Weaver syndrome (WVS) is a rare, multisystem disorder characterized by tall stature, a typical facial appearance (hypertelorism, retrognathia) and variable intellectual disability. Additional features may include camptodactyly, soft doughy skin, umbilical hernia, and a low hoarse cry.

Summary:
Epidemiology
Around 50 cases of Weaver syndrome have been reported to date. Precise prevalence and incidence rates are not available.
Clinical description
WVS is an overgrowth disorder that covers a very wide clinical spectrum: some affected individuals have only tall stature while others have a classic Weaver clinical picture. Tall stature (≥ two standard deviations above the mean) is found in 90% of mutation-positive individuals and most affected patients have higher than normal birth weight and length. The subtle but characteristic facial appearance is most easily recognized in early childhood when there is ocular hypertelorism, large fleshy ears and retrognathia with the appearance of a ''stuck-on'' chin with associated horizontal skin crease. About 80% of patients have mild intellectual disability. A smaller number have moderate intellectual disability with a greater impact on autonomy, while severe deficits are rare. Other variable features include macrocephaly, joint laxity, mild to severe scoliosis, pectus excavatum, hypo- and/or hypertonia, poor coordination, soft skin, clinodactyly, camptodactyly of the fingers and/or toes, umbilical hernia, and a hoarse low cry in infancy. A slightly higher risk of neuroblastoma is suspected. There is currently no data to support an increased risk of other malignancies.
Etiology
WVS is caused by mutations in the EZH2 gene (7q35-q36), a histone methyltransferase involved in transcription control. Currently there are no other known causes of WVS although there has been a single case report of an individual in whom there was a clinical suspicion of WVS and a mutation within EED, which complexes with EZH2.
Diagnostic methods
The clinical suspicion of WVS is confirmed through molecular genetic testing and the identification of a heterozygous germline mutation in EZH2. Given the subtle phenotype associated with WVS, if a germline EZH2 mutation is not identified, alternative diagnoses should be sought.
Differential diagnosis
The main differential diagnosis is Sotos syndrome (see this term) which has considerable overlap with WVS. Other disorders to consider include Beckwith-Wiedemann, Simpson-Golabi-Behmel, Malan overgrowth, tall stature-intellectual disability-facial dysmorphism and Marfan syndromes (see these terms).
Antenatal diagnosis
Prenatal diagnosis in at-risk pregnancies is possible.
Genetic counseling
WVS follows an autosomal dominant pattern of inheritance although the majority of cases to date have arisen de novo. Genetic counseling should be provided to affected families.
Management and treatment
There is no specific treatment for WVS although individual symptom management may be indicated. No specific tumor surveillance is currently recommended but clinical vigilance and early investigation for possible tumor (particularly neuroblastoma)-related symptoms are recommended.
Prognosis
With suitable treatment and support, patients with WVS have a normal life.

                            Last update:
                            January 2016

                            - Expert reviewer(s):
                            Dr Katrina TATTON BROWN


Weaver-Williams syndrome is a multiple congenital anomalies syndrome characterized by moderate-to-severe intellectual disability, decreased muscle mass, microcephaly, facial dysmorphism (prominent ears, midfacial hypoplasia, small mouth and cleft palate), clinodactyly of the fingers, delayed osseous maturation and generalized bone hypoplasia. The syndrome has been described in a brother and sister and an autosomal recessive mode of inheritance has been suggested. There have been no further descriptions in the literature since 1977.


Weill-Marchesani syndrome (WMS) is a rare condition characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities including microspherophakia, ectopia of the lens, severe myopia, and glaucoma.

Summary:
Epidemiology
The prevalence is not documented. Short stature (usually below the third percentile) and brachydactyly are present in 98% of patients.
Clinical description
The following frequencies of ophthalmological manifestations are observed: myopia 94%, microspherophakia 84%, ectopia lentis 73%, glaucoma 80%, and cataract 23%. Other features include joint limitations, muscular build, thickened skin, and cardiac abnormalities (pulmonary valve stenosis, mitral valve insufficiency, aortic valve stenosis, ductus arteriosus, and ventricular septal defect). Intellectual deficit has been reported in 13% of cases and is always mild.
Etiology
Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described. The AR mode of inheritance appears to be more frequent and homozygous mutations within the ADAMTS10 gene (19p13.3-p13.2) have been found. ADAMTS10 is a member of the extracellular matrix protease family and is expressed in skin, fetal chondrocytes, and fetal and adult hearts. Electron microscopy and immunological studies of skin fibroblasts from WMS patients suggest that the syndrome is associated with impairment of the extracellular matrix. Heterozygous mutations within the FBN1 gene (15q21.1) have been identified in patients and are transmitted in an AD manner, giving another example of the large clinical expressivity of fibrillin-1.
Antenatal diagnosis
Prenatal diagnosis has never been reported.
Genetic counseling
Clinical homogeneity has been demonstrated despite the genetic heterogeneity in AR and AD families. However, this leads to difficulties in genetic counseling of sporadic cases. Some heterozygotes for AR WMS present with some mild clinical manifestations of the disease, such as brachydactyly.
Management and treatment
Patients should be followed for ophthalmologic complications in particular, and physiotherapy can be proposed for joint stiffness.
Prognosis
Prognosis is good.

                            Last update:
                            May 2006

                            - Expert reviewer(s):
                            Pr Laurence OLIVIER-FAIVRE


Weismann-Netter syndrome is a rare, genetic, primary, bent bone dysplasia characterized by anterior diaphyseal bowing of the tibia and fibula, broadening of the fibula, posterior cortical thickening of both bones and short stature. Additional skeletal abnormalities include scoliosis with marked lumbar lordosis, horizontal sacrum and square iliac wings and/or, less frequently, vertebral malformations, abnormal shape of the clavicles and ribs, calvarial hyperostosis and delayed eruption of permanent teeth. Delayed ambulation is also frequently associated.


A rare genetic multiple congenital anomalies/dysmorphic syndrome with variable intellectual disability characterized by abnormal head shape/metopic ridging and facial dysmorphism (which may include arched eyebrows, ptosis, downslanting palpebral fissures, epicanthal folds, and short upturned nose). Many patients present variable global developmental delay and/or autism spectrum disorder. Additional reported features are cardiac, skeletal, or urogenital anomalies. Brain imaging may show agenesis of the corpus callosum.


Well-differentiated fetal adenocarcinoma of the lung is a rare, primary, low-grade, bronchopulmonary neoplasm characterized by a well-circumscribed, usually large, pulmonary mass that is histologically composed of glycogen-rich neoplastic glands and tubules that resemble fetal lungs at 10 to 16 weeks of gestation and benign adjacent stroma. It typically presents with chest pain, cough, dyspnea, hemoptysis and/or generalized, non-specific symptoms, such as night sweats, lethargy, poor appetite and weight loss.


Well-differentiated liposarcoma (WDLS), the most common type of liposarcoma (LS; see this term), is a slow growing, painless tumor usually located in the retroperitoneum or the limbs. It is composed of proliferating mature adipocytes.

Summary:
Epidemiology
The incidence is approximately 1/200,000 per year and it accounts for 30-50% of all liposarcomas.
Clinical description
WDLS occurs in adulthood, most often between the ages of 50 to 60 years, and it is seen more frequently in males. A slow growing, painless mass presents most often in the retroperitoneum or the limbs but occasionally in the spermatic cord and the mediastinum. The mass can be soft and fleshy or firm. Symptoms of urinary or bowel obstruction may be experienced if the tumor is large and compresses these organs.
Etiology
WDLS is characterized by extensive chromosomal aberrations, which in 90% of cases include amplification of the chromosomal region 12q13-15. This amplification causes the overexpression of three genes that promote cell growth: MDM2 (that blocks p53 tumor suppressor function), CDK4 (involved in cell cycle regulation) and  HMGA2.
Diagnostic methods
When a mass is detected, computed tomography (CT) or magnetic resonance imaging (MRI) is performed. Chest and abdominal lesions do not require pretreatment biopsy unless resection is likely to be incomplete or highly morbid. Extremity lesions are generally removed completely without prior biopsy. WDLS resembles large, cohesive groups of adipocytes of varying cell size. Fluorescent in situ hybridization (FISH) and immunohistochemistry show the overexpression of MDM2 and CDK4. The four morphological subtypes of WDLS are adipocytic (lipoma-like), sclerosing, inflammatory and spindle cell.
Differential diagnosis
Differential diagnoses include benign lipomas and other types of sarcomas, inflammatory myofibroblastic tumor and Castleman disease (see these terms).
Management and treatment
Surgery is the mainstay of treatment for WDLS. If tumor excision is complete, then no further therapy is recommended, although the patient should be monitored for recurrence. Complete excision is often curative if the tumor is located in an extremity. Lesions in the retroperitoneum and inguinal areas are more difficult to treat and are more likely to recur locally and transform into dedifferentiated liposarcoma (DDLS; see this term). If the tumor is unresectable (or if the excision was incomplete), systemic therapies and radiation can be proposed but have shown little efficacy. Clinical trials are ongoing to assess new therapies in patients with advanced unresectable disease (CDK4 and MDM2 inhibitor trials).
Prognosis
WDLS prognosis depends on the tumor location. Extremity WDLS usually has a good prognosis after the tumor has been removed, with low rates of recurrence and essentially no mortality. Retroperitoneal WDLS, however, has a 5-year probability of freedom from recurrence of only 54% and a 5-year disease-specific survival of 80 to 90%.

                            Last update:
                            January 2013

                            - Expert reviewer(s):
                            Dr Samuel SINGER


Wells syndrome is characterised by the presence of recurrent cellulitis-like eruptions with eosinophilia.

Summary:
Epidemiology
Approximately 80 cases have been described in the literature.
Clinical description
The lesions are usually filled with fluid, tender and progress to form hardened plaques of edema and erythema. They usually resolve without scarring.
Diagnostic methods
Histological studies reveal flame figures and heavy infiltration of eosinophils and histiocytes.
Genetic counseling
The syndrome is usually sporadic but familial cases have been reported.

                            Last update:
                            June 2006


Werner syndrome (WS) is a rare inherited syndrome characterized by premature aging with onset in the third decade of life and with cardinal clinical features including bilateral cataracts, short stature, graying and thinning of scalp hair, characteristic skin disorders and premature onset of additional age-related disorders.

Summary:
Epidemiology
The prevalence among Japanese and Sardinian populations is estimated to be 1/50,000 due to the presence of founder mutations. Prevalence in other populations is unknown, but may be around 1/200,000.
Clinical description
WS patients are normal at birth and during childhood, apart from the absence of a pubertal growth spurt. WS presents between the ages of 20 and 30 with major symptoms of early onset bilateral cataracts, thinning and graying of the hair, short stature and skin changes (ankle ulceration, hyperkeratosis, tight skin, age spots, ''bird-like'' facies and subcutaneous atrophy). In most cases, additional age-related disorders are seen and include osteoporosis, diabetes mellitus, mesenchymal neoplasms and atherosclerosis. Voice changes are frequent and flat feet are sometimes present. Patients with WS have a high risk of developing cancer, in particular sarcomas of mesenchymal origin and melanomas that are not due to sun exposure. Death is usually due to malignancies or myocardial infarction caused by extensive atherosclerosis.
Etiology
WS is caused by a mutation in the WRN gene, located on chromosome 8p11-12. WRN codes for one of the five RecQ helicases in humans. Nonsense mutations, insertions and/or deletions or substitutions in the WRN gene all lead to genome instability. Mutations in the WRN gene are found in approximately 90% of clinically diagnosed WS cases. The other 10% are operationally categorized as atypical Werner syndrome (see this term) and are due to other causes (such as a mutation in the LMNA gene).
Diagnostic methods
A clinical diagnosis is based on the presence of all major symptoms (cataracts, skin changes, premature graying/thinning of hair and short stature) and two additional signs (such as osteoporosis or voice change) presenting after adolescence. Molecular analysis can identify most of the mutations in the WRN gene by standard exon sequencing and sequencing of RT-PCR products, in combination with Western blot analysis showing the absence of normal WRN protein.
Differential diagnosis
Differential diagnoses include mandibuloacral dysplasia (MAD), partial lipodystrophy, Rothmund-Thomson syndrome (RTS) and Hutchinson-Gilford progeria syndrome (HGPS; see these terms). Type 2 diabetes mellitus can also share similarities with WS.
Genetic counseling
WS is inherited in an autosomal recessive manner. Once a patient is diagnosed with WS, the patient and family should receive genetic counseling in order to identify those that could develop the disease and those who are carriers. Offspring of a patient with WS are obligate carriers, but unlikely to be affected, given the low likelihood of marrying a carrier unless there is consanguinity.
Management and treatment
There is no cure for WS and treatment involves a multidisciplinary team. Cataracts can be treated with surgery. Regular physical examinations are needed to check for skin ulcers, diabetes, malignancies or cardiovascular disease. Any malignancies should be treated with surgery, chemotherapy and/or radiation. Smoking should be avoided and a healthy lifestyle, including regular exercise and a diet low in fat, should be followed. Psychological counseling may also be beneficial in supporting patients and family members affected by WS.
Prognosis
Patients with WS have a shortened life expectancy but prognosis depends on the age-related diseases present and their severity.

                            Last update:
                            April 2012

                            - Expert reviewer(s):
                            Dr Fuki HISAMA  - Dr George MARTIN  - Dr Junko OSHIMA


An acute arboviral infection caused by a virus of the Flaviviridae family transmitted by an infected mosquito, that is asymptomatic in the majority of cases but that can present in rare occasions with mild flulike symptoms such as low-grade fever, arthralgia, myalgia, and/or rash, or with neurologic manifestations including meningitis, encephalitis with mental confusion or disorientation, tremors and acute flaccid paralysis/poliomyelitis.


An acute arboviral infection caused by an alphavirus of the Togaviridae family transmitted by an infected mosquito, that more frequently affects children and that is characterized by the presence of mild flulike symptoms (fever, chills, headache, nausea, vomiting, and anorexia) but that can progress to weakness, altered mental status, photophobia, mental confusion, seizures, somnolence, coma and/or even death. The disease can leave neurological sequelae, mainly in infants and children, such as seizures, spasticity or behavioral disorders.


WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a congenital autosomal dominant immune deficiency characterized by abnormal retention of mature neutrophils in the bone marrow (myelokathexis) and occasional hypogammaglobulinemia, associated with an increased risk for bacterial infections and a susceptibility to human papillomavirus (HPV) induced lesions (cutaneous warts, genital dysplasia and invasive mucosal carcinoma).

Summary:
Epidemiology
WHIM syndrome is extremely rare, with 65 cases reported worldwide to date. The incidence in France between 1990 and 2006 has been estimated at less than 1/ 4,000,000 births.
Clinical description
WHIM syndrome has a heterogeneous clinical picture. Onset usually occurs during early childhood with recurrent bacterial infections, including pharyngitis, sinusitis, otitis, meningitis and pneumonia, which respond well to antibiotics. The response to vaccination is poor; when measured by the titer of specific antibodies, a low response is initially observed followed by a rapid disappearance of specific antibodies. More than 80% of the patients develop, by the age of 30 years old, widespread HPV-induced warts that are often difficult to treat, generally starting on hands and feet. 25% develop anogenital condylomata acuminata which may progress to intractable multifocal dysplastic HPV-induced lesions and invasive genital cancer. Tetralogy of Fallot (see this term) has been reported in about 1/4 of cases.
Etiology
WHIM syndrome is caused by heterozygous gain of function mutations in the CXCR4 gene (2q21) encoding a chemokine receptor expressed on mature leukocytes and involved in signal transduction pathways controlling bone marrow cell adhesion and homing, myelopoiesis and lymphopoiesis. Mutations result in prolonged activation of the receptor that leads to retention of neutrophils and other leukocytes in the bone marrow.
Diagnostic methods
Diagnosis is based on the evaluation of clinical signs in addition to the following laboratory findings: cell blood counts usually showing (except in case of acute infection) neutropenia, lymphopenia, and monocytopenia resulting in severe panleukopenia, with normal hemoglobin levels and platelets; serum immunoglobulins G, A and M levels showing mild hypogammaglobulinemia in almost all cases; and bone marrow aspirates demonstrating myelokathexis. Genetic analysis of CXRC4 confirms diagnosis.
Differential diagnosis
Differential diagnosis of diseases with myelokathexis include autosomal dominant severe congenital neutropenia, autosomal recessive severe congenital neutropenia due to G6PC3 deficiency, epidermodysplasia verruciformis, and monocytopenia with susceptibility to infections (see these terms).
Antenatal diagnosis
Prenatal testing by amniocentesis or chorionic villus sampling is possible in case of family history.
Genetic counseling
WHIM syndrome is usually transmitted as an autosomal dominant trait. Autosomal recessive or sporadic cases have also been described.
Management and treatment
Current treatment is symptomatic. Immunoglobulin replacement therapy and prophylactic antibiotic treatment may prevent infections. Treatment with granulocyte-colony stimulating factor (GCSF) may also be used. Standard methods (cauterization, laser therapy) or more aggressive treatments (surgical removal, Interferon, cidofovir, imiquimod) appear mostly ineffective for the management of HPV induced lesions. A clinical trial using CXCR4 antagonist (Plerixafor) is currently ongoing in the USA, and soon in Europe. Case reports suggest that the HPV vaccine may limit the occurrence of HPV infection.
Prognosis
WHIM affected individuals may live well into adulthood. Major risk factors include intractable multifocal dysplastic HPV-induced lesions and invasive genital cancer, and liver failure. By the age of 40, the cancer risk is of about 30%.

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Dr Jean DONADIEU


A rare chronic infectious disorder in which almost all organ systems can be invaded by the rod-shaped bacterium Tropheryma whipplei (TW).

Summary:
Epidemiology
The annual incidence in Central European countries is estimated to be approximately 1/1,000,000.
Clinical description
The disease may occur at any age with diagnosis most frequently made between 50 to 60 years of age. The clinical picture is variable. The following symptoms are frequent but not necessarily observed in each patient: weight loss, polyarthritis, diarrhea/malabsorption, fever, lymphadenopathy, cardiac valvular disease, culture-negative endocarditis, pleuritis, ocular inflammatory disease, and relapsing tenosynovitis. In some cases, complex cerebral manifestations (such as cognitive dysfunction, ophthalmoplegia and myoclonus) can be observed. TW polyarthritis is typically palindromic; however, atypical courses may also occur.
Etiology
TW has been found in sewage plant influx and efflux, and can be excreted in the stool of healthy carriers, of sewage plant workers and of people living in precarious hygienic conditions. The circumstances facilitating infection and disease are unknown, but a genetic or acquired immunological predisposition is suspected.
Diagnostic methods
The gold standard for diagnosis was the histological recognition by an experienced pathologist of free or phagocytised rod-shaped bacteria with periodic-acid-SCHIFF (PAS) staining in macrophages from the duodenal mucosa. However, the combination of PAS staining in an intestinal mucosal biopsy plus a validated specific real time polymerase chain reaction (PCR) for TW will raise sensitivity and specificity of the diagnosis. Cooperation with a laboratory, certified for PCR in Whipple's disease and routinely sequencing the amplification product of the PCR is recommended. Specific immunohistochemistry should be available. An isolated positive PCR in an intestinal mucosal biopsy or in a stool specimen is not sufficient for diagnosis. The diagnosis in extraintestinal tissue is always made by PCR. Immunohistochemistry can be very useful. A positive PCR in pulmonary alveolar lavage or from the oral cavity may mean colonization with TW and not necessarily infection. As the majority of patients with infected cerebrospinal fluid (CSF) are asymptomatic at the time of diagnosis, CSF should be examined with PCR in every patient before antibiotic treatment. Synovial fluid or synovial tissue should be examined by PCR for TW in patients with rheumatic symptoms as the intestinal mucosa is not always involved. Positive PAS staining in cerebral tissues should never be accepted as sole diagnostic tool.
Differential diagnosis
The differential diagnosis includes inflammatory bowel disease, malabsorption syndrome, infectious diarrhea, mesenteric lymphadenitis, seronegative polyarthritis, soft tissue rheumatism, culture-negative endocarditis, vasculitis, lymphoma, cerebrovascular disease, demential processes, HIV infection, atypical mycobacteriosis, sarcoidosis, unclear cutaneous symptoms, exophthalmos and many others.
Management and treatment
According to the only available prospective randomized trial, treatment should consist in: 2 g Ceftriaxon daily intravenously for 14 days, followed by Cotrimoxazol twice daily for 12 months. Control examination of CSF, when initially positive, after termination of treatment is strongly suggested. In recurrent or resistant cerebral infection, contact with a TW. specialist is recommended. Expert advice concerning treatment is indispensable in patients who have received immunosuppressive treatment prior to the diagnosis, including oral steroids, or when a clinical response to Ceftriaxone is not apparent within a few days. In such cases, the occurrence of an immune reconstitution inflammatory syndrome in Whipple's disease (IRIS) must be considered. Treatment with immunosuppressive agents may be lifesaving. Lifelong clinical, non-invasive observation is advised in effectively treated patients, as late recurrences or de novo infections can occur.
Prognosis
Untreated, the disease is relentlessly progressive and leads to death either by wasting or by central nervous system involvement. The treatment schedule and follow up, detailed above, is mostly successful. Fatal courses can occur in patients with advanced cerebral involvement and in patients with the Immune Reconstitution Inflammatory Syndrome (IRIS).

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Gerhard FEURLE


White fibrous papulosis of the neck is a rare, acquired, dermal elastic tissue disorder characterized by multiple, 2-3 mm sized, non-confluent, asymptomatic, white or pale-colored, non-follicular, firm papular lesions occurring predominantly on the lateral or posterior aspects of the neck. Other, rarely reported sites include inferior axillae, central mid-back and upper sternal region.


White forelock with malformations is a multiple congenital anomalies syndrome characterized by poliosis, distinct facial features (epicanthal folds, hypertelorism, posterior rotation of ears, prominent philtrum, high-arched palate) and congenital anomalies/malformations of the eye (blue sclera), cardiopulmonary (atrial septal defect, prominent thoracic and abdominal veins), and skeletal (clinodactyly, syndactyly of the fingers and 2nd and 3rd toes) systems. There have been no further descriptions in the literature since 1980.


White matter hypoplasia-corpus callosum agenesis-intellectual disability syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by severe white matter hypoplasia, corpus callosum agenesis or extreme hypoplasia, severe intellectual disability, failure to thrive and minor midline facial dysmorphism (including hypertelorism, broad nasal root, micrognathia). There have been no further descriptions in the literature since 1993.


White platelet syndrome (WPS) is is a platelet granule disorder characterized by thrombocytopenia, increased mean platelet volumes, decreased platelet responsiveness to aggregating agents, and significant defects in platelet ultrastructural morphology leading to prolonged bleeding times and bleeding.


White sponge nevus (WSN) is a rare and autosomal dominant genetic disease in which the oral mucosa is white or greyish, thickened, folded, and spongy. The onset is early in life, and both sexes are affected equally. Other common sites include the tongue, floor of the mouth, and alveolar mucosa.


A rare, genetic, syndromic intellectual disability disorder characterized by craniofacial features, global developmental delay, intellectual disability and variable neurobehavioral abnormalities (autism spectrum disorder, aggressiveness, and self-injury). Additional features include vision abnormalities and variable sensorineural hearing loss, as well as short stature, hypotonia and gastrointestinal manifestations (e.g. poor feeding, gastroesophageal reflux, constipation).

Summary:
Epidemiology
About 50 patients have been reported in the literature to date. Some researchers estimate that this syndrome may account for up to 1/700 cases of intellectual disability associated or not with autism spectrum disorder.
Clinical description
Presentation may be with neonatal hypotonia or developmental delay during infancy. The main features observed in these patients are developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities (including autism spectrum disorder). Most individuals have been described with mild to moderate ID; but the spectrum ranges from low-normal intelligence to severe ID. Some mild cerebral malformations can be found. Common craniofacial characteristics include microcephaly, high and broad forehead, midface hypoplasia or retrusion, tented or triangular mouth with downturned corners of the mouth, a broad nasal root and flat nasal bridge. Additional features may include hypotonia, seizures, sleep apnea, sensorineural hearing impairment, visual defects (strabismus, refraction errors), tendency to be overweight, short stature and gastrointestinal difficulties.
Etiology
The disorder is caused by heterozygous pathogenic variants in POGZ. POGZ gene mutations are thought to impair the ability of the POGZ protein to bind to chromatin.
Diagnostic methods
Diagnosis is usually made by gene panels or exome/genome sequencing in the absence of distinctive features.
Differential diagnosis
The differential diagnosis includes numerous syndromes with developmental disorders as a feature.
Antenatal diagnosis
Prenatal diagnosis can be considered in cases with an affected parent with a 50% recurrence risk, and in couples with a de novo mutation in a first child for a 1% recurrence risk limited to the risk of germline mosaicism.
Genetic counseling
The disorder usually occurs sporadically due to de novo mutations in POGZ. The pattern of inheritance is autosomal dominant. Genetic counseling should be offered to affected individuals informing them of that there is a 50% risk of transmission to offspring, at each pregnancy. In couples with a de novo mutation in a first child, the recurrence risk is 1% due to the possibility of germline mosaicism.
Management and treatment
Following the initial diagnosis, a comprehensive physical and neurologic examination, genetics consultation, and developmental/behavioral evaluation should be completed if they have not already been done. Careful neuropsychological evaluation should include intellectual quotient with or without verbal working memory, speed of treatment, attention, divided attention, planning and cognitive flexibility, theory of mind, communication, and executive function. Autism evaluation can be proposed in patients with suspicion of autism spectrum disorder. Follow-up of children by a developmental pediatrician, neurologist, or psychiatrist is required in order to propose appropriate therapies (e.g. physical therapy, occupational therapy, speech therapy, behavioral therapy) and individualized education plans. Methylphenidate can be proposed in patients with attention deficit disorders.
Prognosis
There is currently no data on life expectancy but there is no known complication that could lead to early death. The quality of life and functional consequences are variable, and are highly dependent of the severity of neuropsychological problems and the timing of therapeutic management and education plans. Some individuals are able to live independently whilst others will require significant support.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Laurence OLIVIER-FAIVRE | ITHACA*

                                * European Reference Network


A rare bacterial infectious disease characterized by severe coughing paroxysms with inspiratory whooping and posttussive vomiting, caused by infection with Bordetella pertussis. After a variable incubation time, the clinical course progresses through a catarrhal stage with sore throat, nasal congestion, rhinorrhea, and mild progressive dry cough, a paroxysmal stage with the typical paroxysmal coughing, and finally convalescence. Disease duration is usually 2-3 months, often with milder presentation in adolescents and adults than in infants and children.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by marked prenatal and postnatal growth retardation, decreased subcutaneous fat, hypotrichosis, relative macrocephaly and an unusual face. Mild to moderate intellectual disability is common.

Summary:
Epidemiology
More than 30 patients have been reported.
Clinical description
Facial characteristics include triangular face with a relatively large skull, large anterior fontanelle, prominent veins especially on the scalp, sparse scalp hair, decreased eyebrows and eyelashes, small mouth, and micrognathia. Natal teeth represent a common, but variable finding. The clinical spectrum is broad but intrauterine growth retardation and decreased subcutaneous fat have been reported as cardinal features. Mild to moderate intellectual disability is common. In survivors, a progressive ataxia and tremor develops later on. The syndrome is usually lethal in the first year of life but, on rare occasions, patients have survived into adulthood.
Etiology
The syndrome is caused by bi-allelic variants in POLR3A located at 10q22.3, which encodes a subunit of RNA polymerase III. The syndrome is allelic with 4H leukodystrophy and adolescent-onset progressive spastic ataxia.
Diagnostic methods
The diagnosis can be suspected by the clinical presentation and confirmed by molecular genetic testing.
Differential diagnosis
The syndrome can resemble the allelic conditions 4H leukodystrophy and adolescent-onset progressive spastic ataxia, and may also resemble endosteal sclerosis-cerebellar hypoplasia syndrome which is caused by variants in POLR3B. Other entities to be considered are Hutchinson-Gilford progeria syndrome, Nestor-Guillermo progeria syndrome, Fontaine syndrome, SHORT syndrome, and Marfan syndrome lipodystrophy type.
Antenatal diagnosis
Reliable prenatal diagnosis is possible if a pathogenic variant has previously identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
No specific treatment is possible. General supportive care including help in coping with the progressive nature of the disorder is indicated.
Prognosis
Many reported patients died in the first year of life; however, survival into adulthood has also been reported. Survival beyond infancy and childhood is likely possible nowadays using careful, supportive care.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM | ITHACA*

                                * European Reference Network


A rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by short stature, hypertrichosis (most commonly of the back or elbow regions), facial dysmorphism, behavioral problems, developmental delay and, most commonly, mild to moderate intellectual disability.

Summary:
Epidemiology
The estimated prevalence, based on germline mutation rates, is 1/25,000 -40,000; although this may be an underestimate due to clinical misdiagnosis with other disorders such as Kabuki syndrome and Rubinstein-Taybi syndrome as well as a subgroup of patients that have only slight or even no apparent developmental delay and therefore often do not undergo genetic evaluation.
Clinical description
Wiedemann-Steiner syndrome (WSS) has a variable clinical phenotype presenting rarely in the prenatal period and more commonly neonatally or in infancy or childhood. Many infants with WSS have hypotonia and some degree of feeding problems, which may require tube feeding. Constipation also often starts from a young age and early eruption of teeth is typical. Hypertrichosis (often on the back and/or cubiti) can be already present in infancy, but can also develop in childhood. Children often have telecanthus, long/dense eyelashes and vertically narrow palpebral fissures, as well as other dysmorphic features. Short stature or relative short stature compared to target height is often present and most commonly develops during the first year of life. Some degree of developmental delay/intellectual disability, usually mild to moderate, is often present, although it can range from very mild to severe. Behavioral problems are common and include features of autism and attention deficit and hyperactivity disorder. Anxiety issues seem to play an increased role with advancing age. Less common features include congenital cardiac abnormalities (usually minor, such as persistent ductus arteriosus), urogenital abnormalities, skeletal abnormalities (mostly of the cervical vertebrae), dental abnormalities and small puffy hands and feet. A minority of individuals have seizures, which are more commonly observed in combination with severe developmental delay/intellectual disability. Also tethered cord, chiari malformation, and dysmotility of the gut are sometimes present. Growth hormone deficiency and immune deficiency (hypogammaglobulinemia) have been reported in some patients.
Etiology
WSS is caused by variants in the KMT2A gene (11q23.3). This gene is involved in the regulation of many other genes in the genome.
Diagnostic methods
Diagnostic criteria for WSS have not been established. The diagnosis is usually made by DNA-testing. If a mutation is not identified a diagnosis can be suspected by a combination of clinical symptoms and methylation profile (episignature).
Differential diagnosis
The differential diagnosis includes Kabuki syndrome, Coffin-Siris syndrome, Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, and non-syndromic intellectual disability.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disorder is autosomal dominant; whilst the large majority of cases occur de novo, genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Ultrasound of the urinary tract and heart and immunologic screening (immunoglobulins) should be considered in all pediatric patients. Upon indication, cervical X-rays and imaging of the cerebrum or spinal cord can be considered. Growth hormone therapy is indicated for patients with a growth hormone deficiency and is considered in some countries in WSS patients with short stature, although based on very limited evidence.
Prognosis
There is currently no evidence that life expectancy of individuals with WSS is shortened for the majority of individuals with the disorder. Most individuals have mild to moderate intellectual disability.

                            Last update:
                            August 2021

                            - Expert reviewer(s):
                            Pr Hans BJORNSSON  - Dr Floor DUIJKERS | ITHACA* - Dr Wendy JONES

                                * European Reference Network


A form of amyloidosis affecting patients with chronic kidney disease (CKD), on long term dialysis characterized by the accumulation of amyloid fibrils consisting of beta 2 microglobulin (β2M) deposits in the musculoskeletal system leading to carpal tunnel syndrome (CTS), chronic arthropathy, cystic bone lesions, destructive osteoarthropathy, and pathologic fractures.


A common form of systemic amyloidosis characterized by deposition of wild type transthyretin predominantly in the heart and the soft tissues (mainly the carpal tunnel region, lumbar canal and tendons).

Summary:
Epidemiology
The prevalence of wild type ATTR amyloidosis (ATTRwt amyloidosis) is estimated, on average, at 1/5,800 worldwide. In autopsy studies, fibrillar deposits of transthyretin were found in the heart of 25% of elderly people. Many recent reports evaluated the incidence of this disease in patients with heart failure and preserved ejection fraction. In this subset, the incidence could rise to 13% of cases. The disease is more frequent in males.
Clinical description
The disease onset is generally after the age of 60. The clinical picture is dominated by manifestations of cardiac failure as shortness of breath, leg swelling, fatigue, nausea and an irregular heartbeat or palpitations. Progressive renal failure may also occur during the disease history. In some cases, history of carpal tunnel syndrome or lumbar canal stenosis may precede the cardiac failure symptoms by 8-10 years.
Etiology
ATTRwt amyloidosis is caused by the dissociation of transthyretin (TTR) from tetramers to monomers, which leads to misfolding and aggregation as amyloid fibrils in the heart. Amyloid deposits can infiltrate any cardiac tissue including the conduction system, the myocardium and the vessels and it can translate in severe diastolic or systolic dysfunction.
Diagnostic methods
Suspicion of ATTRwt amyloidosis is generally raised by echocardiogram or cardiac magnetic resonance (CMR). Confirmation of diagnosis requires scintigraphy with bone radiotracers, that show increased myocardial and decreased bone uptake of the radiolabeled drug. DNA analysis is also required in order to exclude inherited forms of cardiac ATTR. In patients with a concomitant monoclonal gammopathy or an abnormal serum free light chain ratio, demonstration and typing of amyloid deposits is mandatory. Abdominal fat pad aspirate is non-invasive but has relatively low diagnostic sensitivity in ATTRwt. Endomyocardial biopsy can be considered in selected cases. The severity of the disease should be graded. The combination of cardiac biomarkers, N-terminal pro natriuretic peptide type B (NT-proBNP) and troponin, or NT-proBNP and the estimated glomerular filtration rate (eGFR), accurately predict the prognosis of this disease at the time of diagnosis.
Differential diagnosis
Differential diagnosis includes other forms of cardiac amyloidosis (light chain, AL and mutated forms of ATTRv) and other types of cardiomyopathy.
Management and treatment
Currently, the goal of treatment is to manage cardiac dysfunction in order to reduce the burden of symptoms. Treatment of heart failure based on diuretics, has a central role. The only specific approved drug for the treatment of ATTRwt is tafamidis which stabilizes TTR proteins, reduces the misfolding and accumulation of amyloid deposits in tissue, and thereby slows progression of heart failure. Many other disease specific therapeutic agents (other TTR stabilizers, TTR gene silencers and amyloid fibrils degraders) are under investigation in clinical trials.
Prognosis
Natural history of the disease is characterized by a slow but inevitable progression of heart failure. The severity of cardiac dysfunction, as assessed by cardiac biomarkers and estimated glomerular filtration rate, is the major prognostic determinant. The impact of the use of specific disease modifier drugs in the real-world setting is still under investigation but it will probably change the course of the disease in the upcoming future.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Pr Giovanni PALLADINI | EuroBloodNet*

                                * European Reference Network


Wildervanck syndrome is characterized by the triad of cervical vertebral fusion (Klippel-Feil anomaly, see this term), bilateral abducens palsy with retracted eyes (Duane syndrome, see this term) and congenital perceptive deafness.

Summary:
Epidemiology
It has been described in one family with affected members through 5 generations, almost exclusively females. Single additional sporadic cases have been reported.
Clinical description
Bilateral lens subluxation, facial paralysis, atrial septal defect, scoliosis, cholelithiasis have been found occasionally.
Etiology
The causative gene has not yet been identified.
Genetic counseling
Multifactorial inheritance is likely; sex-linked dominance with lethality in the hemizygous male has been discussed.

                            Last update:
                            November 2009


A rare genetic multisystemic neurodevelopmental disorder characterized by a distinct facial appearance, cardiac anomalies (most frequently supravalvular aortic stenosis), cognitive and developmental abnormalities, and connective tissue abnormalities (e.g., joint laxity). Facial dysmorphism is characterized by a broad forehead, bitemporal narrowing, periorbital fullness, stellate and/or lacy iris pattern, short upturned nose with bulbous tip, long philtrum, wide mouth, full lips and mild micrognathia.

Summary:
Epidemiology
Prevalence is approximately 1/7,500. There is no difference between the sexes.
Clinical description
All individuals have facial dysmorphism; in addition to the characteristic features, young children have epicanthal folds, full cheeks, a flat profile and small, widely spaced teeth. Older children and adults often have a narrow face and long neck. The majority of patients (80%) suffer from cardiovascular disease, primarily stenosis of the medium and large arteries (supravalvular aortic stenosis (70%), hypertension (50%), and degeneration of aortic and/or mitral-valve leaflets). Developmental milestones are delayed. A relative strength in language and verbal short-term memory, and a significant weakness in visuospatial construction is characteristic. Intellectual disability is common (75%), and a characteristic cognitive profile with an overly friendly and social personality with enjoyment of music but hypersensitivity to sound is characteristic (90%). Emotional dysregulation is common and many patients (50%) require pharmacologic treatment for anxiety and/or attention deficit hyperactivity disorder. Endocrine abnormalities include hypercalcemia (15-45%), impaired glucose tolerance/type 2 diabetes mellitus (DM), obesity in adolescents/adults, subclinical hypothyroidism (15-30%), and osteopenia or osteoporosis (50%). Other problems include axial hypotonia, peripheral hypertonia with increased deep tendon reflexes in the lower extremities, ataxia and tremor. Growth in children is approximately 75% of normal growth rate. Young children have joint laxity; joint contractures occur in older childredults leading to an awkward gait. Lordosis, kyphosis and scoliosis are common. Other common problems include ocular, auditory and dental anomalies, sleep disorders, feeding difficulties, gastrointestinal problems, bladder diverticula, urinary tract malformation, urinary infection and enuresis.
Etiology
Williams syndrome (WS) is caused by a microdeletion on chromosome 7q11.23, a region containing 26 to 28 genes including ELN.
Diagnostic methods
Diagnosis is based on phenotype and genetic testing (fluorescence in situ hybridization (FISH) or chromosome microarray).
Differential diagnosis
The primary differential diagnosis is familial supravalvular aortic stenosis.
Genetic counseling
Genetic counselling should be provided to affected families. Most cases arise de novo, and thus the recurrence risk is low (<1%). Affected individuals have a 50% risk of transmitting the deletion to offspring. A specific inversion polymorphism in the area may increase the risk of having a child with WS.
Management and treatment
A lifelong multidisciplinary approach involving medical monitoring, anticipatory guidance, direct therapies, pharmacotherapy, surgery, and adaptive changes is necessary. Close cardiac follow-up during the first year of life, and close monitoring of serum calcium during the first 2 years of life is recommended, as well as careful pre- and postoperative planning due to increased risk of cardiovascular complications during surgery. Children should be referred to an early intervention program for physical, occupational and speech therapy. Information, education and support groups are recommended for affected patients, families and caregivers.
Prognosis
A formal assessment of life expectancy is lacking. Cardiovascular complications are the major cause of death. Cardiovascular stenoses may progress, especially during the first 5 years of life. Peripheral pulmonary stenoses often resolves spontaneously. Most individuals will require lifelong supervision at both their home and their workplace.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Pernille GREGERSEN | ITHACA* - Dr Mette HANDRUP | ITHACA* - Dr Anne LEEGAARD | ITHACA*

                                * European Reference Network


A rare, respiratory malformation characterized by defective or completely absent bronchial wall cartilage in subsegmental bronchi, leading to distal airway collapse and contributing to the formation of bronchiectasis. The defect is mostly present between the fourth and sixth order bronchial divisions. Clinical manifestation includes recurrent pneumonia, coughing and wheezing.


A rare genetic disorder of copper metabolism presenting with non-specific hepatic, neurologic, psychiatric or ophthalmologic manifestations due to impaired biliary copper excretion and consecutive excessive copper deposition in the body.

Summary:
Epidemiology
The estimated prevalence at birth ranges between 1/30,000-110,000 worldwide but may be higher in isolated populations.
Clinical description
The clinical spectrum is very wide, even within affected families. Likewise, age of onset is highly variable. Some patients remain asymptomatic for decades while few present symptoms before age 3 to 5. The disease can be observed in children after 3 years and most cases develop by 40 years of age. Late-onset cases after the fifth decade of life have also been described. Clinical presentation depends on gender and age. In children, at an average age of 10 years, hepatic manifestations typically prevail, most often commencing with liver damage. In general, hepatic manifestations (hepatomegaly, subacute or chronic hepatitis, acute liver failure or cirrhosis with portal hypertension) commonly precedes neurologic symptoms. Neurological manifestations (dystonia, intention tremor, dysarthria, coordination difficulties, chorea, choreoathetosis, and gait disorders) can be found in conjunction with hepatic symptoms or might also be the first clinical symptoms. Isolated psychiatric disorders (depression, phobias, compulsive behavior, personality changes, aggressiveness, or emotional instability) are rare and more commonly observed in conjunction with hepatic or neurologic disease. A wide range of other manifestations may also be present in affected patients: acute hemolytic episodes, delayed puberty, amenorrhea, repetitive miscarriage, Kayser-Fleischer rings due to copper deposits in the Descemet membrane, bone pain, arthralgia and osteoporosis, arrythmia, myocardiopathy, hematuria, nephrotic syndrome and renal lithiasis. Hepatocellular carcinoma has been reported in rare cases.
Etiology
The disease is due to chronic copper toxicosis, caused by pathogenic ATP7B (13q14.3) variants which leads to impaired copper elimination and subsequent accumulation in body tissues, particularly in the liver initially and then the brain and other organs.
Diagnostic methods
The variable presentation (hepatic, neurologic, psychiatric) complicates diagnosis which is based primarily on the combination of clinical features, and abnormal laboratory tests (elevated liver enzymes, thrombocytopenia, low serum ceruloplasmin, elevated urinary copper excretion). Liver biopsy may be performed to demonstrate high copper levels. Evaluation of liver copper from biopsies can be helpful. Diagnostic scoring system is commonly applied to establish diagnosis, still the diagnostic approach should start with ceruloplasmin and urinary copper excretion evaluation. Molecular genetic testing most often confirms the diagnosis in 98% of cases. Family screening identifies 20% of cases.
Differential diagnosis
For the liver presentation, the differential diagnosis includes acute or chronic hepatopathy (viral or autoimmune hepatitis, non-alcoholic steatohepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and alpha-1-antitrypsin); regarding the neurological presentation, it includes essential tremor, early onset Parkinson disease, and dystonia.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples if both individuals are carriers of a disease-causing mutation, informing them of the 25% risk of having an affected child at each pregnancy and the existence of an effective treatment.
Management and treatment
There is currently no cure for Wilson disease. The main aim of current treatment is to establish a negative copper balance with the life-long administration of chelating agents (D-penicillamine, trientine salts) or zinc salt. Treatment helps to improve the manifestations of the disease over time, and its effectiveness depends on strict adherence to it throughout life. Restriction of copper-rich foods may be beneficial. Liver transplantation is the recommended therapy in cases of acute liver failure with encephalopathy or decompensated cirrhosis despite drug therapy.
Prognosis
The prognosis is dependent on timely diagnosis and initiation of treatment, and treatment compliance. If left untreated, the disease is progressive with a severe, life-threatening course but with the correct treatment, long-term prognosis is very good.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Edouardo COUCHONNAL | RARE-LIVER* - Pr Dominique DEBRAY  - Pr Alain LACHAUX | RARE-LIVER* - Dr Aurélia POUJOIS | MetabERN* - Dr Thomas Damgaard SANDAHL | RARE-LIVER* - Pr Piotr SOCHA | RARE-LIVER* - Pr H.J. [Henkjan] VERKADE | RARE-LIVER* - Pr Karl Heinz WEISS | RARE-LIVER*

                                * European Reference Network


Wilson-Turner syndrome (WTS) is a very rare X-linked multisystem genetic disease characterized by intellectual disability, truncal obesity, gynecomastia, hypogonadism, dysmorphic facial features, and short stature.

Summary:
Epidemiology
Prevalence of WTS is not known. The syndrome has been described in two families to date: 14 males in the 3 most recent generations of the first family, and 7 males and 7 females in a 5-generation Dutch family.
Clinical description
Affected males were described as having severe intellectual disability, truncal obesity, gynecomastia, hypogonadism, short stature (in the second family), small hands and feet, tapering fingers and facial dysmorphism including a small head, short ears, prominent supraorbital ridges, deep-set eyes, high malae, broad nasal tip, thin upper vermillion, and retrognathia. In obligate female carriers in the second family, a milder phenotype including learning disorders and recognizable facial features was reported. The described phenotype overlaps with Börjeson-Forssman-Lehmann syndrome, a form of X-linked intellectual disability. Differences between the two described families are small, but there is a possibility that they represent different clinical entities.
Etiology
The syndrome has been linked to a mutation in the consensus donor splice site of the histonedeacetylase 8 HDAC8 gene (Xq13).
Genetic counseling
X-linked recessive transmission and X-linked dominant inheritance with absence of male-to-male transmission have been reported.

                            Last update:
                            October 2015

                            - Expert reviewer(s):
                            Dr J.K. [Hans Kristian] PLOOS VAN AMSTEL


A primary immunodeficiency disease characterized by microthrombocytopenia, eczema, infections and an increased risk for autoimmune manifestations and malignancies.

Summary:
Epidemiology
The incidence of WAS has been estimated at less than 1 in 100,000 live births. The disease almost exclusively affects males.
Clinical description
WAS usually manifests in infancy but onset may also occur during the neonatal period. In most cases the first clinical features are hemorrhagic manifestations with petechiae, bruising, purpura, epistaxis, oral bleeding, bloody diarrhea and intracranial bleeding. Acute or chronic eczema is the second characteristic finding of WAS. Due to combined immunodeficiency, most patients also have airway, gut or skin infections caused by regular or opportunistic germs. Autoimmune manifestations are seen in approximately 40% of cases and include autoimmune hemolytic anemia, neutropenia, vasculitis, inflammatory bowel disease, renal disease, and arthritis. WAS patients have a higher risk of developing tumors (mainly B-cell lymphomas) at any age.
Etiology
WAS is due to hemizygous mutations in the WAS gene (Xp11.4-p11.21), coding for the Wiskott-Aldrich syndrome protein, exclusively expressed in hematopoietic cells and having a major role in the reorganization of the actin cytoskeleton, signal transduction and apoptosis. Usually, hypomorphic mutations in the WAS gene can lead to an attenuated form of WAS called X-linked thrombocytopenia with normal platelets (XLTT; see this term), that is characterized by mild to moderate thrombocytopenia and eczema and a lower risk of autoimmunity and malignancy, but usually showing no immunodeficiency. Recently, a mutation in the WIPF1 gene (WAS/WASL interacting protein family, member 1; 2q31.2), coding for a protein that stabilizes and prevents the degradation of WASp, was also found in a patient who displayed some features of WAS.
Diagnostic methods
Diagnosis is based on family history, physical examination and laboratory investigations that reveal severe thrombocytopenia with reduced platelet size with a usually normal number of megakaryocytes, as well as altered antibody production (mainly antipolysaccharidic antibodies). Absent or decreased WAS protein levels and genetic testing confirm the diagnosis.
Differential diagnosis
Main differential diagnosis is acute or chronic idiopathic thrombocytopenia (ITP) or platelet alloimmunization in neonates.
Antenatal diagnosis
Prenatal diagnosis is feasible in male fetuses when the causal mutation in the family is known.
Genetic counseling
WAS is an X-linked recessive disease. Carrier women have a 50% risk of transmitting the disease to their male progeny. Some de novo mutations might also occur.
Management and treatment
The only curative treatment to date is hematopoietic stem cell transplantation (HSCT), performed as soon as possible with the best matched HLA donor. In young patients lacking a HLA matched donor, HSCT with a haploidentical donor can lead to a favorable outcome. Gene therapy, still experimental to date, may be a promising approach for patients lacking a suitable donor. Immunoglobulin replacement therapy and oral antibiotics prevent infections. Severe eczema requires treatment with topical or short-term systemic steroids. Treatments that could weaken the immune system (steroids, splenectomy, immunosuppressive agents) should be used with the highest caution by trained medical staff. Agonists of the thrombopoietin receptors (such as romiplostim and eltrombopag) can be used to increase the platelet count in severe refractory thrombocytopenia cases that are awaiting HSCT or gene therapy.
Prognosis
HSCT leads to an 80% survival rate, but when no donor is available, the overall prognosis is poor and life expectancy is reduced, especially when malignancy occurs.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                            Pr Alain FISCHER  - Dr Nizar MAHLAOUI


A rare genetic neurodevelopmental syndrome characterized by mild intellectual disability, developmental delay, dysmorphic facial features, growth- and feeding problems, hypotonia, epilepsy, behavioral problems and a variety of congenital abnormalities.

Summary:
Epidemiology
Approximately 40 individuals with mutations in SIN3A have been reported. Males and females are equally affected.
Clinical description
Individuals may present with growth or feeding difficulties, developmental delay and/or intellectual disability. Overall intellectual disability is mild (no cognitive impairment in 25%). Intelligence testing typically shows a disharmonic profile favoring verbal IQ. Facial features include a tall, broad forehead, down-slanting palpebral fissures, triangular face with a pointed chin and a thin upper lip. Half of the patients show epilepsy and/or hypotonia. A third have a psychiatric or behavioral condition, including attention deficit and hyperactivity disorder, autism spectrum disorder, aggressive behavior, obsessive compulsory disorder, depression, psychosis, anxiety and schizoaffective disorder. Other reported manifestations are microcephaly, short stature, palatal defect, hearing loss, ocular abnormalities, and hyperlaxity. Brain abnormalities including ventriculomegaly, anomalies of the corpus callosum, cerebellar atrophy, or Chiari 1 malformation are present in a minority. In a minority of patients, congenital anomalies such as pelvic kidney, atrial/ventricular septal defects (ASD/VSD), cystocele, urethrocele, and thickened aortic valve may occur. Individuals with 15q24 microdeletion syndrome have a more heterogeneous phenotype with moderate to severe intellectual disability and additional features depending on the other genes involved in the deletion.
Etiology
The disorder is either caused by mutations in Switch-insensitive 3 transcription regulator family member A (SIN3A; 15q24.2) or microdeletions, of various sizes, in the chromosome region 15q24 (15q24 microdeletion syndrome). The microdeletions often, but not always, encompass SIN3A.
Diagnostic methods
Most cases will be identified by unbiased genetic testing including chromosomal microarray, intellectual disability gene panels, whole exome or whole genome sequencing. Targeted genetic testing is possible.
Differential diagnosis
Most cases are identified using an unbiased diagnostic approach for syndromic forms of neurodevelopmental delay or intellectual disability.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling should be offered to parents of affected individuals. The majority of cases are sporadic and thus in these cases the sibling recurrence risk is low. If one of the parents is affected, recurrence risk is 50%.
Management and treatment
A multidisciplinary team approach should be considered including a pediatrician, clinical geneticist, and psychiatrist. Referral to other specialists (e.g. neurologist, ophthalmologist) is indicated when specific problems are suspected. Development should be closely monitored and physical and speech therapy should be considered. Early intervention for psychiatric or behavioral conditions is important to ensure optimal treatment and outcome. Clinicians should be aware that affected individuals will likely have a disharmonic intelligence profile; this easily leads to overestimating of the self-management capabilities of patients. Screening of congenital defects (pelvic kidney, ASD/VSD, cystocele, urethrocele, thickened aortic valve) is recommended after diagnosis. Imaging (e.g MRI) should not be performed routinely, but considered on clinical indication, for instance in the occurrence of seizures.
Prognosis
There is insufficient longitudinal follow-up data to determine life expectancy, although survival into adulthood is typical. Individuals will likely require some degree of support throughout life. Quality of life is greatly influenced by the occurrence of psychiatric and/or neurological conditions.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Meena BALASUBRAMANIAN  - Pr T. [Tjitske] KLEEFSTRA | ITHACA* - Dr Jet VAN DER SPEK

                                * European Reference Network


Wolcott-Rallison syndrome (WRS) is a very rare genetic disease, characterized by permanent neonatal diabetes mellitus (PNDM) with multiple epiphyseal dysplasia and other clinical manifestations, including recurrent episodes of acute liver failure.

Summary:
Epidemiology
Fewer than 60 cases have been reported to date. Most patients are from consanguineous families. Prevalence may therefore vary significantly between countries.WRS may be underdiagnosed because of early death before diagnosis.
Clinical description
Diabetes occurs early, generally before six months of age, is permanent and insulin-dependent from the onset. Skeletal dysplasia generally manifests within the 1st or 2nd year of life, and is associated with short stature (dwarfism with short trunk). Deficient mineralization or dysplastic changes, affecting the long bones, pelvis and vertebrae, but usually not the skull, may be seen on radiography as early as diabetes onset. Hepatic dysfunction is a 3rd characteristic feature and the most life-threatening complication, and manifests by elevated hepatic enzymes, liver enlargement and recurrent acute liver failure. Other manifestations vary between patients in type and severity and include renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Clinical course is variable, including within the same sibship.
Etiology
WRS is caused by mutations in the EIF2AK3 gene encoding eukaryotic translation initiation factor 2-alpha kinase 3 (PKR-like endoplasmic reticulum kinase; PERK), which plays a key role in translation control during unfolded protein response.
Diagnostic methods
Diagnosis should be suspected in any infant with permanent neonatal diabetes and skeletal dysplasia and/or episodes of acute liver failure, and family history of consanguinity and/or neonatal diabetes. Diabetes is not autoimmune as shown by absence of antibodies specific for type 1 diabetes. Radiographs show early signs of multiple epiphyseal dysplasia and deficient mineralization. Molecular genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis is based on clinical presentation and, ultimately, genetic testing. That of NDM (see this term) includes transient NDM, and other PNDMs that may be isolated or syndromic. Differential diagnosis of skeletal dysplasia includes other spondylo-epiphyseal dysplasias such as mucopolysaccharidoses (see these terms) where diabetes may occur independently at an older age.
Antenatal diagnosis
Antenatal diagnosis should be offered to parents of a WRS patient with confirmed EIF2AK3 mutation.
Genetic counseling
Inheritance is autosomal recessive and genetic counseling is possible.
Management and treatment
Close therapeutic monitoring of diabetes should be considered and treatment with an insulin pump is recommended, especially in the first months of life, due to the risk of acute episodes of hypoglycemia. At any age, hypoglycemia should be prevented because the disease can decompensate, even if this requires maintaining the level of glucose above the objectives generally recommended in diabetic children. General anesthesia increases the risk of acute aggravation, because of particular sensitivity of patients to anesthetics, and should be avoided wherever possible. Any drug or vaccine not strictly necessary should be limited, due to the risk of triggering secondary liver and/or kidney failure.
Prognosis
Prognosis is poor and most patients die at a young age from multiple-organ failure with predominant liver and renal dysfunction.

                            Last update:
                            February 2011

                            - Expert reviewer(s):
                            Dr Cécile JULIER  - Pr Marc NICOLINO


A developmental disorder characterized by typical craniofacial features, prenatal and postnatal growth impairment, intellectual disability, severe delayed psychomotor development, seizures, and hypotonia.

Summary:
Epidemiology
The disease has an estimated birth prevalence of 1/20,000 - 50,000. Wolf-Hirschhorn syndrome (WHS) occurs more frequently in females than in males (2:1).
Clinical description
Marked intra-uterine growth retardation and slow, postnatal weight gain are observed. The distinctive facies is characterized by a broad nasal bridge continuing to the forehead (which is visible more clearly before puberty), microcephaly, high forehead with prominent glabella, high-arched eyebrows, hypertelorism, epicanthus, poorly formed ears with pits/tags, short philtrum, downturned mouth, micrognathia, and, in some cases, cleft lip/palate. Skeletal anomalies include kyphosis or scoliosis with malformed vertebral bodies, accessory or fused ribs, clubfeet and split hand. Patients suffer from hypotonia with muscle underdevelopment, possibly causing frequent feeding difficulties and failure to thrive. Developmental delay is severe: most children do not achieve sphincter control, self-feeding or dressing, and less than 50% walk, with or without support. Intellectual disability is moderate to severe, rarely mild. Speech is limited to guttural or disyllabic sounds, although a few patients achieve simple sentences. Seizure onset is frequently observed between the neonatal period and 36 months (in up to 95% of patients); seizure type varies and is often triggered by fever. Status epilepticus occurs in half of patients, and children may develop atypical absences (over 30%). Seizures stop in childhood in approximately half of patients. Most patients have structural central nervous system defects, mainly including thinning of the corpus callosum. Other frequent anomalies include congenital heart defects (50%), ophthalmologic, auditory and dental anomalies. Patients may have recurrent respiratory tract infections and otitis media, due to antibodies deficiency (IgA or IgG2 subclass). Urinary tract malformations have been described, and half of male patients have hypospadias and cryptorchidism.
Etiology
WHS is due to a deletion in the short arm of chromosome 4 with contribution of genes within a 1.5-1.6 Mb region in the ~0.4-1.9 Mb terminal of 4p16.3. Deletions greater than 3-5 Mb seem to be associated with higher risk of heart defects and cleft palate.
Diagnostic methods
Diagnosis is based on physical examination and confirmed by molecular genetics or cytogenetic analysis. Fluorescence in situ hybridization (FISH), and genome-wide chromosomal microarray analysis (CMA) being the methods of choice. Electroencephalographic (EEG) investigations show typical findings in 90% of patients.
Differential diagnosis
Differential diagnosis includes many syndromes displaying growth failure, intellectual disability and/or facial dysmorphism such as Seckel, CHARGE, Smith-Lemli-Opitz, Opitz G/BBB, Williams, Rett, Angelman and Smith-Magenis syndromes.
Antenatal diagnosis
Antenatal testing is feasible when a 4p16.3 chromosome rearrangement is already identified in a family member.
Genetic counseling
Most cases are sporadic, but an unbalanced translocation may be inherited from a parent with a balanced rearrangement.
Management and treatment
Treatment is symptomatic and requires multidisciplinary management including diverse rehabilitation programs, appropriate seizure treatment (phenobarbital; valproic acid with or without ethosuccimide; levetiracetam) and feeding therapies.
Prognosis
WHS patients survive into adult life. Most individuals require close to total care; about 30% are partly independent requiring supervision on daily routines. More than 65% enjoy overall good health.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Agatino BATTAGLIA


A rare, genetic, endocrine disorder characterized by type I diabetes mellitus (DM), diabetes insipidus (DI), sensorineural deafness (D), bilateral optical atrophy (OA) and neurological signs.

Summary:
Epidemiology
Estimated prevalence of Wolfram syndrome (WS) is 1/770,000 worldwide.
Clinical description
2 types of WS may be distinguished: type 1 (WS1) and type 2 (WS2). WS1 has onset in the first decade, with DM (91% of cases) and OA (87%) manifestations. Patients present a progressive reduction of visual acuity and loss of color vision. Less frequent ocular abnormalities include abnormal papillary light reflexes, nystagmus, cataracts, pigmentary maculopathy, retinopathy (pigmentary or diabetic) and glaucoma. 50% of patients also develop DI and some degree of deafness (slowly progressive high frequency). The full phenotype spectrum is observed in 65% of cases. Additional features may include urinary tract abnormalities (hydroureter, urinary incontinence, recurrent infections), neurological involvement (ataxia, myoclonus, epilepsy, hyposmia and cognitive disability) and psychiatric manifestations (depression). Life-threatening complications, including central apnea (due to bulbar dysfunction) are frequent and may lead to recurrent aspiration pneumonia. Other reported symptoms are gastrointestinal disorders (bowel dysmotility, gastroparesis, and bowel incontinence), hypogonadism, and delay/disruption of sexual development. Patients with WS2 present early OA, DM, D, and decreased lifespan, but no DI.
Etiology
2 causative genes have been identified: WFS1 (4p16.1) and CISD2 (4q24). WFS1 encodes Wolframin, a protein localized to the endoplasmic reticulum (ER) with roles in calcium homeostasis and unfolded protein response. Mutations in WFS1 are responsible for the majority of the WS phenotypes and account for WS1. CISD2 encodes the ERIS protein, located dynamically between the ER and mitochondria outer membrane, with roles in glucose homeostasis regulation, insulin sensitivity for calcium homeostasis and autophagy. Mutations in CISD2 account for WS2.
Diagnostic methods
The clinical criteria for WS diagnosis are juvenile-onset DM and OA, family history of WS or DM and D. MRI scans show generalized brain atrophy, especially in the cerebellum, medulla, and pons; absence of signal from the posterior pituitary; and reduced signal from the optic nerve. Diagnosis is confirmed by genetic screening.
Differential diagnosis
Differential diagnosis includes mitochondrial disorders such as Maternally-inherited diabetes and deafness, Leber hereditary optic neuropathy, Mohr-Tranebjaerg syndrome, and Autosomal dominant optic atrophy plus syndrome. Other possible differential diagnoses are X-linked Charcot-Marie-Tooth disease type 5, Friedreich ataxia, Thiamine-responsive megaloblastic anemia, Bardet-Biedl and Alstrom syndromes. An autosomal dominant disorder, referred to as Wolfram-like syndrome, with DM occurring in adulthood, a juvenile onset of OA, and/or associated hearing impairment has also been described.
Antenatal diagnosis
In families with characterized causative mutations, molecular carrier detection and preimplantation or prenatal diagnosis can be performed.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling may be offered to at-risk couples carrying mutation either in WFS1 or CISD2 genes. Carrier testing may be possible when the variant associated to WFS1 poses heterozygous individuals at risk of developing low frequency D and DM.
Management and treatment
Management is supportive and includes an annual screening for DM, vision, D, urodynamic testing, nephropathy and daily insulin injections and a controlled diet to treat DM. Treatment of DI, apnea and urinary disorders (i.e. prophylactic antibiotherapy for urinary infections) is needed. Periodic screening for depression and other psychiatric symptoms is necessary to provide patients with specific medical, emotional and psychological intervention.
Prognosis
Progression of the disease to premature death is common, often by respiratory failure.

                            Last update:
                            August 2019

                            - Expert reviewer(s):
                            Dr Miguel LOPEZ DE HEREDIA


Wolfram-like syndrome is a rare endocrine disease characterized by the triad of adult-onset diabetes mellitus, progressive hearing loss (usually presenting in the first decade of life and principally of low to moderate frequencies), and/or juvenile-onset optic atrophy. Psychiatric (i.e. anxiety, depression, hallucinations) and sleep disorders, the only neurologic abnormalities observed in this disease, have been reported in rare cases. Unlike Wolfram syndrome, patients with Wolfram-like syndrome do not report endocrine or cardiac findings.


A severe form of lysosomal acid lipase deficiency characterized by rapidly progressive lipid accumulation in organs and tissues that presents in the neonatal or infantile period with massive hepatosplenomegaly, liver failure, diarrhea/steatorrhea and vomiting.

Summary:
Epidemiology
Approximately 50 cases have been reported in the literature.
Clinical description
The disease can sometimes present in the fetus (hepatomegaly, ascitis, calcified adrenal glands), but onset more typically occurs in the first weeks of life with abdominal distension and major or even massive hepatosplenomegaly (which can occur in the neonatal period) and sometimes ascites. The presence of calcified adrenal glands (as revealed by radiography), is a common and very characteristic sign. . Children present with significant digestive disorders (such as vomiting and diarrhoea with steatorrhoea), which can lead to a sudden arrest of ponderal growth and progressive psychomotor degradation in the absence of specific neurological signs. Later, severe anemia and cachexia become apparent.
Etiology
The enzymatic deficiency results from severe mutations of the acid lipase gene (LIPAor LAL), localised to 10q24-q25.
Diagnostic methods
The diagnosis can be rapidly confirmed by measuring enzymatic activity in leucocytes or dried blood spots , revealing an almost total deficiency.
Differential diagnosis
Differential diagnosis includes familial hemophagocytic histiocytosis and other phagocytic syndromes, Gaucher disease type II, Niemann-Pick disease type A, and malignancies such as leukemia or neuroblastoma.
Antenatal diagnosis
Prenatal diagnosis can be performed by measuring enzymatic activity or by mutational analysis of chorionic villi or amniocytes.
Genetic counseling
The disease follows an autosomal recessive pattern of inheritance.
Management and treatment
Enzyme replacement therapy with sebelipase lipase is available in the US and the European union and has been shown to prolong survival. Very early bone marrow or cord blood transplant has also been used and has provided some benefit in a limited number of cases.
Prognosis
In the absence of definitive therapy, few children survive beyond one year of age. Enzyme replacement therapy, if started in a timely fashion, may prolong survival but the long term impact remains unknown.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Barbara BURTON


Woodhouse-Sakati syndrome is a multisystemic disorder characterized by hypogonadism, alopecia, diabetes mellitus, intellectual deficit and extrapyramidal signs with choreoathetoid movements and dystonia.

Summary:
Epidemiology
Approximately 30 patients from consanguineous Middle Eastern families, together with one Caucasian woman and three sibs from an Indian family, have been reported so far.
Clinical description
The onset is usually in adolescence. Additional manifestations may include sensorineural deafness, flattened T waves on ECG, seizures, sensory polyneuropathy, dysarthria, various craniofacial abnormalities (high forehead, flat occiput, triangular face, prominent nasal root, hypertelorism, and down-slanting palpebral fissures), scoliosis, hyperreflexia, and camptodactyly.
Etiology
Woodhouse-Sakati syndrome is associated with mutations in the DCAF17 gene (2q31.1), encoding a nucleolar protein of unknown function.
Genetic counseling
The disease is transmitted in an autosomal recessive manner.

                            Last update:
                            May 2009


Woolly hair nevus (WHN) is a rare non-familial hair anomaly characterized by kinky, tightly coiled, and hypopigmented fine hair with an average diameter of 0.5 cm, noted, since birth or during the first two years of life, in a localized circumscribed distribution on the scalp. Occassionally, WHN grows in areas observed to be alopecic in the neonatal period. WHN can be associated with features like ocular defects (persistent pupillary membrane, retinal defects), precocious puberty, and epidermal nevi.


Woolly hair-palmoplantar keratoderma syndrome is a very rare, hereditary epidermal disorder characterized by hypotrichosis/woolly scalp hair, sparse body hair, eyelashes and eyebrows, leukonychia, and striate palmoplantar keratoderma (more severe on the soles than the palms), which progressively worsens with age. Pseudo ainhum of the fifth toes was also reported. Although woolly hair-palmoplantar keratoderma syndrome shares clinical similarities with both Naxos disease and Carvajal syndrome, cardiomyopathy is notably absent.


A rare congenital skin disease defined as an abnormality of the structure of the scalp hair and characterized by extreme kinkiness of the hair.

Summary:
Epidemiology
Prevalence of woolly hair is unknown.
Clinical description
Woolly hair can either be present at birth or appear in the first months of life. The curls, with an average diameter of 0.5 cm, lie closely together and usually make the hair difficult to comb; in addition, the hair may be more fragile than usual. The hair growth rate is usually normal but the anagen phase may be truncated, with the result that the hair does not grow to be long. Woolly hair either shows a generalized distribution affecting the entire scalp or a localized circumscribed distribution in the form of a woolly hair nevus. A diffuse partial form, manifesting during adolescence and adulthood, have also been described. In many cases, woolly hair is associated with hypotrichosis. Whilst wooly hair may occur as an isolated finding, it is important to exclude manifestations that occur in syndromic forms such as dilated cardiomyopathy and palmoplantar keratoderma (Carvajal syndrome), arrhythmogenic right ventricular cardiomyopathy and palmoplantar keratoderma (Naxos disease), or with growth failure and neurological symptoms (Menkes disease).
Etiology
Isolated forms are mostly due to homozygous or sometimes compound heterozygous mutations in the genes lipase H (LIPH, 3q27.2) and lysophosphatidic acid receptor 6 (LPAR6, 13q14.2), that act along a common pathway which plays an important role in the control of hair growth as well as hair texture. In only very few patients, heterozygous mutations have been reported in two keratin genes, namely KRT74 (12q13.13) and KRT71 (12q13.13). Mutations have also been reported in KRT25 (17q21.2 ). Recently, a new gene locus was reported for woolly hair on chromosome 4q35.1-q35.2 with a potential disease gene with one affected family only. The etiology of diffuse partial woolly hair and of sporadically occurring woolly hair nevi is unknown.
Diagnostic methods
A thorough dermatological examination with an evaluation of the entire integument should be performed and may also identify any associated manifestations. The examination of the hair shafts by light and electron microscopy reveals an elliptical cross section, variations in caliber, axis rotation and kinked formation, as well as non-homogeneous keratinization. In some cases trichorrexis nodosa is evident. If necessary, the anagen/catagen ratio can be determined using a trichogram. In cases of diffuse partial woolly hair, an increase in intermediate follicles can be detected histopathologically.
Differential diagnosis
Differential diagnosis includes acquired progressive curling of the hair, allotrichia circumscripta symmetrica, acquired partial kinky hair and drug-induced kinky hair. Syndromes with woolly hair should also be excluded, such as Naxos disease, Carvajal syndrome, Woolly hair-hypotrichosis-everted lower lip-outstanding ears syndrome, woolly-hair-palmoplantar keratoderma syndrome, and skin fragility-woolly hair-palmoplantar keratoderma syndrome.
Genetic counseling
Generalized forms due to KRT74 and KRT71 mutations are autosomal dominant, and forms due to LIPH and LPAR6 mutations are autosomal recessive. Sporadic forms may also occur. Follicular mosaicism is likely, while an autosomal dominant transmission has also been discussed for diffuse partial woolly hair.
Management and treatment
No treatment is currently available. Depending on their size and location, woolly hair nevi can be excised. Harsh physical and chemical cosmetic treatments should be avoided. If the presence of a syndrome is suspected, an extensive internal investigation, with a detailed cardiological diagnostic examination, is necessary.
Prognosis
Woolly hair is most pronounced during childhood; the manifestations often become less severe in adulthood.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Pr Regina BETZ  - Pr Ulrike BLUME-PEYTAVI


Wormian bone-multiple fractures-dentinogenesis imperfecta-skeletal dysplasia

A rare skeletal disorder characterized clinically by multiple fractures, wormian bones of the skull, dentinogenesis imperfecta and facial dysmorphism (hypertelorism, periorbital fullness). Although the signs are very similar to osteogenesis imperfecta, characteristic cortical defects in the absence of osteopenia and collagen abnormalities are considered to be distinctive. There have been no further descriptions in the literature since 1999.


Worster-Drought syndrome (WDS) is a form of cerebral palsy characterized by congenital pseudobulbar (suprabulbar) paresis manifesting as selective weakness of the lips, tongue and soft palate, dysphagia, dysphonia, drooling and jaw jerking.

Summary:
Epidemiology
Prevalence is estimated at around 1/25,000-30,000, with a male predominance (male to female sex ratio: 3:1).
Clinical description
Mean age at diagnosis is 6 years. The main clinical features are spasticity and limited movements around the mouth and throat from an early age, and brisk jaw jerks. In severe cases, the muscles of the pharynx and larynx are also involved. Epilepsy, learning difficulties and behavioral disturbances are common. Mild pyramidal tetraplegia, glue ear, recurrent respiratory infections and aspiration, and gastroesophageal reflux may be present in up to 40% of patients. WDS is associated with bilateral lesions of the corticobulbar tract. Cranial nerves VII, X, and XII are implicated.
Diagnostic methods
Diagnosis is made on the basis of patient history, clinical examination and magnetic resonance imaging studies.
Differential diagnosis
The main differential diagnosis is the bilateral perisylvian polymicrogyria (see this term) which manifests with severe epilepsy Clinical overlap of WDS with congenital bilateral perisylvian polymicrogyria and Foix-Chavany-Marie syndrome (see these terms) has been noted. Some authors propose that these three conditions represent a continuum.
Genetic counseling
Most cases are sporadic but several families with more than one affected member have been reported. Inheritance in these families appeared to follow an autosomal dominant pattern with variable expression and penetrance.
Management and treatment
Management is dependent on the degree of feeding difficulties and speech problems but should include multidisciplinary approach by a pediatrician, speech therapist and educational psychologist. Children with epilepsy are treated with antiepileptic drugs.
Prognosis
WDS has a non-progressive course. The overall prognosis is good when nutritional problems, epilepsy and respiratory complications are properly managed.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Pr Jaime CAMPOS-CASTELLÓ


Wound botulism is a rare infectious form of botulism (see this term), a rare acquired neuromuscular junction disease with descending flaccid paralysis due to botulinum neurotoxins (BoNTs), produced after infection of wounds by Clostridium botulinum.

Summary:
Epidemiology
Prevalence is unknown. So far, about 700 cases have been reported worldwide.
Clinical description
Clinical manifestations are similar to other forms of botulism (symmetrical cranial nerve palsy, followed by symmetrical descending flaccid motor paralysis) in particular those of foodborne botulism (see this term), except for the lack of gastrointestinal symptoms (nausea, vomiting, and diarrhea) and the possible presence of fever. The disease, formerly related to traumatic injury, or rarely to surgery, nowadays affects mainly intravenous drug users (IDUs), mostly adults in the fourth or fifth decade of life with a long history of use of injected (``skin popping'') or inhaled drugs and is related to contaminated material or to contaminated black tar heroin. Wound botulism is an infectious but non communicable disease. The incubation period, in case of traumatic injuries, is considered to be 7 to 14 days, but it is difficult to establish for IDUs, as they may inject drugs several times daily.
Etiology
Wound botulism is due to the colonization of a wound, boil, abscess, or inoculation site by C. botulinum spores with subsequent germination and BoNT production in vivo, at the site of infection. The toxin reaches the neuromuscular junctions through the blood stream. The reported cases are related to C.botulinum type A and type B but one case has been related to C.botulinum type E.
Diagnostic methods
Initial diagnosis of wound botulism is based on clinical suspicion in patients with a recent infected wound or history of drug use. Sometimes lesions are not apparent and the presence of deep-seated abscess or sinusitis should be considered. Definitive diagnosis requires laboratory investigations for the detection of BoNTs in serum and wounds. The detection of BoNT-producing Clostridia/i> in wound cultures is generally satisfactory for laboratory diagnosis. Analysis of stools and food may be useful to exclude other forms of botulism.
Differential diagnosis
Differential diagnosis includes myasthenia gravis, Guillain-Barré syndrome (Miller-Fisher syndrome), Lambert-Eaton syndrome, and foodborne and adult intestinal botulism (see these terms).
Management and treatment
Antitoxin therapy must be associated with supportive care in an intensive care unit (ICU). Antitoxin therapy is effective when it is administrated at the onset of symptoms. In Europe, the formulation currently available for adults is trivalent (anti A, B, E). A heptavalent (anti A to G) product is also available. In the USA, a bivalent (anti A, B) and a monovalent (anti E) antitoxin are available. Specific management of wound botulism includes surgical debridement of the wound with irrigation to remove the source of the toxin and antibiotic therapy with penicillin and metronidazole. Aminoglycoside and clindamycin should be avoided as they may exacerbate the neuromuscular blockade.
Prognosis
With appropriate intensive care, prognosis is good; death occurs in only 7% of cases and results from respiratory failure. Wound botulism may recur in IDUs.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr Lucia FENICIA


A rare cutaneous myiasis characterized by infestation of open wounds by dipterous fly larvae. Mucous membranes and body cavity openings can also be affected. The condition may be accompanied by fever, pain, and secondary infections and can lead to massive tissue destruction and even death. Predisposing factors for larval infestation are poor hygiene, advanced or very young age, alcoholism, diabetes, and vascular occlusive disease, among others.


Wrinkly skin syndrome (WSS) is characterized by wrinkling of the skin of the dorsum of the hands and feet, an increased number of palmar and plantar creases, wrinkled abdominal skin, multiple skeletal abnormalities (joint laxity and congenital hip dislocation), late closing of the anterior fontanel, microcephaly, pre- and postnatal growth retardation, developmental delay and facial dysmorphism (a broad nasal bridge, downslanting palpebral fissures and hypertelorism).

Summary:
Epidemiology
Prevalence is unknown but only around 30 cases have been reported in the literature so far.
Clinical description
Although the clinical picture is milder, WSS also shows significant overlap with classic features of ARCL2 (also known as Debré-type cutis laxa), leading to the suggestion that WSS and ARCL2 are variable manifestations of the same disorder. The clinical spectrum in WSS also closely resembles that of geroderma osteodysplastica (GO) and to some extent that of De Barsy syndrome (DBS; see these terms).
Etiology
Although the etiology in some patients remains unknown, mutations in the ATP6V0A2 gene (12q24.31) have been identified both in patients with WSS and in those with autosomal recessive cutis laxa (ARCL) type 2 (see this term). Mutations in the PYCR1 gene (17q25.3) have recently been identified in patients with phenotypes (wrinkly skin, osteopenia and progeroid features) overlapping with ARCL2, GO and DBS.
Diagnostic methods
Histological findings are not pathognomonic for WSS (elastic fiber abnormalities may be mild or nonspecific) but may allow WSS to be distinguished from ARCL2 and ARCL1 (see this term).
Genetic counseling
WSS is transmitted in an autosomal recessive manner.
Management and treatment
Treatment is symptomatic.
Prognosis
Patients with WSS syndrome have a variable outcome. The prognosis depends on the underlying mutation and appears to be most benign in children with a mutation in the ATP6V0A2 gene.

                            Last update:
                            July 2010

                            - Expert reviewer(s):
                             M GUILLARD  - Pr D.J. [Dirk] LEFEBER  - Pr Eva MORAVA-KOZICZ  - Pr R.A. [Ron] WEVERS


A rare constitutional aplastic anemia disorder characterized by severe hypo/aplastic anemia or pancytopenia associated with skeletal anomalies (such as radial/ulnar defects and hand/digit abnormalities) and an increased risk of leukemia. There have been no further descriptions in the literature since 1995.


Wyburn-Mason syndrome or Bonnet-Dechaume-Blanc syndrome is characterized by the association of arteriovenous malformations of the maxilla, retina, optic nerve, thalamus, hypothalamus and cerebral cortex.

Summary:
Epidemiology
The prevalence is not known but it is very rare: fewer than 100 cases have been reported in the literature to date. The sex ratio is even.
Clinical description
Malformations appear successively, sometimes over several tens of years. Neurological clinical signs include: progressive neurological deficits depending on the location of the malformation, epilepsy or cephalalgia. These symptoms result in venous congestion and hemorrhage. Psychomotor delay in childhood is not common. The associated maxillofacial lesions lead to asymmetries or deformations of the face, impairment of maxillofacial osseous growth and, in intraosseous maxillo-mandibular locations, serious oral hemorrhages. The visual symptoms are caused by arteriovenous malformations of the retina and depend on the size and location of malformations (retina, optical nerve, chiasma). Partial manifestations of the syndrome (incomplete spectrum) are possible.
Etiology
Wyburn-Mason syndrome is caused by an anomaly in organogenesis, however the etiology and risk factors are unknown. There are no familial forms of the syndrome. The connection between lesions of the same angio-architectural nature, but in different locations, can be explained by the regionalized origin of cells of the vascular walls in the cephalic region, and their migration. The cells of vessels in the facial, orbital, maxillary or mandibular, and encephalic areas come from three large embryonic regions. An embryonic defect in a cellular group before its migration to its final destination may `spread' vascular lesions along the route of migration. This gives rise to cerebrofacial metameric or segmental syndromes (CAMS) called CAMS1, CAMS2 and CAMS3 according to the region from which the cells depart: CAMS1 (corpus callosum, hypothalamus, olfactory tract, forehead, nose), Wyburn-Mason syndrome that has been renamed CAMS2 (cortex and diencephalon, optic chiasma, optic nerve, retina, sphenoid, maxilla, cheek) and CAMS3 (cerebellum, temporal bone, mandible).
Diagnostic methods
Magnetic resonance imaging (MRI) is the best diagnostic instrument and provides information on the extent of the anomalies. An arteriogram then allows a more detailed analysis of the angio-architecture of the lesions, revealing the absence of capillary vessels that normally connect arteries and veins. It is most often impossible to completely treat cerebral vascular malformations because of the extent and architecture of the lesions.
Management and treatment
Targeted partial treatment through the endovascular route aims to isolate the region at risk of malformation. It can be successful in dentoalveolar and cerebral locations if a particular weakness has been identified using MRI or arteriogram. Combined management with embolization and surgery is most often necessary for maxillofacial malformations.
Prognosis
The early appearance of neurological problems is an unfavorable factor for long term prognosis.

                            Last update:
                            March 2007

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


X small rings is a rare chromosome X structural anomaly, with highly variable phenotype, principally characterized by developmental delay, intellectual disability, short stature, craniofacial dysmorphism (incl. microcephaly, facial asymmetry, hypertelorism, long palpebral fissures, epicanthus, low-set or malrotated ears, broad nose with a flat nasal bridge, anteverted nares, long philtrum, thin upper lip, high arched palate, micrognathia) and skeletal anomalies (e.g. cubitus valgus, talipes equinovarus). Patients may also present heart malformations (e.g. ventricular septal defects, mitral valve stenosis), sacral dimple, soft tissue syndactyly, pigmented nevi, and seizures.