldwide but is more commonly observed in the Indian subcontinent where the estimated annual incidence is 1/135-1/200 ophthalmic patients. Males are predominantly affected. Of late, the disease incidence seems to be reducing.
Clinical description
The predominant age of onset is 20-30 years (earlier in Asians). The disorder can appear in adolescence. Eales disease (ED) is characterized by 3 sequential vascular responses that determine the course of the disease: inflammation (peripheral retinal perivasculitis); occlusion (peripheral retinal capillary non-perfusion); and neovascularisation of the retina or disk, which often leads to vitreous hemorrhage. The first 2 stages are generally asymptomatic while vitreous hemorrhage (often sudden and unilateral) is characterized by small specks, floaters, ''cobwebs'' and a decrease in visual acuity (often remission). The fellow eye is affected in 50-90% of cases after a gap of 3-10 years. Recurrences are common. Recurrent bleeds result in tractional retinal detachments, retinal tears, and epimacular membranes. Others may show a mild reduction of vision associated with retinal vasculitis (without vitreous hemorrhage). In addition, headache, variation in peripheral circulation, dyspepsia, chronic constipation, and epistaxis have also been associated with ED. Saxena and Kumar classification is based on visual outcomes and is as follows: Stage 1: periphlebitis of small (1a) and large (1b) calibre vessels with superficial retinal hemorrhages; Stage 2a: capillary non-perfusion, 2b: neovascularization elsewhere/of the disc; Stage 3a: fibrovascular proliferation, 3b: vitreous hemorrhage; Stage 4a: traction/combined rhegmatogenous retinal detachment and 4b: rubeosis iridis, neovascular glaucoma, complicated cataract and optic atrophy.
Etiology
The etiology of ED remains elusive; Several immunological, molecular biological, and biochemical studies have indicated the roles of human leukocyte antigen, retinal S-antigen autoimmunity, Mycobacterium tuberculosis genome, free radical damage, and hyperhomocysteinemia in the pathogenesis of Eales disease. An increase of peptide growth factors like platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, transforming growth factors alpha and bêta, vascular endothelial growth factor, urokinase, metalloprotease enzymes, and a 88 kDa protein has been reported.
Diagnostic methods
Diagnosis is based on fundus fluorescein angiography (FFA) findings that may show early changes such as periphlebitis, vascular sheathing or peripheral nonperfusion and neovascularization. Wide field angiography is useful for the detection of peripheral lesions in the retina. Ultrasonography is needed to rule out associated retinal detachment and ocular coherence tomography (OCT) offers high-resolution imaging of the retina.
Differential diagnosis
Differential diagnosis includes retinopathy of prematurity (ROP) sequelae, familial exudative vitreoretinopathy, sarcoidosis, Behçet disease, sickle cell anemia, Terson syndrome, posttraumatic vitreous hemorrhage, juvenile diabetes and primary branch retinal vein occlusion.
Management and treatment
Management is symptomatic and depends on the stage of the disease. It includes periodic assessment (in the regressed stage of periphlebitis or fresh vitreous hemorrhage), steroids (periocular injections or systemic) and antitubercular drugs (in the active perivasculitis stage). Laser photocoagulation is used in case of neovascularisation of retina or gross capillary nonperfusion. Vitreous surgery is indicated in non-resolving vitreous hemorrhage (usually > 3 months). Intravitreal anti-VEGF therapy is currently being tested as a definitive therapy for ED.
Prognosis
Isolated episodes of vitreous hemorrhage usually settle down without visual deficit. However, some patients may lose vision significantly due to recurrent episodes of vitreous hemorrhage, macular changes, and tractional or combined retinal detachment involving the macula. Blindness due to ED is rare. There is no known mortality associated with the disease.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Dr Pukhraj RISHI


A rare microcephalic primordial dwarfism characterized by the association of bilateral microtia (severe hypoplasia of ear pinnae), absent patellae, short stature and characteristic facial features such as high forehead, micrognathism with full lips and small mouth, and accentuated nasolabial folds (smile wrinkles linking the nostrils to the labial commissure).


Early infantile epileptic encephalopathy

A severe form of age-related epileptic encephalopathies characterized by the onset of tonic spasms within the first 3 months of life that can be generalized or lateralized, independent of the sleep cycle, and that can occur hundreds of times per day, leading to psychomotor impairment and death.

Summary:
Epidemiology
Incidence has been estimated at 1/100 000 births in Japan and 1/50,000 births in the U.K.
Clinical description
Onset of EIEE occurs within the first 3 months of life but some present within the first few weeks after birth. Neonates have poor suckling reflexes, hypotonia and manifest with generalized and symmetrical tonic spasms that can appear in clusters or singly and can last for up to 10 seconds. The pattern of these spasms remains unchanged during wakefulness and sleep and they can occur hundreds of times per day. Other seizure types, including generalized tonic-clonic seizures, focal motor seizures and hemiconvulsions, are seen in 1/3 of cases. Those who live past the age of 2 years manifest with severe psychomotor deficits. In some, EIEE can transition into West syndrome (between 2-6 months of age) and later into Lennox-Gastaut syndrome (see these terms). Certain genetic variants manifest with additional signs such as dyskinetic movements and an atypical Rett-syndrome phenotype (see this term). Death is often due to pneumonia or other complications of a complex disability.
Etiology
EIEE may be the result of different etiologies. Many cases have been associated with structural brain abnormalities. Some cases are due to metabolic disorders (cytochrome C oxidase deficiency, carnitine palmitoyl transferase II deficiency; see these terms) or brain malformations (such as porencephaly, hemimegalencephaly; see these terms) that may or not be genetic in origin. Genetic variants of EIEE have been associated with mutations in certain genes such as ARX (Xp22.13) , CDKL5 (Xp22) , SL25A22 (11p15.5) and STXBP1 (9q34.1), among others. The genetic abnormalities are thought to lead to EIEE as they are related to neuronal dysfunction or brain dysgenesis.
Diagnostic methods
Diagnosis is based on clinical and electroencephalographic findings. The characteristic electroencephalogram (EEG) displays a suppression burst pattern (which appears with the onset of spasms) that is comprised of bursts of high amplitude spikes and polyspikes that alternate with periods of low voltage basic rhythm (suppression). This EEG pattern is continuous and remains unchanged during both waking and sleeping states. Structural abnormalities can often be seen on cranial MRI.
Differential diagnosis
Differential diagnoses include other epileptic encephalopathies such as early myoclonic encephalopathy, West syndrome (see these terms) and other early onset epileptic encephalopathies.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known genetic etiology.
Genetic counseling
Autosomal recessive inheritance has been reported, but most cases of EIEE are sporadic (de novo mutations). Genetic counseling is therefore very valuable to inform parents that their risk of having further children with EIEE is low.
Management and treatment
There is no cure for EIEE and patients require constant supervision and care. Antiepileptic drugs such as benzodiazepines, valproate, levetiracetam, zonisamide and phenobarbital have shown limited success in controlling seizures as has pyridoxine. A ketogenic diet has been reported to show some success in seizure control. In those with associated metabolic disorders, once these conditions have been treated there can be an improvement in the course of EIEE. Similarly, EIEE patients with certain structural abnormalities have benefited from surgical intervention, if unilateral.
Prognosis
Prognosis is poor with death usually occurring in infancy (50% before age of 2). Survivors have severe psychomotor impairments with continuing seizures.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Helen CROSS


A rare disorder characterized clinically by the onset of fragmentary myoclonus appearing in the first month of life, often associated with erratic focal seizures and a suppression-burst EEG pattern.

Summary:
Epidemiology
The prevalence is unknown but Early myoclonic encephalopathy is a rare disease with only around 30 cases described so far.
Clinical description
Onset sometimes occurs as early as a few hours after birth, and postnatal movements are sometimes reported by the mother to be of the same type as those felt at the end of pregnancy. Other types of seizures, including partial seizures, massive myoclonia, and tonic spasms can also occur; usually at around 3-4 months of age. Neurological abnormalities are constant: very severe delay in psychomotor acquisitions, marked hypotonia, and disturbed alertness, sometimes with a vegetative state. Signs of peripheral neuropathy may also occur in rare cases.
Etiology
Although the etiology is mostly unknown, nonketotic hyperglycinemia, pyridoxine or pyridoxal-phosphate dependency, together with congenital deficiency of the mitochondrial glutamate transporter are known to produce a similar clinical picture. Therefore, this condition may result from excess glutamate delivery in the synaptic cleft by the end of pregnancy.
Genetic counseling
There is a high risk of familial recurrence since in most cases the disease appears to be inherited as an autosomal recessive trait.
Management and treatment
There is no effective treatment.
Prognosis
The prognosis is poor: children with the condition survive in a persistent vegetative state or die within the first or second year of life.

                            Last update:
                            October 2006

                            - Expert reviewer(s):
                            Pr Olivier DULAC


A rare, genetic, non-syndromic developmental defect of the eye disorder, with high clinical and genetic heterogeneity, most frequently characterized by bilateral, symmetrical, non-progressive cataracts which present at birth or in early-childhood. Additional ocular manifestations (e.g. anterior segment dysgenesis, colobomas, nystagmus, microcornea, microphthalmia, myopia) may be associated, however other organs/systems are usually not affected.


Early-onset autosomal dominant Alzheimer disease (EOAD) is a progressive dementia with reduction of cognitive functions. EOAD presents the same phenotype as sporadic Alzheimer disease (AD) but has an early age of onset, usually before 60 years old.

Summary:
Epidemiology
EOAD represents less than 1% of all cases of AD.
Clinical description
Initial findings of EOAD are mainly disorders of episodic memory or changes in behavior. The patient is often anosognosic and the diagnosis is therefore carried out with the help of a family member. Neurological signs that can be associated with EOAD are spastic paraparesis, intracerebral hemorrhages, seizures, extrapyramidal syndrome and exceptionally cerebellar ataxia.
Etiology
EOAD is the consequence of either PSEN1 mutations (69%), APP mutations (13%), or APP duplication (7,5%), and exceptionally of PSEN2 mutations (2%). These mutations result in an incompletely understood cascade of events resulting in neuronal death, synapse loss, and the formation of neurofibrillary tangles and senile plaques.
Diagnostic methods
EOAD is diagnosed using the clinical criteria of the NINCDS-ADRDA(McKahnn, 1984). Brain imaging can be normal. Lumbar puncture for measurement of cerebrospinal fluid tau and amyloid may be useful (tau and phosphorylated tau are often elevated and amyloid is usually low). Age of onset before 60 years suggests an EOAD and needs a pedigree.
Differential diagnosis
Differential diagnosis includes depression and other young dementias such as frontotemporal dementia, Lewy body dementia and Huntington disease (see these terms).
Genetic counseling
Genetic counseling should be offered to the families.
Management and treatment
Management is symptomatic and includes the use of cholinesterase inhibitors and partial N-methyl-D-aspartate antagonists. Psychotrops may also be useful.
Prognosis
The disease is progressive; patients have deterioration in their behavior, cognition, and ability to perform activities of daily living. At an advanced stage, patients are confined to bed.

                            Last update:
                            December 2009

                            - Expert reviewer(s):
                            Dr Lucie GUYANT-MARECHAL


Early-onset calcifying leukoencephalopathy-skeletal dysplasia

A rare genetic neurological disorder characterized by pediatric onset of calcifying leukoencephalopathy and skeletal dysplasia. Reported structural brain abnormalities include agenesis of corpus callosum, ventriculomegaly, congenital hydrocephalus, pontocerebellar hypoplasia, periventricular calcifications, Dandy-Walker malformation and absence of microglia. Characteristic skeletal features include increased bone mineral density (reported in skull, pelvic bone and vertebrae), platyspondyly, and under-modeling of tubular bones with widened/radiolucent metaphysis and constricted/sclerotic diaphysis.


Early-onset cerebellar ataxia with retained tendon reflexes

Early onset cerebellar ataxia with retained reflexes (EOCARR) or Harding ataxia is a cerebellar ataxia characterized by the progressive association of a cerebellar and pyramidal syndrome with progressive cerebellar ataxia, brisk tendon reflexes, and sometimes profound sensory loss.

Summary:
Epidemiology
The prevalence of EOCARR ataxia has been estimated to be around 1/100,000, and the birth prevalence at 1/48,000 births in North-western Italy.
Clinical description
EOCARR is a progressive cerebellar ataxia, with disease onset occurring in childhood or in juveniles (ranging from 3 to 20 years with a mean age of 9 years). EOCARR is characterized by dysarthria, gait ataxia, nystagmus, brisk tendon reflexes in the upper and lower limbs, absent ankle reflexes, and discrete or absent deep sensory loss. The association of brisk jerks and absent ankle reflexes may occur. Oculomotor disturbances, dysphagia, tremor, scoliosis, pes cavus, extensor plantar response, and lower limb wasting and weakness may be observed while amyotrophy is rarely observed. Moreover, spasticity may become progressively severe.
Etiology
The exact etiology of EOCARR is still unknown. However, molecular genetic analysis in a Tunisian family confirmed the genetic heterogeneity of this syndrome and mapped the gene locus to chromosome 13q11-12.
Diagnostic methods
Diagnosis relies on physical examination as well as on imaging findings (magnetic resonance imaging (MRI) or computed tomography (CT)) revealing cerebellar atrophy. Peripheral nerve conduction and nerve biopsy findings may show moderate to severe axonal sensory-motor neuropathy with axonal regeneration.
Differential diagnosis
Differential diagnosis includes Friedreich ataxia (FRDA; in contrast to EOCARR shows cardiomyopathy, diabetes mellitus, scoliosis, skeletal deformities or optic atrophy), autosomal dominant cerebellar ataxia (ADCA), autosomal recessive spastic ataxia of Charlevoix-Saguenay, ataxia with vitamin E deficiency (see these terms), and inherited metabolic disorders that may express ataxia.
Genetic counseling
Transmission is autosomal recessive. The parents of an affected child should be informed of the 25% risk of transmitting the disease to future offspring.
Management and treatment
Treatment is symptomatic, aimed towards the control of spasticity, and should include physiotherapy and pharmacotherapy (that may include spasmolytic drugs such as baclofen).
Prognosis
The period of latency before becoming wheelchair-bound is significantly longer in EOCARR than in FRDA, resulting in a better prognosis in patients with EOCARR than in those with FRDA.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Pr Francesc PALAU


Early-onset epilepsy-intellectual disability-brain anomalies syndrome

A rare congenital disorder of glycosylation characterized by early onset of hypotonia, severe global developmental delay, intellectual disability, and seizures. Ataxia, mild facial dysmorphism, and autistic behavior have also been reported. Brain MRI findings are variable and include cerebral atrophy, cerebellar hypoplasia/atrophy, and thin corpus callosum.


Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation is a rare intellectual disability and epilepsy syndrome characterized by global developmental delay and mild to profound intellectual disability, multiple types of usually intractable focal and generalized seizures with variable abnormal EEG findings, and bilateral progressive parenchymal volume loss and thin corpus callosum on brain MRI.


Early-onset epileptic encephalopathy-cortical blindness-intellectual disability-facial dysmorphism syndrome is a rare, syndromic intellectual disability syndrome characterized by cortical blindness, different types of seizures, intellectual disability with limited or absent speech, and dysmorphic facial features. Brain imaging typically shows mild pontine hypoplasia, hypoplasia of the corpus callosum and atrophy in the occipital region.


A rare type of familial hypoaldosteronism characterized by early infantile onset of vomiting, diarrhea, severe dehydration, and failure to thrive. Analysis of plasma electrolytes shows hyponatremia, hyperkalemia, and acidosis. Plasma renin activity is elevated, and aldosterone levels are low.


Early-onset generalized limb-onset dystonia

A rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures that typically begins in a single limb and, in most individuals, followed by progressive involvement of other limbs and the trunk, typically sparing the cranial and cervical region.

Summary:
Epidemiology
The prevalence varies according to region and ethnic population. In the USA the estimated prevalence in the general population is approximately 1/30,000, whilst in Europe the estimated prevalence ranges from 1/ 200,000-330,000, although precise figures are currently not available. The estimated prevalence in the Ashkenazi Jewish population is much higher at 1/3,000-9,000, due to a founder effect.
Clinical description
Symptoms typically develop first in an arm or leg with dystonic muscle contractions in middle to late childhood, and may first become apparent with specific actions such as writing or walking. In approximately 60-70% of patients, the disease progresses to other body regions (multifocal or generalized dystonia) within about five years, involving at least one leg and one arm, and often axial muscles. Spread to craniocervical muscles may rarely occur. Distribution and severity of symptoms vary widely between affected individuals and even within the same family. This type of dystonia is not associated with other neurologic or systemic abnormalities.
Etiology
The majority of cases are caused by a heterozygous deletion of three base pairs (GAG) in the /TOR1A gene (chromosome 9q34). This gene encodes the protein torsinA, which is ubiquitously expressed and, as an AAA+ ATPase, appears to play a role in various cellular compartments (cytoskeletal dynamics, vesicle fusion, membrane trafficking, and protein folding). The protein shuttles between the endoplasmic reticulum (ER) and the nuclear envelope, where it plays a role in ER-associated degradation, rendering cells less sensitive to ER stress.
Diagnostic methods
The diagnosis is established in a proband by identification of a heterozygous TOR1A three base-pair deletion, c.907_909delGAG, which is the only definitely pathogenic variant in the TOR1A gene identified to date.
Differential diagnosis
Differential diagnosis includes other forms of isolated dystonia such as Dopa-responsive dystonia (due to either GCH1, SPR, TH), Primary dystonia, DYT6 type (THAP1), and Autosomal dominant focal dystonia, DYT25 type (GNAL). Whilst presenting symptoms may be similar, DYT25 is frequently distinguished by adult-onset focal dystonia, whereas individuals with DYT6 dystonia frequently have prominent cranio-cervical and laryngeal involvement.
Genetic counseling
The pattern of inheritance is autosomal dominant with low penetrance (approximately 30% of carriers become symptomatic) and variable expressivity with respect to age, site of onset, and progression. Molecular testing and genetic counseling are recommended for individuals with an age of onset below 26 years, and may also be considered in those with onset after 26 years who have a relative with typical early-onset isolated dystonia.
Management and treatment
Treatment options include botulinum toxin injections for focal symptoms and pharmacological therapy such as anticholinergics (most commonly trihexyphenidyl) for generalized dystonia. In severe cases with medically refractory early-onset dystonia, surgical approaches, especially deep brain stimulation (DBS) of the internal globus pallidus (GPi) or, in some cases, intrathecal baclofen application should be considered. In recent years, GPi-DBS has been established as an important treatment option for medically refractory isolated generalized dystonia, with most individuals experiencing good or sometimes even dramatic improvement.
Prognosis
All patients have normal cognitive function, and despite a high rate of generalization of dystonic symptoms, approximately 75% of patients are able to maintain ambulation and independence, and therefore a comparatively good quality of life, with modern treatment modalities. In children and adults with severe, medically refractory dystonia, GPi-DBS should be considered early in the course of the disease, since shorter disease duration has been correlated with improved outcomes.

                            Last update:
                            April 2019

                            - Expert reviewer(s):
                            Dr Christoph KAMM


A rare genetic progressive myoclonic epilepsy characterized by childhood onset of progressive dysarthria, myoclonus, ataxia, seizures, and cognitive decline. The disease takes a protracted course with patients surviving into adulthood, developing signs and symptoms like psychosis with outbursts of prolonged agitation and screaming, spasticity and hyperreflexia, confusion, mutism, and incontinence. There are no visual disturbances. Muscle biopsy shows numerous periodic acid-Schiff-positive inclusions, so-called Lafora bodies.


Early-onset myopathy with fatal cardiomyopathy

A rare genetic neuromuscular disease characterized by neonatal or infancy onset of delayed motor development, generalized muscle weakness involving also the facial muscles, pseudohypertrophy of lower limb muscles, and joint contractures, associated with childhood onset of rapidly progressive dilated cardiomyopathy with arrhythmias leading to sudden cardiac death. Muscle biopsy in early childhood shows minicore-like lesions and centralized nuclei, with dystrophic features being more conspicuous in the second decade of life.


Early-onset myopathy-areflexia-respiratory distress-dysphagia syndrome

A rare congenital myopathy characterized by early onset of severe muscular weakness, respiratory distress due to diaphragmatic paralysis, dysphagia and areflexia, joint contractures, and scoliosis. Decreased fetal movements are seen in some individuals. Muscle biopsy may show a combination of dystrophic and myopathic features. The clinical course is variable, with some patients becoming ventilator-dependent and never achieving ambulation.