A rare, congenital head and neck malformation characterized by the association of retrognathia and glossoptosis, with or without cleft palate, and respiratory obstruction.

Summary:
Epidemiology
The prevalence of this syndrome has been estimated at 1 in 10 000 births. However, precise values are difficult to obtain because historically the definition varied and studies often included cases which occurred as part of a recognised syndrome.
Clinical description
.Isolated Pierre Robin sequence (PRS), occurring without any other associated malformation, constitutes about 50% of cases presenting with these orofacial malformations. At birth and during the first weeks of life, the main troubles are functional and include upper airway obstruction, difficulties in respiration, poor sucking and swallowing, reflux, oesophageal motor anomalies, and vagal syncope.
Etiology
This condition is referred to as a sequence because the posterior cleft palate is a secondary defect associated with abnormal mandibular development and glossoptosis. Mandibular hypoplasia, occurring early in gestation, causes the tongue to be maintained high-up in the oral cavity, preventing normal fusion of the palatal shelves (secondary palate). The mandibular growth defect can be either the consequence of antenatal orofacial hypomobility (usually related to a brainstem dysfunction, or from peripheral origin), or the consequence of a primary growth defect from tissue origin (bone, connective tissue). Molecular identification of isolated PRS is rare. Only mutations in regulatory elements upstream from SOX9 were identified in families with PRS.
Diagnostic methods
Pierre-Robin sequence is usually diagnosed at birth based on clinical presentation. It is more and more often evoked during prenatal life.
Differential diagnosis
PRS often occurs as part of a complex malformation syndrome. The nature of these anomalies is heterogeneous but they are most commonly collagenopathies, first arch anomalies, various chromosomal disorders (including microdeletion 22q11), phenocopy syndromes associated with toxic agents (alcohol, sodium valproate) and other more complicated associations.
Antenatal diagnosis
Prenatal diagnosis is possible if the retrognathia is detected on the strict profile of the fetus at ultrasound. Several angle measures may help discern retrognathia, leading to screening of the cleft palate and the tongue position (posterior and high-up in the oral cavity). An excess of amniotic fluid is a good diagnostic indicator.
Genetic counseling
The majority of cases occur sporadically; however, approximately 10% cases are familial (mainly dominant). Genetic counselling is subtle and should be offered to all families, even in the event of sporadic cases, by expert teams.
Management and treatment
Most of the time, respiratory and feeding problems resolves during the first year of life. The growth of the mandible leads to correction of retrognathia and tongue position within the first years. In cases of mandibulofacial dysostosis, surgery of the mandible may be necessary. The cleft palate is corrected by surgical intervention (one or two steps) before the age of one year. However, the persistent risk of otitis, transmission hearing loss and phonation difficulties necessitate follow-up by an ear, nose and throat specialist, and speech therapist.
Prognosis
For patients with isolated PRS, the prognosis is very favourable.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr Véronique ABADIE


Isolated polycystic liver disease (PCLD) is a genetic disorder characterized by the appearance of numerous cysts spread throughout the liver and that in most cases is described as autosomal dominant polycystic liver disease (ADPCLD).

Summary:
Epidemiology
The prevalence of ADPCLD is 1/100, 000.
Clinical description
Women are predominantly affected and have a larger number of cysts than affected males. Cysts are undetectable early in life and usually appear after the age of 40 years. Their number and size increases with age. Symptoms depend on the mass (compression effect) and can include abdominal distension, gastro-esophageal reflux, early satiety, dyspnea, decreased mobility and back pain due to hepatomegaly. Some patients are asymptomatic. Other complications (intracystic hemorrhage or infection, torsion or rupture of cysts) can cause acute abdominal pain. Liver function is usually normal. There is no portal hypertension. Extrahepatic manifestations are very rare and may include intracranial aneurysms (usually small sized and at a low risk of rupture) and mitral leaflet abnormalities. In rare cases hepatomegaly can lead to malnutrition which can be lethal.
Etiology
Liver cysts result from overgrowth of biliary epithelium or from dilatation of peribiliary glands. Some cases occur sporadically, but most are inherited as an autosomal dominant trait (ADPCLD). ADPCLD is caused in 1/3-1/2 of cases by mutations in the PRKCSH or SEC63 genes. As not all cases of PCLD have a mutation in one of these genes, other not yet discovered genes and modes of transmission may exist.
Diagnostic methods
Ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) is used for diagnosis. Among patients at risk (belonging to a family known to be affected), diagnostic criteria include more than one cyst in patients below the age of 40 years, and more than three cysts in those over 40. For patients with no known affected relatives, the usual criterion is more than 20 cysts.
Differential diagnosis
Differential diagnoses include multiple liver cysts, found in association with autosomal dominant polycystic kidney disease (ADPKD; see this term), but PCLD is genetically distinct from ADPKD with liver cysts. Simple liver cysts are also a differential diagnosis. Caroli disease (see this term), characterized by cysts communicating with the biliary tract, is differentiated by using imaging with contrast agents specifically excreted into the bile.
Management and treatment
Most patients are asymptomatic and do not require treatment. For those with symptoms, management depends on the extent, distribution, and anatomy of the cysts and may include percutaneous cyst aspiration, alcohol sclerosis, cyst fenestration, partial hepatectomy, and even liver transplantation (in rare cases where the massively enlarged liver considerably alters the quality of life). Any form of estrogen therapy should be stopped immediately. Recently, lanreotide and long acting octreotide (somatostatin analogues) have been shown to be safe and effective treatments for PCLD that reduce moderate polycystic liver volume and prevent its growth.
Prognosis
Most patients with PCLD have good prognosis and do not require treatment.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Dominique VALLA


Posterior meningocele is a rare neural tube closure defect characterized by the herniation of a cerebrospinal fluid-filled sac, that is lined by dura and arachnoid mater, through a posterior spina bifida and covered by a layer of skin of variable thickness, which may be dysplastic or ulcerated. The spinal cord and nerves are generally not included and function normally, although sometimes a tethered cord may be associated. They are most commonly located in the lumbar or sacral region.


A rare, genetic, non-syndromic limb malformation characterized by delayed union or non-union of a long bone, resulting in formation of a false joint, with abnormal mobility and angulation at the pseudoarthrosis site, which manifests with progressive anterolateral forearm or leg bowing, limb shortening, and non-healing fractures. Typical histopathological findings include fibromatosis-like proliferation in the soft tissues with cystic or dysplastic lesions. Neurofibromatosis and osteofibrous dysplasia are frequently associated.


Isolated pauciimmune pulmonary capillaritis is a small vessel vasculitis restricted to the lungs that may induce diffuse alveolar hemorrhage with dyspnea, anemia, chest pain, hemoptysis, bilateral and diffuse alveolar infiltrates at chest X-rays, without any underlying systemic disease. ANCA are frequently positive but could be negative.


A rare congenital limb malformation characterized by partial or total absence of the radius.

Summary:
Epidemiology
The disorder occurs in 1/5,000-30,000 live births, and is slightly more common in males than in females (sex ratio of 3:2).
Clinical description
The disorder is bilateral in 60% of cases and the right side is more commonly involved than the left. The degree of malformation varies greatly. In mild cases, only a minor shortening of the radius is present. In the most severe cases in contrast, the radius is completely absent (including presence of aberrant muscles, nerves, tendons, ligaments and blood vessels). The disorder is thus characterized by varying degree of deficiencies of the radius, carpal bones, and the thumb that produces radial deviation of the hand and marked shortening of the forearm. There may also be underdevelopment or absence of the thumb, and malformation of the elbow joint with restricted motion. Radial longitudinal deficiency is frequently (67%) associated with other congenital anomalies or syndromes, including chromosomal anomalies (trisomy 13, 18 and 21), Holt-Oram syndrome, Roberts syndrome, Rothmund-Thomson syndrome, thrombocytopenia-absent radius (TAR) syndrome, Townes-Brocks syndrome, VACTERL association and Fanconi anemia.
Etiology
The etiology remains unknown. The deformities are believed to develop early in pregnancy, between the 26th and 52th day of gestation. The disorder is being caused by reduction in FGF function.
Diagnostic methods
Diagnosis is based on clinical examination and X-rays. In utero, prenatal ultrasound may potentially detect this malformation and thus be a valuable imaging modality for early diagnosis.
Antenatal diagnosis
Prenatal diagnosis is possible using ultrasound, 3D-ultrasound or fetal magnetic resonance imaging.
Genetic counseling
Approximately 5-10% of cases are familial. Routine genetic counseling is recommended for these cases.
Management and treatment
Management aims at reducing the functional deficit. Initial therapy consists of straightening of the hand and stabilization of the wrist by serial splinting or casting that should be undertaken shortly after birth. Various surgical methods of correction have been described, such as soft tissue releases with or without ulnar osteotomy, soft tissue distraction to distalize the hand, centralization and radialization, pollicization, microvascular epiphyseal transfer and forearm lengthening.
Prognosis
The prognosis is generally good. If an early individualized treatment plan is followed a good clinical outcome can be achieved. However, the more extensive the radial longitudinal deficiency type, the more impaired is the finger function and mobility.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Sebastian FARR  - Pr Christof RADLER


Congenital radioulnar synostosis is a rare bone disorder that may be isolated or associated with other disorders and that is characterized by failure of segmentation of the radius and ulna during embryological development, causing limited rotational movements of the forearm, which may lead to difficulties with some activities of daily living.


Isolated right ventricular hypoplasia (IRVH) is a rare congenital heart malformation (see this term) characterized by underdevelopment of the right ventricle associated with patent foramen ovale or interauricular communication (see these terms) and normally developed tricuspid and pulmonary valves. IRVH manifests with severe cyanosis, congestive heart failure, and in severe cases, death in early infancy.


A rare, hereditary disorder of pentose phosphate metabolism characterized by increased urine levels of sedoheptulose and erythritol, and low-to-normal excretion of sedoheptulose-7P. Clinical presentation of this disorder is currently unclear.


A rare gastroenterologic disease characterized by isolated thrombotic obstruction of the splenic vein, typically due to pancreatic disorders, in particular acute or chronic pancreatitis or pancreatic neoplasms. It is the main cause of left-sided portal hypertension. Patients may be asymptomatic or present with abdominal pain, gastrointestinal bleeding, nausea, and vomiting, as well as signs of portal hypertension.


A rare, non-syndromic visceral malformation characterized by an abnormal, continuous or discontinuous attachment of the spleen to the gonad, epididymis or vas. Continuous type has a direct connection between spleen and the gonad, whereas discontinuous type indicates gonadal tissue fused with an accessory spleen or ectopic spleen tissue without connection to the principal spleen. Males typically present with a scrotal mass or as an incidental finding during the management of cryptorchidism, testicular tumors or inguinal hernia. In females this is usually an incidental finding during laparotomy.


Isolated split hand-split foot malformation

A rare, congenital, bone development disorder characterized by a spectrum of terminal limb malformations including hypoplasia/absence of central rays of the hands and feet (that can occur in one to all four digits), variable degrees of median clefts of the hands and/or feet, aplasia and syndactyly, with a wide range of severity ranging from malformed central finger/toe to a lobster claw-like appearance of the hands and feet. It can occur as an isolated malformation or it can be a feature in various syndromes.


Isolated sternocostoclavicular hyperostosis is a rare rheumatologic disease characterized by predominantly bilateral, chronic, sterile inflammation and progressive sclerosis and hyperostosis of the sternocostoclavicular joint, with adjacent soft tissue ossification, in the absence of other joint involvement. It presents as recurrent episodes of pain, edema and/or erythema of the sternoclavicular region. Palmoplantar pustulosis may be additionally observed in some cases.


Isolated succinate-CoQ reductase deficiency

A rare, mitochondrial oxidative phosphorylation disorder characterized by a highly variable phenotype. The severe, multisystemic disease involves brain, heart, muscles, liver, kidneys, and eyes and results in death in infancy. Mildly affected individuals have only isolated cardiac or muscle involvement in the adulthood. Histochemical and biochemical analysis reveals a global reduction of succinate dehydrogenase activity.


A rare, non-syndromic, limb reduction defect characterized by the partial or complete absence of all four limbs. Sometimes, other malformations may be associated.


Isolated thyroid-stimulating hormone deficiency

A type of central congenital hypothyroidism, a permanent thyroid deficiency that is present from birth, characterized by low levels of thyroid hormones due to a deficiency in TSH synthesis.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own. More specific symptoms and signs often do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age.
Etiology
Isolated TSH deficiency is transmitted in an autosomal recessive manner and is caused by mutations in the TSHB subunit gene (1p13).

                            Last update:
                            August 2010

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


A rare congenital limb formation characterized by partial or complete absence of the tibia with a relatively intact fibula.

Summary:
Epidemiology
Tibial hemimelia incidence is reported to be 1/1,000,000.
Clinical description
The disorder presents with a shortened lower limb and deformities at the knee, foot and ankle. The fibula is always present and may be quite normally formed or dysplastic, might be migrated proximally or can be hypertrophied to match a hypoplastic tibia. The tibia can be shortened, partially absent or completely absent. The quadriceps muscle and patella may be normally formed, deficient or absent, which is an important factor regarding reconstruction. Similarly, the cruciate and collateral ligaments may be present or absent. The knee may fully extend or have a flexion contracture or dislocation. The foot can show duplication or deficiency of the medial rays and can be in equinus or equino-varus. Tibial hemimelia is found bilateral in approximately 30%. The degree of dysplasia and type may vary significantly between sides. Unilateral cases have a leg length discrepancy. Various classifications are published, with early classification based on radiographic appearance, while later included the status of knee motion and also the cartilaginous anlage. The most recent classification additionally focuses on prognosis and treatment. Associated anomalies include congenital femoral deficiency, bifid femur, radial dysplasia, lobster claw deformity, hand syndactyly, polydactyly, triphalagism, missing fingers or toes, hip dysplasia, hip dislocation, hemivertebrae and myelomeningocele. The disorder is associated with several syndromes. Werner's syndrome, Gollop-Wolfgang, chromosome 8q deletion, Langer-Giedion syndrome or type II tricho-rhino-phalangeal syndrome (TRPS II) may also be responsible for the disorder.
Etiology
The etiology is unknown.
Diagnostic methods
Diagnosis is based on clinical and radiological findings.
Antenatal diagnosis
Prenatal diagnosis using ultrasound is possible.
Genetic counseling
Although the majority of cases with tibial hemimelia are sporadic, affected families with possible autosomal dominant or autosomal recessive inheritance have been reported.
Management and treatment
Surgical correction is generally possible for most subtypes. However, in cases with absent patella and/or no quadriceps function a through-knee amputation is usually recommended. The functional result after reconstruction mostly depends on knee stability and the position of the foot. Reconstruction of more severe types includes multiple surgeries and residual knee-instability requiring bracing might persist. Reconstruction versus amputation must be discussed with the family. Associated ray duplications on the foot need to be addressed.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Sebastian FARR  - Pr Christof RADLER


Tibio-fibular synostosis is a rare, non-syndromic limb malformation characterized by fusion of the proximal or distal tibial and fibular metaphysis and/or diaphysis, frequently associated with distal positioning of the proximal tibiofibular joint, leg length discrepancy, bowing of the fibula, and valgus deformity of the knee.


A rare, congenital, esophageal malformation characterized by the presence of an abnormal connection between the esophagus and the trachea (typically occurring in the lower cervical or upper thoracic area and taking an oblique path upward to trachea), without concomitant esophageal atresia. Depending on the size of the lumen, presentation varies from neonatal episodes of choking and cyanosis on feeding to subtle symptoms of wheezing and recurrent respiratory infections in childhood or early adulthood.


A rare congenital limb malformation characterized by complete or partial absence of the ulna.

Summary:
Epidemiology
Ulnar longitudinal deficiency incidence is estimated at 1/25,000-100,000 live births, with a male to female ratio of 3:2. The prevalence is unknown.
Clinical description
The disorder is reported to be unilateral in about 70% of cases, and is mostly right-sided and incomplete. The most common feature is the shortening of the entire upper limb and mainly the forearm, radial bowing and tendency of the hand to drift to the ulnar side of the wrist. Other skeletal upper limb anomalies such as humeroradial synostosis, congenital radial head dislocation, carpal or metacarpal coalition, and digital abnormalities such as syndactylies or thumb malformations are frequently seen. In total, 90% of cases have missing fingers. In rare cases (type 0), missing finger rays are the only clinical feature. The disorder is mostly non-syndromic and may be associated with scoliosis, fibular hemimelia, proximal focal femoral deficiency and phocomelia. The patients may be asymptomatic in the presence of isolated mild ulnar deficiency. Cases of prominent ulnar deficiency accompanied by complex upper limb abnormalities leading to severe disability may however also be observed. The disability caused by the disorder and associated anomalies may lead to severe functional limitations of daily life activities in childhood necessitating surgical correction early in life.
Etiology
The ulnar longitudinal deficiency is caused by an interruption of the sonic hedgehog (SHH) pathway, which is responsible for the development of ulnar-sided forearm structures during embryogenesis. The deformity is believed to develop between the 4th and 7th week of gestation.
Diagnostic methods
Diagnosis is based on clinical examination and X-rays. In utero, prenatal ultrasound may potentially detect this malformation and thus be a valuable imaging modality for early diagnosis.
Differential diagnosis
The differential diagnosis should include focal fibrocartilaginous dysplasia, dyschondrogenesis, congenital pseudarthrosis of the ulna, Nievergelt syndrome and embryofetopathy due to maternal diabetes mellitus.
Antenatal diagnosis
Prenatal diagnosis is possible using ultrasound, 3D-ultrasound or fetal magnetic resonance imaging.
Genetic counseling
Most of the reported cases are sporadic but a few familial cases have been described.
Management and treatment
Management should be highly individualized. The timing and procedure to be performed may be dictated by the age of the patient, bilaterality, and the extent of the hand malformations and forearm stability. Nonsurgical management approaches may rarely be sufficient. Different surgical approaches including syndactyly separation, thumb metacarpal rotation osteotomy, pollicization, ulnar anlage resection, one-bone forearm creation, and humeral derotational osteotomy are possible.
Prognosis
Patients with ulnar longitudinal deficiency may have limited motion, function and strength, but in general, the limb and hand will function as supportive limb. The severity of the disorder and the presence or absence of the accompanying skeletal anomalies determine the time of presentation and the clinical course.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Sebastian FARR  - Pr Christof RADLER


Isolated unilateral hemispheric cerebellar hypoplasia is a rare, non-syndromic cerebellar malformation characterized by loss of volume in the right or left cerebellar hemisphere, with intact vermis and no other neurological anomalies (i.e. normal cerebral hemispheres, fourth ventricle, pons, medulla and midbrain). Patients may be asymptomatic or may present developmental and speech delay, hypotonia, abnormal ocular movements, persistent headaches and/or peripheral vertigo and ataxia. Neurological examination is otherwise normal.


Isosporiasis (also known as cystoisosporiasis) is an exclusively human parasitosis occurring mainly in the tropics and subtropics, due to infection with Isospora belli (through ingestion of contaminated food), that is frequently asymptomatic or that can cause fever and diarrhea, but that is usually a self-limiting condition in the immunocompetent. HIV-positive individuals are particularly at risk of suffering from symptomatic isosporiasis and can manifest with a more severe clinical course of chronic diarrhea and severe weight loss.


A rare tetrogenic embryofetopathy due to exposure to isotretinoin, an oral synthetic vitamin A derivative, which is used to treat severe recalcitrant cystic acne. Exposure to isotretinoin during the first trimester of pregnancy has been associated with an increased risk of spontaneous abortions and severe birth defects including serious craniofacial (microcephaly, asymmetric crying facies, microphthalmia, developmental abnormalities of the external ear, ocular hypertelorism), cardio vascular (conotruncal heart defects, aortic arch abnormalities), and central nervous system (hydrocephalus, microcephaly, lissencephaly, Dandy-Walker malformation, cognitive deficit) anomalies and thymic aplasia.


Isotretinoin-like syndrome is a phenocopy of the isotretinoin embryopathy.

Summary:
Epidemiology
It has been described in six male patients, three of them being sibs born to nonconsanguineous parents.
Clinical description
It is characterized by the same anomalies as those described after maternal treatment with the drug isotretinoin (a vitamin A analog used for treatment of acne): malformations of the face (small, malformed, or missing ears, micrognathia, cleft palate), conotruncal heart defects, aortic arch anomalies, and central nervous system anomalies (hydrocephalus and posterior fossa abnormalities).
Etiology
The etiology is unknown.
Diagnostic methods
Diagnosis may be suspected in patients with a conotruncal heart and ear anomalies. Computed tomography of the temporal bone may reveal agenesis of the external auditory canals and bilateral ossicular chain abnormalities.
Antenatal diagnosis
Prenatal diagnosis may be performed by ultrasonography with careful examination of facial and cardiac structures.
Genetic counseling
As the syndrome has only been reported in males, X-linked recessive inheritance is possible, but autosomal recessive inheritance cannot be ruled out.
Prognosis
Survival may be influenced by the severity of the heart defect and no data are available on long term prognosis.

                            Last update:
                            October 2006


A rare, autosomal recessive, organic aciduria that is characterized by variable clinical presentation ranging from acute neonatal onset of metabolic decompensation to later onset of chronic, non-specific manifestations including failure to thrive and/or developmental delay. All patients are prone to intermittent, acute metabolic decompensation. During metabolic episodes, urine analysis demonstrates elevated isovaleric acid derivatives.

Summary:
Epidemiology
Accurate data on the prevalence is not readily available. Best estimates come from newborn screening studies that estimate prevalence at birth between 1/50,000-150,000.
Clinical description
Patients present along a spectrum. Acute, neonatal presentation is characterized by onset in the first two weeks of life with vomiting, seizures, and lethargy, progressing to coma. Metabolic acidosis with an increased anion gap is apparent on laboratory evaluation. Hyperammonemia may occur. Later onset is relatively non-specific with failure to thrive and/or developmental delay. Patients who survived an early acute presentation are subsequently indistinguishable from those with the chronic phenotype. All patients are prone to intermittent acute episodes of decompensation with minor illnesses. Childhood onset metabolic acidosis is typically brought on by prolonged fasting, increased intake of protein-rich food or infections, and can be fatal if not treated immediately. The characteristic smell of isovaleric acid may be present, and is likened to sweaty feet/body sweat. Though severe developmental delay and neurologic sequelae are present in some patients, they are likely related to severe biochemical presentations.
Etiology
Isovaleric acidemia (IVA) is caused by mutations in the IVD gene (15q15.1) encoding the enzyme isovaleryl-CoA dehydrogenase (IVDH) resulting in accumulation of isovaleric acid and its derivatives. Asymptomatic patients with specific mutations have been reported, especially when identified through newborn screening.
Diagnostic methods
Where implemented, diagnosis is through newborn blood spot screening. Otherwise, in symptomatic individuals diagnosis is suspected based on the clinical presentation. Metabolite or molecular genetic testing confirms diagnosis. Characteristic urine metabolites includes elevated N‐isovalerylglycine, N‐isovalerylcarnitine and 3‐hydroxyisovaleric acid. Isovalerylcarnitine (''C5 carnitine'') is elevated in blood. The urine organic acids may normalize when a patient is well.
Differential diagnosis
In acutely decompensating patients, the differential diagnosis includes other organic acidemias (including lactic acidosis), urea cycle defects, and sepsis. On newborn screening, ''C5-carnitine'' may also indicate 2-methylbutyryl-CoA dehydrogenase deficiency; urine organic acids and molecular testing readily differenciate the two disorders.
Antenatal diagnosis
Prenatal genetic testing is possible when the mutation of a proband has previously been determined.
Genetic counseling
The pattern of inheritance is autosomal recessive; genetic counseling is recommended for affected families. The risk of disease transmission at each pregnancy is 25% when the parents are proven or obligate carriers.
Management and treatment
Lifelong management is with a low protein diet. Children diagnosed with IVA should be referred to a metabolic dietician who can tailor the diet to support normal growth and development. Supplementing with artificial protein restricted in leucine may be required. L-carnitine and glycine may be prescribed to clear excess isovaleric acid. Emergency treatment in times of metabolic stress (including illness and fasting) is with an anabolic diet. Reducing, but not eliminating, natural protein in the diet for 12-24 hours may help, but only if additional other calories can be given to promote anabolism.
Prognosis
Prognosis for patients diagnosed by newborn screening is excellent with the potential for normal neurodevelopmental outcome with appropriate metabolic management. Patients who present symptomatically can have significant neurologic sequelae including neurodevelopmental delay, especially if acidosis and hyperammonemia are severe.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Jerry VOCKLEY


ISPD-related limb-girdle muscular dystrophy R20

A rare subtype of autosomal recessive limb-girdle muscular dystrophy disorder characterized by infantile to childhood-onset of slowly progressive, principally proximal, shoulder and/or pelvic-girdle muscular weakness that typically presents with positive Gowers' sign and is associated with elevated creatine kinase levels, hyporeflexia, joint and achilles tendon contractures, and muscle hypertrophy, usually of the thighs, calves and/or tongue. Other highly variable features include cerebellar, cardiac and ocular abnormalities.


A rare, neurodegenerative disease characterized by progressive dementia and ataxia, widespread cerebral amyloid angiopathy and parenchymal amyloid deposition. Two subtypes have been identified, ABri amyloidosis and ADan amyloidosis.


ITPA-related lethal infantile neurological disorder with cataract and cardiac involvement

A rare, genetic, neurometabolic disease characterized by early onset encephalopathy with progressive microcephaly, severe global development delay, seizures, hypotonia, feeding difficulties, variable cardiac abnormalities, and cataracts. Brain MRI shows distinct pattern with high T2 signal and restricted diffusion in the posterior limb of the internal capsule in combination with delayed myelination and progressive cerebral atrophy. The disease is typically fatal.


IVIC syndrome is a very rare genetic malformation syndrome characterized by upper limb anomalies (radial ray defects, carpal bone fusion), extraocular motor disturbances, and congenital bilateral non-progressive mixed hearing loss.

Summary:
Epidemiology
Prevalence of IVIC is not known. To date, four affected families from Venezuela, Italy, Hungary, and Turkey (discordant monozygotic twins) have been described.
Clinical description
Asymmetrical upper limbs are a characteristic clinical manifestation. Thumb involvement is the most typical clinical manifestation and can range from absence or hypoplasia to the presence of a triphalangic thumb. Other upper limb anomalies include radial ray defects and carpal bone fusion. Upper limbs may be severely malformed. Extraocular motor disturbances and hearing loss of variable severity have also been reported. Some affected individuals have been reported to have mild thrombocytopenia, leukocytosis, shoulder girdle hypoplasia, cardiac involvement, kidney malrotation, intermediate anorectal malformation (see this term), or rectovaginal fistula. The clinical presentation is highly variable but lower limbs are normal. There have been reports of sudden death.
Etiology
The syndrome has been linked to mutations in the SALL4 gene (20q13.2) encoding a transcription factor involved in the maintenance and self-renewal of embryonic and hematopoietic stem cells. Okihiro syndrome (see this term) is a disorder allelic to IVIC syndrome.
Genetic counseling
IVIC syndrome is inherited in an autosomal dominant manner. Genetic counseling should be offered to affected families, informing them of the 50% risk of offspring inheriting the disease-causing mutation and therefore being affected with the syndrome.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Pr Giovanni NERI


Jackson-Weiss syndrome (JWS) is a rare genetic disorder characterized by foot malformations (tarsal and metatarsal fusions; short, broad, medially deviated great toes) and in some patients craniosynostosis with facial anomalies. Hands are normal in affected patients.


A rare genetic disorder caused by deletions in the long arm of chromosome 11 (11q) and mainly characterized by craniofacial dysmorphism, congenital heart disease, intellectual disability, Paris Trousseau bleeding disorder, structural kidney defects and immunodeficiency.

Summary:
Epidemiology
Whilst prevalence of Jacobsen syndrome is unknown, the birth prevalence has been suggested at 1/50,000-100,000 in the United States, with a female/male ratio of 2:1.
Clinical description
Jacobsen syndrome is contiguous gene disorder, characterized by craniofacial dysmorphism (skull deformities, hypertelorism, ptosis, coloboma, downslanting palpebral fissures, epicanthal folds, a broad nasal bridge, short nose, V-shaped mouth, and small, low-set and posteriorly rotated ears), craniosynostosis, eye abnormalities, congenital heart disease, intellectual disability, behavioral problems including ADHD and autism, seizures, Paris-Trousseau bleeding disorder, structural kidney defects and other urogenital anomalies including undescended testes in males, chronic constipation, pyloric stenosis, and immunodeficiency.
Etiology
The syndrome is caused by deletion of one copy of the long arm of chromosome 11 (11q). Most of the deletions are terminal, i.e. extending to the end of the chromosome. The deletion size ranges from ~7 to ~16Mb, with the proximal breakpoint within or telomeric to subband 11q23.3 and the deletion usually extending to the telomere. Interstitial deletions in this region and terminal deletions less than 7Mb can cause a ''partial Jacobsen syndrome'' phenotype. In a minority of cases the breakpoint is at the FRA11B fragile site. There are a few reported cases of mosaicism for the deletion, which may lessen the severity of the clinical phenotype.
Diagnostic methods
Diagnosis is based on clinical findings and confirmed by array comparative genomic hybridization, and/or FISH.
Differential diagnosis
Differential diagnoses may include the Turner and Noonan syndromes, as well as acquired thrombocytopenia due to sepsis.
Antenatal diagnosis
Prenatal diagnosis of 11q deletion is possible through array comparative genomic hybridization analysis of genomic DNA from amniocytes or chorionic villus samples. Deletions can also potentially be detected by non-invasive prenatal testing from a maternal blood sample, although the reliability of this test for Jacobsen syndrome is unknown.
Genetic counseling
About 90% of cases are de novo. The remainder are inherited from an affected parent, either from one carrying a balanced translocation (giving rise to an unbalanced translocation in the offspring) or from a parent carrying a terminal 11q deletion. Genetic counseling is not possible.
Management and treatment
Management is multi-disciplinary and requires evaluation by a pediatrician, pediatric cardiologist, neurologist, hematologist, allergy/immunologist, endocrinologist and ophthalmologist. Additional subspecialty evaluations might include neurosurgery, urology, and nephrology. Follow-up with subspecialists varies between individuals, depending on need. Most individuals with JS have intellectual disability (ranging from mild learning disabilities to severe intellectual disability) and behavioral problems, requiring care by a pediatrician specializing in behavioral/developmental disabilities. Psychological and psychiatric care may also be warranted. Cardiac malformations can be severe and require heart surgery in the neonatal period. Newborns with Jacobsen syndrome may also have feeding difficulties requiring tube feeding. Special attention should be devoted to hematological problems.
Prognosis
Historically, the most common causes of death in people with JS have been from congenital heart disease, bleeding and immunodeficiency. Early diagnosis of the syndrome can lead to lifesaving interventions including the need for prophylactic platelet transfusions at times of risk to prevent bleeding, prophylactic antibiotic or IVIG infusions to prevent life-threatening infections, early medical or surgical intervention for complex congenital heart defects, and brain imaging to identify potential life-threatening brain aneurysms. Intellectual disability can range from mild to severe. For patients who survive the neonatal period and infancy, the life expectancy remains unknown.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Paul GROSSFELD


Jalili syndrome is characterized by the association of amelogenesis imperfecta (AI; see this term) and cone-rod retinal dystrophy (CORD; see this term).

Summary:
Epidemiology
It has been described in only one family with 29 affected individuals.
Clinical description
AI is a generic term for an inherited group of dental diseases in which the common clinical feature is an abnormality of tooth enamel. The enamel may be thin but normal, and/or hypomineralized. CORD is a rare retinal disorder that leads to an initial loss of central vision, color vision and photophobia before the age of 10 years with subsequent night blindness and visual field restriction.
Etiology
Mutations in the CNNM4 gene (2q11.2), which is implicated in metal ion transport, have been identified in several families.
Genetic counseling
Jalili syndrome is transmitted in an autosomal recessive manner.

                            Last update:
                            April 2009


Japanese encephalitis is an arboviral disease (i.e. a disease due to a virus transmitted by an arthropod).

Summary:
Epidemiology
The estimated annual incidence of the disease is 1/160 000 but it is 20 times higher in endemic areas. It mainly occurs in rural areas of China, Korea and Japan, in sub-tropical regions of Asia, and in some regions of Oceania. Imported cases are exceptional. The disease is symptomatic in 1-20/1000 infections, and children and young adults are predominantly affected.
Clinical description
After an incubation period of four to 14 days, infected individuals present with signs ranging from moderate with a headache and low-grade fever to more severe infection with high fever, meningeal syndrome (neck stiffness, vomiting), disorientation and sometimes tremors or coma.
Etiology
The disease is caused by a flavivirus spread by wild birds, amplified by domestic pigs, and transmitted to humans mainly by a mosquito of the genus Culex.
Management and treatment
There is no specific treatment, but intensive supportive therapy should be provided. A vaccine is available, but its prescription should be adapted to each case and depends on the risks of transmission when travelling to endemic areas (length of the stay, transmission season, visits to rural areas).
Prognosis
The disease, when it is symptomatic, can leave neurological sequelae and leads to death in 25 to 30% of the cases.

                            Last update:
                            September 2006


Jawad syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by congenital microcephaly wih facial dysmorphism (sloping forehead, prominent nose, mild retrognathia), moderate to severe, non-progressive intellectual disability and symmetrical digital malformations of variable degree, including brachydactyly of the fifth fingers with single flexion crease, clinodactyly, syndactyly, polydactyly and hallux valgus. Congenital anonychia and white café au lait-like spots on the skin of hands and feet are also associated.


Jejunal neuroendocrine tumor is a rare, primary, malignant, epithelial neoplasm of the small intestine arising from enterochromaffin cells in the jejunum. Clinical behavior depends on the histologic grade, but initially it is generally characterized by vague abdominal symptoms (cramping, bloating, diarrhea) with insidious onset, although sometimes it could present with signs of bowel obstruction/perforation or gastrointestinal bleeding. Diagnosis in advanced stages with regional or distant spread is common, but signs of carcinoid syndrome (flushing, sweating, diarrhea) are usually not apparent until hepatic metastasis has occurred.


A rare, severe, familial long QT syndrome characterized by congenital profound bilateral sensorineural hearing loss, a long QT interval on electrocardiogram and life-threatening ventricular tachyarrhythmias.

Summary:
Epidemiology
The disease is very rare. Prevalence is unknown and varies depending on the population studied (1/100,000-1/1,000,000) but is more common in countries in which consanguineous marriage is frequent.
Clinical description
Almost 50% of patients become symptomatic before age of 3 years. The typical presentation of Jervell and Lange-Nielsen syndrome (JLNS) is a congenitally deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. Deafness is congenital, bilateral, profound and sensorineural. The QT interval is usually markedly prolonged (>500 ms) and associated with tachyarrhythmias (including ventricular tachycardia, episodes of Torsades de Pointes (TdP) ventricular tachycardia and ventricular fibrillation) that may cause syncope or sudden death. It is one of the most severe forms of LQTS. Patients become symptomatic much earlier than in any other LQTS form, with the exception of calmodulin-related LQTS. Almost 90% of patients have cardiac events triggered by intense or sudden emotion, competitive sports, fright or jumping into cold water.
Etiology
The disease is caused by homozygous or compound heterozygous mutations in either the KCNQ1 gene (locus LQT1; 11p15.5) or the KCNE1 gene (locus LQT5; 21q22.1-q22.2) and is inherited in an autosomal recessive manner.
Diagnostic methods
Diagnosis is based on the presence of congenital sensorineural deafness, long QT intervals and disease-causing mutations in either KCNQ1 or KCNE1. Molecular genetic testing is clinically available.
Differential diagnosis
Differential diagnosis for hearing loss includes other forms of syndromic and nonsyndromic congenital and acquired disorders associated with sensorineural hearing loss. Differential diagnosis for cardiac events includes other forms of LQTS, electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypocalcemia), orthostatic hypotension, vasovagal syncope, and drug-induced LQTS.
Antenatal diagnosis
Prenatal testing and preimplantation genetic diagnosis may be available for families in which the disease-causing mutation is known.
Genetic counseling
The pattern of inheritance is autosomal recessive, and genetic counseling is recommended. The risk of offspring inheriting the disease is 25% where both parents are heterozygous carriers of the mutation. Parents may have Romano-Ward syndrome, but typically this is very mild.
Management and treatment
Hearing loss in JLNS benefits from cochlear implantation. The main goal in management of JLNS is prevention of syncope, cardiac arrest and sudden death. The therapeutic approach is complicated by the early age at which most of the patients become symptomatic. As the efficacy of beta-blockers in JLNS while good is not complete, an implantable cardioverter defibrillator (ICD) should be seriously considered and, if necessary, left cardiac sympathetic denervation (LCSD). However, even with additional therapies (pacemakers, ICDs, and LCSD), more than 50% of patients experience additional symptoms and are at risk of sudden death. Family members should be trained in cardiopulmonary resuscitation as up to 95% of patients with JLNS have a cardiac event before adulthood.
Prognosis
More than half of untreated children die before 15 years of age.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Peter SCHWARTZ


A rare chronic benign cutaneous disease characterized by asymptomatic non-scaly erythematous papules or plaques on the face and neck.

Summary:
Epidemiology
Jessner lymphocytic infiltration of the skin (JLIS) is rare, but the exact prevalence is unknown. There is no sex or ethnic predominance. It usually occurs in adults between 30 and 50 years of age. Few cases are reported in childhood.
Clinical description
Cutaneous lesions are mainly localized on the malar region of the face, neck, shoulders, upper back, arms, and hands (sun-exposed skin). Their diameter usually varies between 1 cm and 3 cm. They consist of annular, pink or red papules, sometimes resulting in plaques. No follicular plugging or atrophy appears on the surface of the lesions. The lesions may be singular (approximately 15% of cases) or multiple. When multiple, they are often grouped with an arciform disposition. The lesions may have a chronic waxing and waning course, or more rarely, remain unchanged for several weeks. Onset or exacerbation of the lesions may occur after sun exposure. In general, the lesions are asymptomatic, but they may be sometimes associated with a burning sensation or pruritus. They frequently spontaneously disappear, without resulting scars.
Etiology
JLIS is an inflammatory disease of unknown etiology caused by an accumulation of T cells within the dermis of the skin. There may be a genetic/hereditary component due to multiple reported familial cases. A history of photosensitivity may be associated with the disease. Drug induced JLIS have been described as a reaction to ustekinumab, etanercept, leflunomide, glatiramer acetate, duloxetine and ACE inhibitors. Association with cutaneous B cell lymphoma, Borrelia burgdorferi infection and immune reconstitution syndrome in HIV has been reported.
Diagnostic methods
Diagnosis may be only clinical. Histology reveals nodular perivascular or periadnexal lymphocytes, and dermal infiltration under a normal or only slightly modified epidermis. Infiltrate consists predominantly of reactive CD8+ T cells, with a few CD4+ T cells and B cells. Clusters of plasmacytoid dendritic cells (CD123+) mostly accumulated in the deep vascular plexus, have been described in JLIS as well with identical pattern in lupus erythematous tumidus. Mild mucin deposition may be seen in the dermis. Direct immunofluorescence analyses are usually negative (absence of lupus band test).
Differential diagnosis
Differential diagnoses include rosacea, granuloma annulare, granuloma faciale, cutaneous B-cell lymphomas or pseudolymphoma and idiopathic photodermatoses such as polymorphic light eruption. The differential diagnosis with lupus erythematosus tumidus is much more difficult and some recent studies suggest JLIS cannot be separated from lupus tumidus.
Management and treatment
Treatment of JLIS is not mandatory in all cases. Topical and intralesional corticosteroids are first line therapies. In cases in which photosensitivity is relevant antimalarial drugs (chloroquine and hydroxychloroquine) are generally effective. Multiple therapies have been used even if data on efficacy are scarce, including topical calcineurin inhibitors, auranofin, methotrexate, etretinate, proquazone, thalidomide, and even pulsed dye laser and photodynamic therapy. Photoprotection is advised. Remission, exacerbation or spontaneous resolution may occur.
Prognosis
The overall prognosis is favorable and no systemic involvement has been reported so far.

                            Last update:
                            June 2024

                            - Expert reviewer(s):
                            Pr Giampiero GIROLOMONI


Jeune syndrome, also called asphyxiating thoracic dystrophy, is a short-rib dysplasia characterized by a narrow thorax, short limbs and radiological skeletal abnormalities including 'trident' aspect of the acetabula and metaphyseal changes.

Summary:
Epidemiology
Annual incidence at birth is unknown but is estimated to be 1-5/500,000.
Clinical description
The syndrome is recognizable during the antenatal period or at birth. In rare cases, postaxial polydactyly may also be present. The narrow thorax may cause neonatal respiratory failure, and may be associated with persistent respiratory manifestations. Some cases are severe while others have a benign course. The growth rate is variable but may be almost normal. Hepatic and renal failure has been reported in rare cases (liver fibrosis or nephronophthisis) occurring at any age. Retinal pigmentary degeneration could also be observed. Intellectual development is normal.
Etiology
The molecular basis of the syndrome has been partially elucidated indicating involvement of the IFT80 (3q25.33), DYNC2H1 (11q22.3), WDR19 (4p14) and TTC21B (2q24.3) genes, each encoding an intraflagellar transport protein, which confirms that Jeune syndrome belongs to the ciliopathies group. Mutations in other genes may also be implicated in the disease and remain to be identified.
Diagnostic methods
The diagnosis is based on radiologic findings: ribs are short and the pelvis has an abnormal morphology, with a horizontal acetabular roof and a trident aspect formed by a median protrusion and two lateral spurs. Hands are normal or short with possible cone-shaped epiphyses in the phalanges.
Differential diagnosis
Differential diagnosis should include thoracolaryngopelvic dysplasia, Ellis-van Creveld syndrome, Sensenbrenner syndrome and paternal uniparental disomy of chromosome 14 (see these terms).
Antenatal diagnosis
Molecular diagnosis must be confirmed in the proband before proposing prenatal molecular testing. In other cases, only a careful antenatal ultrasound examination can detect the disease.
Genetic counseling
The syndrome is transmitted as an autosomal recessive trait. The recurrence risk is 25% for every pregnancy after the birth of an affected child.
Management and treatment
Treatment consists of management of respiratory infections, which may lead to severe complications. Renal and hepatic function should be monitored regularly, and retinal examination performed.
Prognosis
Prognosis is highly variable depending of the visceral associated diseases, and the risk of severe respiratory complications decreases after 2 years of age.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Geneviève BAUJAT


Johanson-Blizzard syndrome (JBS) is a multiple congenital anomaly characterized by exocrine pancreatic insufficiency, hypoplasia/aplasia of the nasal alae, hypodontia, sensorineural hearing loss, growth retardation, anal and urogenital malformations, and variable intellectual disability.

Summary:
Epidemiology
The prevalence of JBS in Europe has been estimated to be around 1/250,000 live births.
Clinical description
Onset of symptoms is usually during infancy with hallmark features being aplasia/hypoplasia of nasal alae and pancreatic exocrine insufficiency (presenting in the newborn or young infant with failure to thrive, oily stools and fat-soluble vitamin malabsorption). Additional features include dental anomalies (oligodontia/hypodontia (see these terms) of permanent teeth; >90%), sensorineural hearing loss (~75%), scalp defects (aplasia cutis congenital; ~65%), short stature (~60%), hypothyroidism (~40%), microcephaly (~35%), intrauterine growth restriction (~30%), genitourinary malformations (~30%; cryptorchidism, micropenis, hypospadias, clitoral hypertrophy/clitoromegaly, uterovaginal anomalies, hydronephrosis), congenital heart defects (25%; atrial and ventricular septal defects, patent arterial duct, tetralogy of Fallot, hypertrophic cardiomyopathy; see these terms), and imperforate anus (~20%). A presumably high risk for diabetes mellitus development during adolescence or adulthood has been reported. Developmental and intellectual delays of variable degree are present in ~60% of cases. Other frequent minor signs include abnormal frontal hair pattern (upsweep), lacrimal duct anomalies, severe facial clefting (cleft lip/palate) and lower eyelid coloboma. Less common features are natal teeth, tethered spinal cord, poly-/syndactyly of the feet, prostate aplasia, gastroesophageal reflux, cholestatic liver disease, café au-lait spots, growth hormone deficiency, hypopituitarism, brain malformations (e.g. arhinencephaly), situs inversus, and osseous malformations (left hip dislocation).
Etiology
Most cases of JBS are caused by mutations of UBR1 gene (15q13) which encodes a protein highly expressed in pancreatic acinar cells. UBR1 deficiency may contribute to gradual destruction of previously formed acinar cells starting prenatally, thereby leading to pancreatic enzymes deficiency.
Diagnostic methods
Diagnosis is based on identification of the pathognomonic combination of congenital or infantile exocrine pancreatic insufficiency (fecal fat quantification; fecal elastase; C-triglyceride breath test) with other characteristic anomalies such as aplasia/hypoplasia alae nasi. Diagnosis is confirmed by genetic screening of UBR1.
Differential diagnosis
Differential diagnosis includes cystic fibrosis, Shwachman-Diamond syndrome, Pearson Marrow-Pancreas syndrome, partial pancreatic agenesis (for congenital exocrine pancreatic insufficiency), oculodentodigital dysplasia (for hypoplasia of the alae nasi) and Adams-Oliver syndrome (for aplasia cutis congenita) (see these terms).
Antenatal diagnosis
Prenatal diagnosis is suspected by a beak-like nose (due to aplasia/hypoplasia of nasal alae) and a dilated sigmoid colon suggestive of imperforate anus at 21 weeks of gestation. Molecular testing of UBR1 confirms the diagnosis.
Genetic counseling
Transmission is autosomal recessive. Inter- rather than intrafamilial variability have been described.
Management and treatment
Treatment includes oral administration of exogenous pancreatic enzymes and nutritional support (high-calorie diet with 30-40% calories from fat, lipase, fat-soluble vitamins and mineral supplementation) for pancreatic insufficiency; thyroid hormone substitution; surgery for anorectal and genitourinary malformations; hearing aids for deafness; insulin for diabetes mellitus; early intervention programs and specific education for patients with intellectual disabilities; and dental implantation during the teenage years. Facial malformations may be corrected by plastic surgery.
Prognosis
Pancreatic insufficiency and complications of severe malnutrition (e.g. severe hypoproteinemia, vitamin deficiency, immunodeficiency) may lead to death in infancy or early childhood. For patients managed appropriately, survival into adulthood is the rule.

                            Last update:
                            July 2016

                            - Expert reviewer(s):
                            Pr Martin ZENKER


Johnson neuroectodermal syndrome is characterised by alopecia, anosmia or hyposmia, conductive deafness with malformed ears and microtia and/or atresia of the external auditory canal, and hypogonadotropic hypogonadism.

Summary:
Epidemiology
So far, less than 30 cases have been described in the literature.
Clinical description
Other variable features include a congenital heart defect, facial asymmetry, intellectual deficit, cleft palate, choanal stenosis and an increased tendency for dental caries.
Etiology
The aetiology is unknown but the combination of developmental anomalies present in patients with this syndrome is suggestive of an embryological defect in the formation of the neuroectodermal derivatives of cephalic neural crest.
Genetic counseling
The syndrome is transmitted as an autosomal dominant trait.

                            Last update:
                            October 2006


Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomaly syndromes in which the mandatory feature is the ``molar tooth sign'' (MTS), a complex midbrain-hindbrain malformation recognizable on brain imaging. The MTS is characterized by cerebellar vermis hypodysplasia, thickening and malorientation of the superior cerebellar peduncles and abnormally deep interpeduncular fossa.

Summary:
Epidemiology
The prevalence of JSRD at birth has been estimated to be between 1/80,000 and 1/100,000 live births, although this frequency is probably underestimated.
Clinical description
The neurological features of JSRD include neonatal hypotonia, developmental delay, which is particularly related to language and motor skills, mild to severe intellectual disability, ataxia, and abnormal eye movements including oculomotor apraxia and primary position nystagmus. A subset of patients present neonatal breathing abnormalities, that are characterized by episodes of apnea and hyperpnea starting shortly after birth and improving with age. These neurological manifestations may occur alone or be variably associated with multiorgan features, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. Depending on the associated multiorgan involvement, JSRD is classified in six clinical subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defect; JS with hepatic defect; and JS with orofaciodigital defect (see these terms).
Etiology
Twelve causative genes have been identified to date, all encoding proteins that are part of the primary cilium or its apparatus, making JSRD part of the expanding group of diseases called ``ciliopathies''.
Diagnostic methods
The diagnosis of JSRD should be suspected in all infants presenting with hypotonia, abnormal eye movements and developmental delay, especially if breathing abnormalities are also present. In children, the diagnosis is suspected in presence of neurological signs suggestive of cerebellar involvement (ataxia, developmental delay, intellectual disability, abnormal eye movements) variably associated with involvement of other organs. Brain magnetic resonance imaging is necessary and sufficient to confirm or exclude the diagnosis of JSRD based on the detection of the MTS. This should be followed by a specific diagnostic protocol to assess the potential multiorgan involvement.
Differential diagnosis
Differential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis, Senior-Loken syndrome, and Bardet-Biedl syndrome; see these terms), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations.
Antenatal diagnosis
Mutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. The identification of the molecular defect in at-risk couples enables early prenatal genetic testing, whereas fetal brain neuroimaging may remain uninformative until the end of the second trimester of pregnancy.
Genetic counseling
With the exception of rare X-linked recessive cases, JSRDs are transmitted in an autosomal recessive manner.
Management and treatment
Optimal management requires a multidisciplinary approach, with particular attention to respiratory and feeding problems in neonates and infants, while cognitive and behavioral assessments are recommended to provide young patients with adequate neuropsychological support and rehabilitation.
Prognosis
After the first months of life, when prognosis is primarily linked to the extent and severity of breathing abnormalities, global prognosis varies considerably among JSRD subgroups, depending on the extent and severity of organ involvement.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE


Joubert syndrome with hepatic defect is a very rare subtype of Joubert syndrome and related disorders (JSRD, see this term) characterized by the neurological features of JS associated with congenital hepatic fibrosis (CHF).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
The age of onset and severity of hepatic manifestations are variable. Some patients may also present chorioretinal or optic nerve colobomas and nephronophthisis (NPH), but these are not mandatory features.
Etiology
Over 70% of cases are due to mutations in the TMEM67 gene (8q22.1).
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE


Joubert syndrome with Jeune asphyxiating thoracic dystrophy

A rare genetic developmental defect during embryogenesis characterized by the association of the classic features of Joubert syndrome (congenital midbrain-hindbrain malformations causing hypotonia, abnormal breathing and eye movements, ataxia and cognitive impairment) together with the skeletal anomalies of Jeune asphyxiating thoracic dystrophy (short ribs, long and narrow thorax causing respiratory failure, short-limbs, short stature, and polydactyly). Additional variable manifestations include cystic kidneys, liver fibrosis, and retinal dystrophy.


Joubert syndrome with ocular defect is, along with pure JS, the most frequent subtype of Joubert syndrome and related disorders (JSRD, see these terms) characterized by the neurological features of JS associated with retinal dystrophy.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Age of onset and severity of retinal involvement are variable, ranging from congenital blindness in patients with Leber congenital amaurosis (LCA, see this term) to progressive retinopathy with partial conservation of vision.
Etiology
To date, the most frequently mutated gene in this subtype is AHI1 (6q23.2), which accounts for about 20% of cases, following autosomal recessive inheritance.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE


A rare subtype of Joubert syndrome (JS) and related disorders (JSRD) characterized by the neurological features of JS associated with both renal and ocular disease.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Patients present retinal involvement (manifesting with either Leber congenital amaurosis (LCA, see this term), or progressive retinal dystrophy) and nephronophthisis (NPH, usually juvenile). Retinal involvement is present at birth (LCA) or may manifest later in life. Juvenile NPH usually becomes clinically symptomatic towards the late first decade or the early second decade of life.
Etiology
About 50% of patients carry mutations in the CEP290 gene (12q21.33), transmitted in an autosomal recessive manner.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE


Joubert syndrome with renal defect is a rare subtype of Joubert syndrome and related disorders (JSRD, see this term) characterized by the neurological features of JS associated with renal disease, in the absence of retinopathy.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
In most cases, renal disease manifests as juvenile nephronophthisis, with onset of clinical symptoms in the late first/early second decade of life, although in rare cases there may be infantile NPH, with onset in the first years of life.
Etiology
The most commonly mutated genes in this subtype are NPHP1 (2q13) and RPGRIP1L (16q12.2) with autosomal recessive inheritance.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE


A rare, autosomal recessive congenital cerebellar ataxia characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis leading to an abnormal respiratory pattern, nystagmus, hypotonia, ataxia, and delay in achieving motor milestones.

Summary:
Epidemiology
Prevalence is estimated at approximately 1/100,000.
Clinical description
Disease onset is antenatal, although clinical presentation is typically in the neonatal period with irregular breathing pattern (episodic tachypnea and/or apnea), and nystagmus. During infancy, hypotonia may appear. Cerebellar ataxia (staggering gait and imbalance) may develop later. Delayed acquisition of motor milestones is common. Cognitive abilities are variable, ranging from severe intellectual deficit to normal intelligence. Neuro-ophthalmologic examination may show oculomotor apraxia. In some cases, seizures occur. Careful examination of the face often shows a characteristic appearance: large head, prominent forehead, high rounded eyebrows, epicanthal folds, ptosis (occasionally), an upturned nose with prominent nostrils, an open mouth (which tends to have an oval shape early on, a 'rhomboid' appearance later, and finally can appear triangular with downturned angles), tongue protrusion and rhythmic tongue motions, and occasionally low-set and tilted ears. Other features sometimes present in Joubert syndrome include retinal dystrophy, hepatopathy, nephronophthisis, and polydactyly.
Etiology
JS is due to dysfunction of the primary, non-motile cilium found in most cells. The syndrome is genetically heterogeneous with numerous genes and two loci on chromosomes 9q34 (INPP5E) and 11p12-q13 (TMEM216) associated with the disease so far. Most of these genes encode proteins that constitute the primary cilium or the regulatory proteins and transcription factors involved in its development and function.
Diagnostic methods
Diagnosis is based on the main clinical features (hypotonia, ataxia, development delay and oculomotor apraxia), which must be accompanied by the presence of a neuroradiological hallmark, designated as the ''molar tooth sign'' (MTS) on magnetic resonance imaging (MRI). MTS results from hypoplasia of the cerebellar vermis and midbrain-hindbrain malformations. Moreover the clinical distinct sign is oculomotor apraxia.
Differential diagnosis
Differential diagnoses include Joubert syndrome-related disorders (JSRD), cerebellar vermis malformations without the MTS (which include Dandy-Walker malformation), X-linked cerebellar hypoplasia, ataxia with oculomotor apraxia types 1 and 2 (AOA1, AOA2), congenital disorders of glycosylation (CDG), 3-C syndrome, pontocerebellar hypoplasias/atrophies, orofaciodigital syndromes II and III, and Meckel-Gruber syndrome.
Antenatal diagnosis
Antenatal diagnosis is feasible through genetic testing where both disease-causing mutations have been previously identified in an affected family member. Imaging studies can suggest the disease (fetal ultrasonography and MRI) but cannot be use to conduct any antenatal diagnosis.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is recommended for families with an affected child; the recurrence risk for future offspring is 25%.
Management and treatment
Management is symptomatic and should be multidisciplinary. Education programs, physical, occupational, and speech therapy may improve the hypotonia and reduce the delay in achieving motor milestones. In general, the neurological disability and amaurosis are not progressive. Particularly relevant is the detection of nephronophthisis (NPH) which leads to chronic kidney disease which occurs in about 30% of subjects with all genetic types (with higher risk for mutations in the following genes: CEP290 (12q21.32), RPGRIP1L ( 16q12.2), TMEM216 (11q13.1), TMEM67 (8q22.1), NPHP4 (1p36.31; 1 case), AHI1 (6q23.3). Another aspect that may determine progressivity is the association with a liver disease, and particularly a liver fibrosis that may need liver transplantation.
Prognosis
Prognosis is favorable for moderate forms of the disease. In patients with nephronophthisis (NPH), end stage renal disease occurs in the second decade of life. Management of patients with more severe forms should be carried out by a specialized reference center. Liver disease does not recur in the transplanted liver.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Enrico BERTINI  - Pr Enza Maria VALENTE


Juberg-Hayward syndrome is a polymalformative syndrome that associates multiple skeletal anomalies with microcephaly, facial dysmorphism, urogenital anomalies and intellectual deficit.


Junctional epidermolysis bullosa inversa

A rare intermediate form of junctional epidermolysis bullosa characterized by congenital blistering and erosions confined to intertriginous skin sites, the esophagus, groin, and perineum. Blistering is usually severe and lesions may heal with atrophic scarring and milia formation. Extracutaneous manifestations include nail dystrophy, enamel hypoplasia and dental caries, oral, esophageal and vaginal blisters and erosions.


Junctional epidermolysis bullosa with pyloric atresia

A severe form of junctional epidermolysis bullosa (JEB) characterized by generalized blistering at birth and congenital atresia of the pylorus and rarely of other portions of the gastrointestinal tract.

Summary:
Epidemiology
Prevalence of junctional epidermolyis bullosa-pyloric atresia syndrome (JEB-PA) is unknown. More than 100 cases have been reported worldwide.
Clinical description
Skin manifestations include severe blistering, atrophic scarring, and nail dystrophy. Congenital absence of skin (aplasia cutis congenita) is common, and ear anomalies are also relatively common. The manifestations of pyloric atresia include intractable vomiting, abdomen distension, and an absence of stools. Patients present oral cavity involvement and, if they survive, enamel hypoplasia. Other extracutaneous manifestations include involvement of the respiratory, gastrointestinal and genitourinary tracts. In particular, genitourinary malformations and acquired genitourinary abnormalities (polypoid bladder wall lesions, hemorrhagic cystitis, urethral strictures) are relatively frequent and characteristic. Growth delay and anemia, secondary to the extensive cutaneous and mucosal lesions, are common. Polyhydramnios, secondary to pyloric atresia, is usually present in pregnancies with an affected fetus. Some patients with an identical presentation have been found to have intraepidermal rather than intra-lamina lucida blister formation, necessitating their inclusion under the rarer subtypes of EB simplex (EBS; epidermolytic) severe with pyloric atresia rather than under junctional EB. These patients might have mutations in the intracellular domain of integrin beta4, or plectin deficiency.
Etiology
The condition is caused by biallelic mutations in either of the genes encoding the two subunits of alpha6-beta4 integrin, ITGA6 (2q31.1) and ITGB4 (17q11-qter).
Diagnostic methods
Diagnosis in neonates is suspected based on clinical findings of skin fragility and gastric outlet obstruction demonstrated by X-rays without contrast. In addition to the finding of a cleavage plane located within the lamina lucida of the cutaneous basement membrane zone by immunofluorescence antigen mapping and/or transmission electron microscopy, a negative or highly reduced immunofluorescence staining for integrin alpha6beta4 is typical of JEB-PA. Genetic testing should be the gold standard, in order to differentiate from EBS with pyloric atresia, particularly if immunofluorescence mapping and/or transmission electron microscopy are not available/feasible.
Differential diagnosis
The main differential diagnosis is of EBS with pyloric atresia.
Antenatal diagnosis
Diagnosis may be suspected on ultrasound findings of polyhydramnios, secondary to pyloric atresia, with high levels of alpha-feto-protein (> 20 times normal values). Prenatal diagnosis by genetic testing should be offered to the family.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Pyloric atresia must be corrected surgically in the first days of life; without this, the disorder is lethal in the neonatal period. Multidisciplinary management with hospitalization in neonatal intensive care is required. Patients should be monitored and treated for water-electrolyte balance, failure to thrive, anemia, infectious and respiratory complications, etc. Pain management is also extremely important in these patients and often requires opioids. Skin management is based on the avoidance of blistering by meticulous protective padding of the skin, avoidance of trauma in daily life, lancing and draining of new blisters, and prevention of secondary infection by careful wound care.
Prognosis
JEB-PA leads in most cases to early death within the first months of life. Prognosis depends predominantly on the prompt surgical correction of pyloric atresia. Amongst patients in whom this is successful, a minority show mild skin involvement or a gradual improvement of blistering lesions, allowing the recanalized patient to reach a normal life span.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Dr Michela BRENA | ERN-Skin* - Dr Sophie GUEZ | ERN-Skin* - Dr Gianluca TADINI | ERN-Skin*

                                * European Reference Network


A group of inherited epidermolysis bullosa characterized by involvement of the skin and mucous membranes, and is defined by the formation of blistering lesions between the epidermis and the dermis at the lamina lucida level of the cutaneous basement membrane zone and by healing of lesions with atrophy and/or exuberant granulation tissue formation.

Summary:
Epidemiology
Junctional epidermolysis bullosa (JEB) is the less common, but frequently early lethal form of EB. Point prevalence is generally below 1/1,000,000 worldwide except in the Netherlands where it is estimated at 1/475,000. Prevalence at birth ranges from 1/110,000-455,000 worldwide.
Clinical description
Onset is usually at birth with the exception of late-onset JEB. Several JEB subtypes have been described based on clinical features. All subtypes are characterized by the presence of enamel hypoplasia manifesting as localized or more extensive thimble-like pitting of some or all of the tooth surfaces. Blistering is usually associated with atrophic scarring or with exuberant granulation tissue formation and nail dystrophy. Additional skin findings may include congenital aplasia cutis and progressive hair loss. Mucosal involvement is constant, although of variable severity, and can affect the gastrointestinal, respiratory and genitourinary tracts and the eyes. Pyloric atresia is the hallmark of the JEB with pyloric atresia subtype. JEB is divided in the following subtypes: severe JEB, intermediate JEB, localized JEB, JEB with pyloric atresia (JEB-PA), JEB inversa, late-onset JEB, laryngo-onycho-cutaneous syndrome (LOC) syndrome and JEB with interstitial lung disease and nephrotic syndrome.
Etiology
JEB is caused by mutations in various genes, including COL17A1 (10q25.1), ITGA6 (2q31.1), ITGB4 (17q25.1), LAMA3 (18q11.2), LAMB3 (1q32.2), LAMC2 (1q25.3) and ITGA3 (17q21.33).
Diagnostic methods
Diagnosis is based on determination of the level within which blisters develop on skin biopsy samples following minor traction to the skin. The recommended techniques are immunofluorescence antigen mapping and transmission electron microscopy. In JEB, the blister cleavage plane is localized within the lamina lucida of the cutaneous basement membrane zone. Subtypes are then defined on the basis of immunofluorescence and electron microscopic findings, and clinical presentation. Genetic testing should be always performed, as it is necessary for antenatal diagnosis.
Differential diagnosis
Diagnosis is usually straightforward with little need for extensive differential diagnosis. However, in the neonatal period, in utero Herpes simplex infection may need to be considered, especially if there is no family history of blistering disease or if the clinical findings are very atypical for EB. The differential diagnosis in neonates may include inherited or acquired skin disorders with a similar presentation.
Antenatal diagnosis
Prenatal diagnosis should always be offered to families at risk of having a child with severe JEB.
Genetic counseling
Inheritance is autosomal recessive. Parents of a child with JEB are obligate carriers of the pathogenic variants. For each pregnancy of the parents, the risk of having an affected child is 25%.
Management and treatment
Patients affected by most JEB forms require hospitalization in neonatal intensive care because of the severity skin lesions and extracutaneous manifestations, and should be monitored and treated for water-electrolyte balance, failure to thrive, anemia, infectious and respiratory complications, etc. Pain management is also extremely important in these patients and often requires opioids. Subsequently, patient management should involve a multidisciplinary team, to ensure coordinated care. Skin management is based on the avoidance of blistering by meticulous protective padding of the skin, avoidance of trauma in daily life, lancing and draining of new blisters, and prevention of secondary infection by careful wound care.
Prognosis
Patients with JEB, particularly those with severe subtypes (severe JEB, JEB-PA and JEB with interstitial lung disease and nephrotic syndrome) are at major risk of death during the first few years of life.

                            Last update:
                            May 2021

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

                                * European Reference Network


A rare, congenital malformation syndrome characterized by the association of anterior ocular chamber cleavage disorder with developmental delay, short stature and congenital hypothyroidism. Additional manifestations include cerebellar hypoplasia, tracheal stenosis, narrow external auditory meatus, and hip dislocation. There have been no further description in the literature since 1995.


Juvenile absence epilepsy (JAE) is a genetic epilepsy with onset occurring around puberty. JAE is characterized by sporadic occurrence of absence seizures, frequently associated with a long-life prevalence of generalized tonic-clonic seizures (GTCS) and sporadic myoclonic jerks.

Summary:
Epidemiology
The incidence of JAE is still unknown but it accounts for approximately 2-3% of patients with adult epilepsy in general, and about 8-10% of patients with genetic generalized epilepsy (GGE). No sex predominance has been observed.
Clinical description
JAE is characterized by sporadic occurrence of absence seizures (only one or a few absences daily; 100% of cases), frequently associated with a long-life prevalence of generalized tonic-clonic seizures (GTCS; 80%) and sporadic myoclonic jerks (20%). The seizures onset is typically between 9 and 13 years of age and it manifests as a ''staring spell'' that can be accompanied by atonic postures such as drooping of the head and/or automatisms such as lip smacking. GTCS and myoclonic seizures often occur 1-10 years after the absence seizure onset. Patients with JAE usually develop normally, although uncontrolled absence seizures may have an impact on their ability to learn at school.
Etiology
The exact etiology of JAE is still elusive. However, genetic mutations for voltage-gated sodium channels (CACNB4 gene (2q22-q23)), potassium channels (CLCN2 gene (3q27.1)), and EFHC1 (6p12.3) may be involved in a subset of patients. Moreover, different mutations have been found in genes for GABA receptors (ligand ion channels), specifically in the GABRA1 gene (5q34).
Diagnostic methods
Diagnosis relies on the clinical features and on electroencephalogram (EEG) recorded awake and during sleep, that displays a generalized 3-4 Hz spike-and-slow-wave complexes.
Differential diagnosis
Differential diagnosis includes childhood absence epilepsy, juvenile myoclonic epilepsy, Jeavons syndrome (see these terms).
Genetic counseling
The transmission is still unknown although an increased risk for first degree related parents to develop JME may exist.
Management and treatment
The antiepileptic drugs of choice are valproic acid (VPA) and lamotrigine (LTG). In cases where VPA deals with only partial seizure control, add-on of LTG (GTCS) or ethosuximide (absence seizures) can be beneficial.
Prognosis
Prognosis of JAE is usually favorable with good therapy responsiveness. Generally, seizure freedom can be achieved with antiepileptic medication in 62-84% of all patients with JAE. However, the occurrence of GTCS predicts a worse prognosis.

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                            Dr Gabrielle RUDOLF


Juvenile amyotrophic lateral sclerosis (JALS) is a very rare severe motor neuron disease characterized by progressive upper and lower motor neuron degeneration causing facial spasticity, dysarthria, and gait disorders with onset before 25 years of age.

Summary:
Epidemiology
The prevalence and incidence of JALS are not known. A small number of cases have been reported to date. The disorder has been described in various ethnic groups.
Clinical description
Onset is during childhood with a mean age of 6.5 years and a reported range of 3 to 20 years. Patients then develop motor neuron degeneration leading to facial muscle spasticity, spastic dysarthria, and spastic gait. Some patients are reported to have uncontrolled laughter and weeping (pseudobulbar syndrome). Mild atrophy of the legs and hands are observed in some cases. Bladder dysfunction and sensory disturbances are also found. The disease is usually slowly progressive and some patients have been reported to have become bedridden by 12 to 50 years of age.
Etiology
Mutations in the following genes have been found in patients presenting with JALS: ALS2 (2q33-q35), and rarely SIGMAR1 (9p13.3), SPG11 (15q13-q15) and FUS (16p11.2). Mutations in the latter gene are sporadic and appear to be associated with a severe and aggressive course.
Diagnostic methods
Diagnosis is based on the clinical findings. Motor evoked potential studies show absent or reduced action potentials, electromyography demonstrates signs of denervation, while nerve conduction velocities are normal. Magnetic resonance imaging (MRI) scans of the brain and spinal cord are normal.
Differential diagnosis
Differential diagnoses include juvenile primary lateral sclerosis and, to a lesser extent, infantile-onset ascending hereditary spastic paralysis (see these terms).
Genetic counseling
Cases related to the ALS2 and SIGMAR1 genes have an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families.
Management and treatment
There is currently no specific treatment. Management primarily involves physical and occupational therapy to promote mobility and independence.
Prognosis
Prognosis is guarded and quality of life severely affected by the clinical manifestations of the disease.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Pr Enrico BERTINI


Juvenile cataract-microcornea-renal glucosuria syndrome

A rare autosomal dominant association characterized clinically by juvenile cataract associated with bilateral microcornea, and renal glucosuria without other renal tubular defects.


An early-onset form of dermatomyositis (DM), a systemic, autoimmune inflammatory muscle disorder with vasculopathy, characterized by proximal and symmetrical muscle weakness, evocative skin lesions, and systemic manifestations. Vasculopathy occurs in the skin, muscle (mainly in the perifascicular area), and sometimes in the intestinal tissue.

Summary:
Epidemiology
Juvenile dermatomyositis (JDM) is the most common idiopathic inflammatory myopathy of childhood, with an annual incidence of 1/250,000-500,000 children. Females are affected more frequently than males (2-5:1 ratio).
Clinical description
Onset of juvenile dermatomyositis (JM) is on average between 5 to 14 years of age. Patients commonly have the signs of DM, i.e symmetrical proximal muscle weakness and erythematous rash (heliotrope rash, Gottron papules, erythema in sun-exposed areas), that is sometimes pruritic, along with cutaneous vasculitis and ulcerations, calcinosis of soft tissue (20-40%), and vasculopathy affecting the digestive tract (with bowel ischemia and/or infarction, abdominal pain, and melena). Muscle weakness variably impairs physical function. Commonly reported signs also include myalgia and arthralgia. Other associated extramuscular features include dysphagia, sometimes dysphonia, hoarseness, pneumonitis, cardiac manifestations (conduction defects, myocarditis, dilated cardiomyopathy), Raynaud's phenomenon and inflammatory arthritis. Specific clinical and histological characteristics are described according to myositis-specific antibody presence. Calcinosis is associated with a younger age at disease onset and positivity for anti-NXP2 antibody. Macrophage activation syndrome, a severe sometimes life-threatening condition, is described in some children. Unlike adult-onset DM, there is no association between malignancy and anti-TIF1-γ antibody positivity. The rare reported malignancies include lymphoma and leukemia.
Etiology
The pathogenesis of JDM has been partially elucidated and is associated with certain HLA regions (different associations compared to adult onset DM) as well as several triggers such as infections. The interferon (IFN) pathways play a key role, especially type I IFNs and an IFN signature has been detected in muscle fibers, and endothelial cells.
Diagnostic methods
Diagnosis is based on the clinical signs and magnetic resonance imaging (MRI) of muscle. Muscle and skin involvements should be evaluated with specific standardized tools. Muscle biopsy and electromyographic testing may also be used, especially in case of atypical JDM. Muscle enzymes (creatine kinase) may be elevated. In JDM, 65% of the patients have myositis-specific antibodies with different prevalence compared to adult onset DM (20-25% with anti-TIF1-γ, 18-20% with anti-NXP2, 4-10% with anti-Mi2). Lung and cardiac involvement should be assessed at diagnosis.
Differential diagnosis
Differential diagnosis in JDM may include mitochondrial myopathies, infectious myopathies, other forms of inflammatory myopathies, particularly autoimmune necrotizing myopathy, as well as Duchenne muscular dystrophy or Becker muscular dystrophy, systemic lupus erythematosus, and juvenile idiopathic arthritis. Monogenic interferonopathies, such as proteasome-associated autoinflammatory syndrome and STING-associated vasculopathy with onset in infancy syndrome, may mimic JDM.
Management and treatment
The aim of treatment is to reduce long-term morbidity and to restore physical function. High-dose corticosteroids are the mainstay of treatment, with dose tapering after a few weeks of therapy depending on patient response. Methotrexate may also be used, and for severe disease, intravenous methylprednisolone (IVMP). In case of refractory disease, other immunosuppressive treatments may be prescribed. Physical therapy is important to maintain or restore muscle strength. Topical corticosteroids and tacrolimus have been used to treat skin manifestations. Patients should avoid direct UV light and use high-factor sunscreen. There is no validated treatment for calcinosis.
Prognosis
The course of JDM is highly variable: 30-50% patients go into remission within 2 to 3 years, whilst others have a cyclic course marked by relapse or an ulcerative or chronic disease course. Treatment is generally effective, with very low mortality rates (less than 4%). The disorder may however be associated with significant morbidity (calcinosis, persistent muscle weakness, skin and muscle atrophy).

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE


A rare primary early-onset glaucoma characterized by early onset, severe elevation of intra ocular pressure of rapid progression, leading to optic nerve excavation and, when untreated, substantial visual impairment.

Summary:
Epidemiology
The disorder is estimated to occur in 0,32/100 000 individuals before the age of 20 years.
Clinical description
Juvenile glaucoma (JG) typically presents between the ages of 5 to 18 years, but it can appear later. Patients are initially asymptomatic and are often discovered incidentally on a routine examination. JG is generally bilateral; there can be a marked asymmetry between the two eyes. The intraocular pressure increases progressively leading to optic nerve excavation and eventually, substantial visual impairment and field loss.
Etiology
JG is caused by impaired outflow of aqueous humor through the trabecular meshwork and into the Schlemm canal. Mutation in MYOC (1q23-q24) genes have been found in patients with JG. MYOC gene codes for the glycoprotein myocilin that is found in the trabecular meshwork and ocular tissue and mutations are disease-causing.
Diagnostic methods
The diagnosis is suspected with the presence of clinical features such as increased intraocular pressure and optic nerve excavation. On gonioscopy the angle appears normal. Typical features of primary congenital glaucoma such as corneal edema and Haab's striae are not present. The refraction test reveals myopia. Typical glaucomatous field defects can be documented. Optic nerve head shows glaucomatous optic neuropathy.
Differential diagnosis
Differential diagnoses include other forms of open angle glaucoma that can occur at any age, late recognized congenital glaucoma, steroid induced glaucoma, traumatic glaucoma and inflammatory glaucoma.
Genetic counseling
Transmission is autosomal dominant with high penetrance. Genetic testing can be used to identify family members at risk of developing JG. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Medical therapy (carbonic anhydrase inhibitors, beta blockers, prostaglandin analogues) is often useful in the treatment of JG. When the condition becomes unresponsive to medications, angle surgery (goniotomy, trabeculotomy), filtration surgery (trabeculectomy), LASER treatment (angle laser surgery or cyclodiode laser therapy) and/or aqueous shunt devices can be considered.
Prognosis
Prognosis is good in patients diagnosed and treated early. Without treatment, the evolution towards blindness is possible.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Dr Pascal DUREAU  - Dr Emmanuel MARCIANO


Juvenile Huntington disease (JHD) is a form of Huntington disease (HD; see this term), characterized by onset of signs and symptoms before 20 years of age.

Summary:
Epidemiology
Exact prevalence of the juvenile form is not known, but is estimated to be about 1/166,000. JHD is reported in 6% of the total cases of HD, which has a prevalence of 1/10,000.
Clinical description
Behavioral disturbances and learning difficulties at school are often the first signs. Motor behavior is often hypokinetic and bradykinetic with dystonic components. Dementia is present in the early stage of the disease. Chorea, the classical sign of HD, is rarely seen in the 1st decade and only appears in the 2nd decade. Seizures, ataxia and weight loss are common.
Etiology
HD is caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4 (4p16.3) in the huntingtin gene, HTT. In juvenile Huntington disease, the CAG repeat length is over 55 in most cases. The length of the repeat determines about 70% of the variance in age at onset but gives no indication of initial symptoms, course, or duration of illness. In 75% of patients with JHD, the father is the affected parent.
Diagnostic methods
Diagnosis is based on clinical manifestations in an individual with a parent with proven HD, and is confirmed by DNA testing. Premanifest testing has been codified in the Guidelines of the International Huntington Association (IHA) and the World Federation of Neurology (WFN) Research Group, and is not performed in at-risk patients below the age of 18.
Differential diagnosis
Differential diagnoses of JHD are young-onset type 2 spinocerebellar ataxia (SCA2: 12q) with chorea, dystonia, and dementia, and dentatorubral pallidoluysian atrophy (DRPLA: 12p) with chorea and myoclonic epilepsy, but also SCA3 (14q) with rigidity, ataxia, and dystonia and SCA17 (6q) with psychiatric features and dementia (see these terms). Other causes of chorea including general internal disorders or iatrogenic drug-induced disorders must also be considered. Sydenham chorea and post-streptococcal chorea are is still present in many parts of the world.
Management and treatment
No cure is currently available. Management should be multidisciplinary and is based on treating manifestations with a view to improving quality of life. Chorea should be treated with dopamine receptor blocking (risperidone, tiapride, pimozide) or depleting agents (tetrabenazine). None of these drugs are officially approved for use in children but are prescribed off-label as treatment of the main symptoms of the disease. Attempts have been made to treat hypokinesia with a number of antiparkinsonian drugs, but without success. Paramedical care with speech, occupational, and physical therapy with psychological support for the patient and family are recommended.
Prognosis
The progression of the disease leads to complete dependency in daily life, which results in patients requiring full-time care, and finally death. The mean disease duration is comparable or slightly shorter than adult HD. The most common cause of death is pneumonia.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Pr R.A.C. [Raymund] ROOS


A rare hyaline fibromatosis syndrome characterized by papulo-nodular skin lesions (especially around the head and neck), soft tissue masses, gingival hypertrophy, joint contractures, and osteolytic bone lesions in variable degrees. Joint contractures may cripple patients and delay normal motor development if occuring in infancy. Severe gingival hyperplasia can interfere with eating and delay dentition. Histopathology analysis of involved tissues reveals cords of spindle-shaped cells embedded in an amorphous, hyaline material.


A rare, heterogeneous group of rheumatologic diseases characterized by arthritis which has an onset before 16 years of age, persists for more than 6 weeks, and is of unknown origin.