Babesiosis is an infectious disease caused by protozoa of the genus Babesia and characterized by a febrile illness and hemolytic anemia but with manifestations ranging from an asymptomatic infection to a fulminating illness that can result in death.

Summary:
Epidemiology
The worldwide prevalence is unknown but it is most frequently reported in the U.S. In 2011, 1,124 cases were reported in the U.S. with 92% of those cases occurring in northeastern and upper midwestern states. Sporadic cases have also been reported in Europe, Asia, Africa, Australia and South America.
Clinical description
Most immunocompetent patients experience mild to moderate illness or are asymptomatic. Symptoms usually begin 1-4 weeks after being bitten by an infected tick, or 1 week to 6 months after a transfusion with contaminated blood. The most common symptoms are fever (that can reach up to 40.9 °C and may be accompanied by splenomegaly), malaise and fatigue. Other common manifestations include chills, sweats, headache, myalgia, arthralgia, nonproductive cough, nausea, and anorexia. Less frequently, some may experience sore throat, photophobia, vomiting, weight loss and depression. Symptoms can last 1-2 weeks but fatigue may persist for several months. In the immunocompomised or the elderly, more severe and prolonged infections with relapses can occur that require hospital admission. B. divergens and B. duncani infections are generally severe and often occur in people who lack a spleen. Complications occur in about half of hospitalized patients and include disseminated intravascular coagulopathy and acute respiratory distress syndrome and less frequently liver, renal or congestive heart failure, coma and death.
Etiology
Babesiosis is caused by infections with one of several Babesia species that infect humans, including: B. microti (most common, in the U.S.), B. duncani, B. divergens (most common in Europe), and B. venatorum. Most patients are infected by a bite from an infected nymphal Ixodes scapularis (in the U.S), or Ixodes ricinus (in Europe) tick during early summer to late fall. The parasite can also be transmitted to humans through transfusion of contaminated blood or blood products. A few cases of transplacental transmission have been reported.
Diagnostic methods
Babesiosis should be considered in patients with an unexplained febrile illness who reside in or have recently traveled to a Babesia endemic area or who have received a blood transfusion within the previous 6 months. Laboratory tests usually reveal hemolytic anemia, thrombocytopenia and a normal or slightly decreased leukocyte count. Giemsa or Wright stains of blood smears identify the parasites within host erythrocytes that appear round, pear-shaped or oval with a blue cytoplasm with red chromatin. Polymerase chain reaction (PCR) can confirm diagnosis by detecting babesia DNA in a patient's blood. Serological testing can also be useful in confirming the diagnosis.
Differential diagnosis
Differential diagnoses include other infectious diseases such as malaria, Lyme disease, ehrlichiosis, Rocky Mountain spotted fever, typhoid (see these terms) and infectious mononucleosis.
Management and treatment
Treatment for mild to moderate babesiosis consists of the administration of antimicrobial agents, atovaquone and azithromycin, for 7-10 days. Oral quinine and intravenous clindamycin are recommended for those with a severe babesiosis, but patients must be more closely monitored due to higher frequency of adverse effects. Severe disease is treated with partial or complete exchange transfusion. Severely immunocompromised patients may require 6 weeks of antimicrobial therapy if infection persists or recurs. Preventive measures include avoidance of areas where ticks, mice and deer thrive and the use of tick checks, protective clothing and tick repellents.
Prognosis
Prognosis depends on the species involved and the health of the patient, but is excellent in most immunocompetent patients.

                            Last update:
                            October 2013

                            - Expert reviewer(s):
                            Dr Peter KRAUSE


A rare acquired skeletal muscle disease characterized by diffuse muscle infection without an intramuscular abscess. Although a wide variety of bacteria can be causative, the majority of cases are due to streptococcal infection. Signs and symptoms depend on the underlying infectious agent and include muscular pain, swelling, weakness, rash, acute rhabdomyolysis, myonecrosis, and gangrene.


Bacterial susceptibility due to TLR signaling pathway deficiency

Pyogenic bacterial infection due to MyD88 deficiency is a primary immunodeficiency characterized by increased susceptibility to pyogenic bacterial infections, including invasive pneumococcal, invasive staphylococcal and pseudomonas disease.

Summary:
Epidemiology
Prevalence is unknown. Only 24 cases have been reported.
Clinical description
The disease presents in childhood with recurrent, life-threatening, pyogenic bacterial infections caused by Streptococcus pneumoniae, Staphylococcus aureus or Pseudomonas aeruginosa. Patients are normally resistant to most other agents. This predisposition to life-threatening infections seems transient and lasts during the first 10 years of life in the cases reported so far. Acute phase responses seen in invasive infections such as elevated temperature and C-reactive protein (CrP) levels may be lower or absent.
Etiology
MyD88 deficiency, resulting from mutations in the MYD88 gene (3p22-3p21.3), generally abolishes the cytokine responses of the blood cells.
Diagnostic methods
MyD88 deficiency should be suspected in patients with recurrent pyogenic bacterial infections. Diagnosis can be suspected if whole blood cells do not produce inflammatory cytokines upon activation with IL-1beta or Toll-like receptor agonists. Diagnosis can be confirmed by observation of mutations in the MYD88 gene.
Differential diagnosis
Differential diagnoses include interleukin-1 receptor associated kinase-4 (IRAK4) deficiency (see this term), which can be ruled out by the absence of mutations in the IRAK4 gene, NF-kappaB essential modulator (NEMO) deficiency and inhibitor of NFkappaB essential modulator (IkappaB-alpha) deficiency (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible by trophoblast biopsy when the mutation is identified in the family.
Genetic counseling
Transmission is autosomal recessive and the disease has been observed in consanguineous and nonconsanguineous families. Genetic counseling is available.
Management and treatment
Treatment is based on prophylactic antibiotic therapy to prevent infections. Additional IgG substitution may be considered, in particular for patients with impaired antibody responses to polysaccharides. The most important advice for the families and physicians of MyD88-deficient patients is to initiate empiric parenteral antibiotic treatment against Streptococcus pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa, as soon as an infection is suspected or if the patient develops a moderate fever, without taking inflammatory parameters into account, as patients may die from rapid invasive bacterial infection despite appropriate prophylaxis. Secondary adaptation of antibiotic treatment should be done once the causal bacterium has been documented.
Prognosis
Prognosis in infancy and early childhood is poor, in particular if the disease is not known to parents and physicians. With appropriate prophylactic antibiotic treatment, the prognosis for most patients improves, with infections becoming less frequent with age.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Pr Jean-Laurent CASANOVA  - Pr Capucine PICARD  - Pr Horst VON BERNUTH


Bacterial toxic shock syndrome (TSS) is a potentially fatal, acute disease characterized by a sudden onset of high fever along with nausea, myalgia, vomiting and multisystem organ involvement, potentially leading to shock and death. TSS is mediated by superantigenic toxins, usually caused by an infection with Staphylococcus aureus in staphylococcal TSS (see this term) or Streptococcus pyogenes in streptococcal TSS (see this term).

Summary:
Epidemiology
The worldwide prevalence is estimated at 1/30, 000.
Clinical description
The disease affects mainly young adult women with no previous medical conditions. However, non-menstrual TSS, which can also be observed in men and children, represents up to 50% of Staphylococcal TSS cases. Onset is sudden and includes high fever (>38.9°C), nausea, diarrhea, vomiting, myalgia, abdominal pain and sore throat. Staphylococcal TSS almost always exhibits an erythematous rash and skin peeling as one of its manifestations, whereas it is very rarely seen in streptococcal TSS, which can show signs of soft tissue infection. Serious manifestations include confusion, shock, renal and myocardial dysfunction, acute respiratory distress syndrome (ARDS; see this term) and coma.
Etiology
Staphylococcal TSS is due to an infection with Staphylococcus aureus and streptococcal TSS is due to an infection with Streptococcus pyogenes, or rarely, group C or G Streptococcus. Superantigens produced by both bacteria are responsible for the massive and sudden immune reaction seen in TSS. Both forms have been associated with recent traumas (surgery or childbirth) and viral infections, while staphylococcal TSS has also been associated with high absorbency tampon use.

                            Last update:
                            November 2015

                            - Expert reviewer(s):
                             Claude-Alexandre GUSTAVE  - Pr Gerard LINA  - Dr Anne TRISTAN


A rare, genetic, syndromic intellectual disability disorder with a variable phenotypic presentation typically characterized by microcephaly, severe feeding difficulties, failure to thrive, severe global development delay that frequently results in absent/poor speech, moderate to severe intellectual disability and hypotonia. Distinctive craniofacial features include prominent forehead, high-arched, thin eyebrows, hypertelorism, downslanting palpebral fissures, long, tubular nose with broad tip and prominent nasal bridge and wide mouth with full, everted lower lip. Joint laxity and ulnar deviation of wrists are also frequently observed.

Summary:
Epidemiology
Less than 100 cases have been reported in literature and databases to date.
Clinical description
Presentation is usually in the first months of life; however, intrauterine growth retardation has been reported in some cases. Symptoms of global development delay include hypotonia, delay in achieving independent sitting and walking, and marked language delay. Intellectual disability ranges from moderate to severe. Affected individuals may also display autistic features. Feeding difficulties requiring support are frequent. Other frequent gastrointestinal features include gastroesophageal reflux and constipation. Distinct facial features include highly arched or delineated eyebrows and also synophrys, and frequently a highly arched palate. Patients may exhibited skeletal anomalies including scoliotic attitude, joint laxity, pectus excavatum or carinatum and ulnar deviation of wrists.
Etiology
The disorder is due to loss of function mutations in ASXL3 gene (18q12.1).
Diagnostic methods
Diagnosis is based on presentation of clinical features, and can be confirmed by genetic testing. Most of the patients described so far had been confirmed by next generation sequencing techniques.
Differential diagnosis
Differential diagnosis includes other syndromes with moderate-severe intellectual disability and poor language. In some reported cases Cornelia de Lange syndrome was suspected due to feeding difficulties, developmental delay and eyebrow characteristics.
Antenatal diagnosis
There is no definitive antenatal diagnosis available, however ultrasound may show intrauterine growth retardation which should be investigated further. As germline mosaicism has been described, prenatal diagnosis may be considered where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disorder is autosomal dominant; however, no familial transmission has been observed so far. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that, for each pregnancy, there is 50% risk of passing the mutation to offspring. It is also important to counsel affected families about the possibility of recurrence due to germline mosaicism.
Management and treatment
Given the multisystemic involvement, multidisciplinary follow-up is needed and should include neurological follow up, developmental assessments, physiotherapy (particularly for joint laxity and musculoskeletal issues), feeding interventions for those with persistent feeding issues, and ophthalmologic follow up for patients with strabismus and/or refractive error.
Prognosis
Quality of life and the functional consequences depends on the severity of the developmental delay and intellectual disability.

                            Last update:
                            March 2021

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

                                * European Reference Network


Balantidiasis is an infectious disease, rare in western countries. It is caused by Balantidium coli, a single celled parasite (ciliate protozoan) that is usually associated with intestinal infection in areas associated with pig rearing. It infects humans occasionally, mostly immunocompromised patients. Some infected people may have no symptoms or only mild diarrhea and abdominal discomfort but others may experience more severe symptoms reminiscent of an acute inflammation of the intestines. Symptoms of Balantidiasis may be similar to those of other infections that cause intestinal inflammation, for example, amoebic dysentery. On very rare occasions this bacterium may invade extra-intestinal organs, mostly the lungs. Metronidazole is the treatment of choice.


Balint syndrome is a rare neurologic disease characterized by the triad of optic ataxia, ocular apraxia and simultanagnosia due to posterior parietal lobe lesions. Patients report ophthalmologic difficulties in the absence of underlying ophthalomologic anomalies and present severe visual and spatial disabilities in locating and reaching objects, initiating voluntary eye movements and perceiving more than one object at a time.


Baller-Gerold syndrome is characterized by the association of coronal craniosynostosis with radial ray anomalies (oligodactyly, aplasia or hypoplasia of the thumb, aplasia or hypoplasia of the radius).

Summary:
Epidemiology
Around 30 cases have been reported but the prevalence of the syndrome is unknown.
Clinical description
Craniosynostosis and radial ray anomalies present at birth and are associated with facial dysmorphism (brachycephaly, ocular exophthalmia, frontal bossing, nasal hypoplasia, small mouth, ogival palate). An inconstant poikiloderma can appear during the first months of life. Delayed growth is nearly always present, usually around -4SD. Patellar aplasia or hypoplasia can be observed during childhood. Intelligence is usually normal. Patients have a predisposition to cancer, in particular osteosarcoma.
Etiology
Baller-Gerold syndrome is secondary to mutations of the RECQL4 gene (8q24.3). RECQL4 is a member of the RecQ helicase gene family which cause other diseases predisposing to cancer. The proportion of patients with mutations in this gene has not been determined.
Diagnostic methods
Diagnosis of Baller-Gerold syndrome relies on clinical criteria. Given the numerous differential diagnoses, finding a mutation of the RECQL4 gene can help clarify the diagnosis spectrum, genetic counseling and management.
Differential diagnosis
The principal differential diagnoses include Rothmund-Thomson syndrome (RTS) and RAPADILINO syndrome, also secondary to mutations of the RECQL4 gene (see these terms). A phenotypic continuum between these diseases has been suggested by numerous authors: it is possible that they represent different expressions of the same pathology. Other differential diagnoses include Roberts syndrome and Fanconi anemia, which are frequently associated with radial ray anomalies but rarely with craniosynostosis, and Saethre-Chotzen syndrome which is characterized by coronal craniosynostosis usually without radial ray anomalies (see these terms). The combinationof craniosynostosis and radial ray hypoplasia is also associated with fetal valproic syndrome (see this term). The presence of poikiloderma allows other pathologies to be excluded.
Antenatal diagnosis
Prenatal diagnosis by chorionic villus sampling (CVS) is suggested when pathogenic mutations of the RECQL4 gene are found in an index case (homozygous or heterozygous). Ultrasound can be used to identify limb anomalies and an abnormally shaped cranium.
Genetic counseling
Baller-Gerold syndrome is inherited in an autosomal recessive manner.
Management and treatment
Treatment consists of surgery of the bilateral craniosynostosis in the first 6 months of life and, if necessary, pollicization of the index finger for thumb reconstruction. When monitoring patients particular clinical attention should be paid to bone pain, limpness or fractures, because of the risk of osteosarcoma. Exposure to the sun should be avoided because of a risk of skin cancer and photosensitivity.
Prognosis
The prognosis for patients with mutations of the RECQL4 gene, homozygous or heterozygous, is related to an increased risk of cancer.

                            Last update:
                            April 2009

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


A rare multiple sclerosis variant characterized by discrete concentrically layered, ring-like lesions in the cerebral white matter, consisting of alternating layers of myelinated and demyelinated tissue. Patients most commonly present with symptoms of an intracerebral mass lesion, including headache, cognitive abnormalities, behavioral changes, seizures, aphasia, or hemiparesis, among others, although there may also be classic focal symptoms of multiple sclerosis, such as focal weakness, ataxia, sensory disturbance, or diplopia.


A very rare syndrome of congenital hypothyroidism characterized by thyroid dysgenesis (in most cases athyreosis), cleft palate and spiky hair, with or without choanal atresia, and bifid epiglottis. Facial dysmorphism and porencephaly have been reported in isolated cases.

Summary:
Epidemiology
Only 8 patients from 6 families have been reported to date.
Clinical description
The syndrome is typically observed at birth with cleft palate, spiky hair and thyroid dysgenesis (in most cases athyreosis) leading to congenital hypothyroidism that manifests with lethargy, poor feeding, macroglossia, cold or mottled skin, persistent jaundice, and umbilical hernia. Neonatal hyperbilirubinemia is also common. Some may also present with choanal atresia and bifid epiglottis. Facial dysmorphism, consisting of microcephaly, hypertelorism, anteverted nares, narrow nasal bridge, low-set ears, small jaw and retrognathia, has been reported in one case. Porencephaly was also recently described in one case.
Etiology
Bamforth-Lazarus syndrome is due to homozygous loss-of-function missense mutations located within the forkhead domain of the FOXE1 gene (9q22), encoding thyroid transcription factor 2 (TTF-2). TTF-2 is expressed in the thyroid gland (as well as elsewhere like the tongue, epiglottis and palate) and is thought to play a crucial role in thyroid morphogenesis. Cases reported so far have all been due to homozygous loss-of-function mutations apart from one case described with a novel FOXE1 homozygous mutation causing increased thyroid gene expression.
Diagnostic methods
Diagnosis is based on clinical findings of congenital hypothyroidism with cleft palate and spiky hair along with findings of thyroid ultrasonography (USG) and computed tomography examination. Thyroid tissue is either completely absent or non-functional. Serum thyroid stimulation hormone (TSH) levels should be measured (levels will be elevated on newborn screening filter paper test, as is seen in all cases of athyreosis) to determine necessary treatment dosage. Molecular genetic testing can identify a mutation in the FOXE1 gene, confirming diagnosis.
Differential diagnosis
Differential diagnoses include other forms of syndromic hypothyroidism such as Johanson-Blizzard syndrome.
Antenatal diagnosis
Whilst prenatal diagnosis is not performed, a cleft palate and, in some cases, polyhydramnios (resulting from choanal atresia) may be observed during routine antenatal sonography.
Genetic counseling
The disease is inherited autosomal recessively and genetic counseling is possible. Most of the patients reported to date came from consanguineous parents, both being heterozygous for the genetic mutation. Where both parents are heterozygous carriers, there is 25% risk of transmitting the disease to offspring.
Management and treatment
Thyroid hormone replacement therapy is the standard treatment for those with Bamforth-Lazarus syndrome and should be started as soon as possible. The dosage of synthetic thyroxine (T4) necessary depends on the patient's age, weight and any other medical conditions. Regular follow up is recommended to monitor any fluctuation in TSH levels and treatment is lifelong. In neonates born with hyperbilirubinemia, phototherapy is often effective. Surgical procedures for cleft palate (maxillo-facial reconstruction and plastic surgery) and choanal atresia (surgery to reopen the nasal passages) should be discussed in a specialized health center. Speech therapy may also be required.
Prognosis
With proper treatment adherence the prognosis is good and children can have normal physical growth, pubertal development, and anterior pituitary function. Quality of life, however, can be affected by cleft palate/choanal atresia as multiple surgeries may be necessary. Intellectual development is normal if treatment for hypothyroidism is not delayed.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr John LAZARUS


Bangstad syndrome is a rare endocrine disease characterized by the association of primordial birdheaded nanism, progressive ataxia, goiter, primary gonadal insufficiency and insulin resistant diabetes mellitus. Plasma concentrations of TSH, PTH, LH, FSH, ACTH, glucagon, and insulin are usually elevated. A generalized cell membrane defect was suggested to be the pathophysiological abnormality in these patients. The mode of inheritance was thought to be autosomal recessive. There have been no further descriptions in the literature since 1989.


Banki syndrome is a synostosis syndrome, reported in a single Hungarian family in which members of 3 generations showed lunotriquetral synostosis, clinodactyly, clinometacarpy, brachymetacarpy and leptometacarpy (thin diaphysis). It appeared to be a unique dominant mutation. There have been no further descriptions in the literature since 1965.


A rare developmental defect during embryogenesis characterized by hamartomatous intestinal polyposis, lipomas, macrocephaly and genital lentiginosis.

Summary:
Epidemiology
The prevalence is unknown, but Bannayan-Riley-Ruvalcaba syndrome (BRRS) is generally considered as a rare disease.
Clinical description
BRRS shares some of the clinical characteristics of Cowden syndrome (CS;) but with differing frequencies. Unlike CS, the classic presentation of BRRS occurs neonatally or shortly thereafter with macrocephaly, Hashimoto struma, lipomatosis, vascular malformations and speckled lentiginosis of the penis or vulva. Developmental delay and gastrointestinal hamartomatous polyposis occur in a subset of BRRS patients. There should be a low threshold to evaluate for autism spectrum disorder in BRRS, especially if a PTEN mutation is found. It is unclear if the case-based signs of myopathic processes in proximal muscles, pectus excavatum, joint hyperextensibility, scoliosis and high birth weight are truly components of BRRS. Although predisposition to cancer was not thought to be a feature of this syndrome, it is now believed that BRRS patients with a germline PTEN mutation share the same risk of cancer development as CS patients.
Etiology
BRRS is caused (in 60% of cases) by a mutation in the phosphatase and tensin homolog (PTEN) gene (10q23) that encodes PTEN, a dual-specificity phosphatase. When BRRS is accompanied by germline PTEN mutations, it belongs to the PHTS group. Because the non-PTEN CS-related genes (ex. SDHB-D, AKT1, PIK3CA and KLLN) have not been formally studied in BRRS, it is not clear if they are also etiologic for non-PTEN-related BRRS.
Diagnostic methods
There are no specific criteria for diagnosis of BRRS but it is usually determined by the clinical presentation. The pediatric criteria of the PTEN scoring systemcan be used and are heavily based on the presence or absence of macrocephaly and the presence of one of four sub-criteria (autism spectrum disorder, dermatologic features, vascular malformations and/or gastrointestinal polyposis). A germline PTEN mutation confirms that the BRRS patient belongs to the PHTS group.
Differential diagnosis
Differential diagnoses include Lhermitte-Duclos syndrome, juvenile polyposis syndrome, Peutz-Jeghers syndrome (PJS), Birt-Hogg-Dube syndrome, Proteus syndrome, Cowden syndrome, Gorlin syndrome, and neurofibromatosis type 1.
Antenatal diagnosis
Antenatal diagnosis is possible for at-risk pregnancies if the disease-causing mutation is discovered in an affected family member.
Genetic counseling
BRRS is inherited autosomal dominantly. Genetic counseling can be offered to patients with germline PTEN mutations and asymptomatic family members should also be tested for the mutation to identify those that need to be monitored before symptom onset.
Management and treatment
Management and treatment are multidisciplinary. Monitoring for symptoms of gastrointestinal hamartomatous polyposis is important as they can be more severe than those seen in CS. Once a germline PTEN mutation is identified, the patient should undergo a screening thyroid ultrasound exam, starting at the age of 7, and a low threshold for evaluation for autism spectrum disorder is strongly recommended. In patients over the age of 18, a yearly skin check is recommended. A colonoscopy and biennial renal imaging should begin between the ages of 35-40, unless symptomatic. Women should perform monthly breast self-examinations and yearly breast screenings as well as transvaginal ultrasounds (postmenopausal) or endometrial biopsies beginning at the age of 35. It is also important to pay attention to neurological and vascular malformations as well as GI symptoms.
Prognosis
The prognosis is unknown and is dependent on initial presentation and likely genotype.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Charis ENG


BAP1-related tumor predisposition syndrome (TPDS) is an inherited cancer-predisposing syndrome, associated with germline mutations in BAP1 tumor suppressor gene. The most commonly observed cancer types include uveal melanoma, malignant mesothelioma, renal cell carcinoma, lung, ovarian, pancreatic, breast cancer and meningioma, with variable age of onset. Common cutaneous manifestations include malignant melanoma, basal cell carcinoma and benign melanocytic BAP1-mutated atypical intradermal tumors (MBAIT) presenting as multiple skin-coloured to reddish-brown dome-shaped to pedunculated, well-circumscribed papules with an average size of 5 mm, histologically predominantly composed of epithelioid melanocytes with abundant amphophilic cytoplasm, prominent nucleoli and large, vesicular nuclei that vary substantially in size and shape.


Baraitser-Winter syndrome (BWS) is a malformation syndrome, characterized by facial dysmorphism (hypertelorism with ptosis, broad bulbous nose, ridged metopic suture, arched eyebrows, progressive coarsening of the face), ocular coloboma, pachygyria and/or band heterotopias with antero-posterior gradient, progressive joint stiffening, and intellectual deficit of variable severity, often with severe epilepsy. Pachygyria - epilepsy - intellectual disability - dysmorphism (Fryns-Aftimos syndrome (FA); see this term) corresponds to the appearance of BWS in elderly patients.

Summary:
Epidemiology
BWS and FA were initially considered separate entities. They were reported collectively in approximatively 30 unrelated patients so far.
Clinical description
The clinical picture includes striking dysmorphism, hypertelorism, metopic ridging giving a trigonocephalic appearance to the skull, wide palpebral fissures, long downslanted palpebral fissures, congenital ptosis, broad nose with large bulbous or flat tip, prominent nasal root, long philtrum, mild micrognathia and highly arched eyebrows. Facial characteristics get coarser in late infancy and adolescence, with marked nasogenian folds. Cleft lip and palate may be present. Ocular anomalies such as iris and/or retinal coloboma (see these terms) with or without microphthalmos (see this term) are frequent. Most patients present with some degree of cortical dysplasia, pachygyria (often more marked in the frontal area) and subcortical band heterotopias (see this term). In most severe cases, the brain has a lissencephalic aspect, but some patients have a normal MRI. Head circumference tends to evolve to microcephaly during infancy. Growth is mildly delayed, and final stature is below normal. Patients have been reported with hydronephrosis, but, visceral malformations are rare. Intellectual deficiency ranges from mild to profound and correlates with the severity of brain anomalies and the presence of seizures which may be drug-resistant. Limitation of movement in large joints (knee, shoulder, elbow) become apparent in adolescence, and affect walking abilities in adulthood. Kyphoscoliosis may also develop. In infancy, neurological problems are prominent and facial dysmorphism less obvious.
Etiology
BWS is a genetically heterogeneous disorder, caused by a heterozygous mutation in one of the 2 genes coding for ubiquitously expressed actins: ACTB, located to 7p22-p12 (BRWS1) and ACTG1 on 17q25.3 (BRWS2). All mutations are missense and probably act by a gain of function mechanism, as deletions of the same genes do not result in BWS phenotype.
Diagnostic methods
Diagnosis is confirmed by DNA sequencing of ACTG1 and ACTB.
Differential diagnosis
In infancy, BWS may resemble Noonan syndrome. Teebi Type Hypertelorism has similar palpebral appearance. CHARGE syndrome, Norman-Roberts type lissencephaly syndrome (see these terms) and other syndromes with lissencephaly/pachygyria as a major feature are partially overlapping.
Antenatal diagnosis
Abnormal gyration pattern may be detected prenatally. Recurrence risk is probably < 1%. Antenatal diagnosis is possible, but the low recurrence risk and the risk of induced miscarriage have to be discussed.
Genetic counseling
All molecularly confirmed cases are sporadic, with, in theory, an autosomal dominant transmission, but effective transmission has never been reported.
Management and treatment
Developmental delay is managed by appropriate educative measures. Epilepsy management is difficult, as in other forms of pachygyria, some patients are drug resistant, even with polytherapies. Orthopedic monitoring is mandatory, considering progressive joint limitations that could lead to loss of autonomous ambulation.
Prognosis
Early prognosis may be poor in those with severe brain anomalies, but most patients with milder CNS anomalies can reach adulthood, although most patients will never be autonomous.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Pr Alain VERLOES


Barber Say syndrome (BSS) is a rare ectodermal dysplasia with neonatal onset characterized by congenital generalized hypertrichosis, atrophic skin, ectropion and microstomia.

Summary:
Epidemiology
BBS is a rare entity described in eleven patients to date.
Clinical description
BBS presents with congenital generalized hypertrichosis, facial dysmorphism (typically with bilateral ectropion, absent or sparse eyebrows and lashes, hypertelorism/telecanthus, broad nasal bridge, bulbous nose, anteverted nostrils, macrostomia, thin lips and misshapen ears), hyperlaxity and redundancy of the skin with deep folds, nipple hypoplasia and absence of mammary glands. Teeth are present, but with overgrown gingiva. Dental abnormalities described include taurodontism, shovel-shaped incisors, delayed eruption of deciduous dentition and premature apical closure. Other less frequent findings include cleft palate, hearing loss, mild psychomotor delay and genital abnormalities.
Etiology
Autosomal dominant and autosomal recessive transmission, as well as sporadic cases have been reported.

                            Last update:
                            January 2014


A rare genetic multisystem disorder characterized by the variable association of retinal dystrophy, obesity, polydactyly, genitourinary and kidney anomalies, learning disability and hypogonadism, with a wide spectrum of other minor manifestations.

Summary:
Epidemiology
In the USA, the prevalence is estimated at 1/100,000. Whilst epidemiological data is limited in Europe, a prevalence of 1/59,000 has been estimated in Denmark and 1/45,000-66,000 in the Reunion Island, France (due to a founder effect).
Clinical description
The clinical manifestations are highly variable, even within affected families. Post-axial polydactyly, sometimes associated with brachydactyly and/or syndactyly, is a common congenital feature. Other manifestations develop gradually over the first decade of life. Rapid weight gain is often described in early childhood, with obesity/overweight present in over 90% of individuals after 5 years of age; it is often difficult to treat and is associated with the metabolic syndrome in adults. Rod-cone or choroidal dystrophy causes decreased visual acuity, night blindness, photophobia and loss of central and color vision by late childhood/early adulthood. Other ocular manifestations include strabismus, cataracts, and astigmatism. Kidney and urinary tract abnormalities are common and may lead a progressive decline of kidney function: stage II-V chronic kidney disease (CKD) is described in 30 to over 40% of affected individuals. Developmental delay, cognitive deficit and behavioral disorders (autism, psychosis) are frequent features. Hypogonadism is often reported, especially in males. Minor signs include diabetes mellitus, heart (valvular stenoses, patent ductus arteriosus, cardiomyopathy), gastrointestinal tract (Hirschsprung disease), central nervous system (clumsiness, ataxia), liver (fibrosis, biliary cirrhosis, portal hypertension), and dentition (dental crowding, hypodontia, malocclusion, enamel hypoplasia) abnormalities. Subtle and inconsistent dysmorphic features (brachycephaly, macrocephaly, hypertelorism, midface hypoplasia, retrognathia) have also been reported. Anosmia or hyposmia may also be found as well as bilateral sensorineural hearing loss.
Etiology
Bardet-Biedl syndrome (BBS) is a ciliopathy associated with abnormalities in proteins involved in the development and function of primary cilia. Pathogenic or likely pathogenic variants in at least 24 different genes have been associated with BBS to date. Depending on the population origin, BBS1 (11q13.2) and BBS10 (12q21.2) are the most frequent genes, respectively accounting for ~23% and 15% of genotyped BBS patients.
Diagnostic methods
The diagnosis of BBS is based on the clinical manifestations (at least four major clinical signs or 3 major and 2 minor clinical signs) and can be confirmed by molecular genetic testing of the causative genes in more than 80% of patients. Visual manifestations are often the first sign leading to diagnosis in patients with no polydactyly; polydactyly and kidney anomalies (hyperechoic or multicystic kidneys) can be antenatal presenting signs.
Differential diagnosis
Main differential diagnoses include Alström syndrome, McKusick-Kaufman syndrome, Joubert syndrome, Jeune syndrome, Sensenbrenner syndrome and Senior-Løken syndrome.
Antenatal diagnosis
Genetic prenatal testing for BBS is possible in families with an identified gene mutation.
Genetic counseling
BBS is inherited in an autosomal recessive manner. Oligogenic inheritance has also been reported is some affected families. Genetic counseling should be provided to affected families.
Management and treatment
Multidisciplinary management and treatment is required. Most manifestations are treated following standard practice for the general population (obesity, learning disability, kidney anomalies). Setmelanotide was approved for hunger control in genetically confirmed Bardet-Biedl syndrome patients. Genital abnormalities and polydactyly may be treated with surgery.
Prognosis
Chronic kidney disease is considered the main cause of morbidity and mortality; its severity varies among patients but may potentially lead to end-stage kidney disease requiring dialysis or transplantation. Progressive vision loss due to retinal dystrophy, together with moderate intellectual deficit (when present), behavioral anomalies, hypomimia and obesity will affect the social life of these patients.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Jean MULLER | ERN-EYE* - Pr Miriam ZACCHIA | ERKNet*

                                * European Reference Network


A rare autonomic nervous system disorder characterized by diminished or absent buffering capability to prevent blood pressure from rising or falling excessively, due to abnormalities in the vascular baroreceptors, the glossopharyngeal or vagal nerves, or the brain stem. Typical clinical presentations are acute severe sustained hypertension, tachycardia, and headache, or volatile hypertension and tachycardia with headache, diaphoresis, flushing, and emotional instability. Rare cases rather present with hypotension, bradycardia, and dizziness or syncope.


Barth syndrome (BTHS) is an inborn error of phospholipid metabolism characterized by dilated cardiomyopathy (DCM), skeletal myopathy, neutropenia, growth delay and organic aciduria.

Summary:
Epidemiology
Prevalence is estimated at 1/454,000 and incidence at 1/140,000 (South-West England, South Wales) to 1/300,000-1/400,000 live births (USA). BTHS affects male patients.
Clinical description
Clinical presentation is highly variable. Most boys will develop DCM during the first decade, generally during the first year of life, which may be accompanied by endocardial fibroelastosis (EFE) and/or left ventricular noncompaction (LVNC). It may start in utero, causing cardiac failure, fetal hydrops and miscarriage or stillbirth during the 2nd/3rd trimester of pregnancy. Ventricular arrhythmia, especially during adolescence, can lead to sudden cardiac death. There is a significant risk of stroke. Skeletal (mostly proximal) myopathy causes delayed motor milestones, hypotonia, severe lethargy or exercise intolerance. There is a tendency to hypoglycemia during the neonatal period. Ninety percent of patients show mild to severe intermittent or persistent neutropenia with a risk of septicemia, severe bacterial sepsis, mouth ulcers and painful gums. Lactic acidosis and mild anemia may occur. Affected boys usually show delayed puberty and growth delay that is observed until the late teens or early 20s, when a substantial growth spurt often occurs. Patients may also present severe difficulties with adequate food intake. Episodic diarrhea is common. Many patients have a similar facial appearance with chubby cheeks, deep-set eyes and prominent ears.
Etiology
BTHS is caused by mutations in the TAZ gene (tafazzin; Xq28) which encodes Taz1p acyltransferase involved in the metabolism of cardiolipin, a major phospholipid in inner mitochondrial membranes. Defective Taz1p function results in abnormal remodelling of cardiolipin which ultimately compromises mitochondrial structure or respiratory chain function.
Diagnostic methods
Diagnosis was historically based on metabolic screening of urine showing elevated excretion of organic acids (typically 3-methylglutaconic acid (3-MGCA)), followed by TAZ gene sequencing. However, 3-MGC excretion may be normal even in severe cases. Analysis of the ratio of monolysocardiolipin (MLCL) / cardiolipin (CL) on blood, tissue, fibroblasts or stored neonatal bloodspots is therefore the diagnostic test of choice.
Differential diagnosis
Differential diagnosis includes hereditary, dilated and nutritional cardiomyopathy and idiopathic/cyclic neutropenia (see these terms).
Antenatal diagnosis
Prenatal diagnosis (chorionic villus biopsy and/or amniocentesis) is possible in families in which the mutation is known.
Genetic counseling
Transmission is X-linked recessive. A son born to a female carrier has a 50% risk of inheriting the mutation and developing the disease, while a daughter has a 50% risk of being a carrier. All daughters of an affected male will be carriers but none of his sons will be affected.
Management and treatment
Treatment is essentially supportive and multidisciplinary. Cardiac failure is treated with conventional drugs or by cardiac transplantation if refractory. The risk of bacterial sepsis in cases of intermittent neutropenia can be reduced by the use of prophylactic antibiotics and/or intermittent use of granulocyte-colony stimulating factor (G-CSF). Difficulties in feeding may necessitate nasogastric or gastrostomy tube feeding.
Prognosis
Prognosis has greatly improved with early detection and improvements in treatment and management. Patients are already surviving into their 40s and are expected to live beyond this age.

                            Last update:
                            June 2011

                            - Expert reviewer(s):
                            Pr Colin STEWARD


A rare bacterial infectious disease transmitted between humans via bites from infected sand flies in high-altitude valleys of the South American Andes, characterized by two disparate syndromes which can arise independently or sequentially. The first, Oroya fever, occurs about 60 days after the fly bite as a severe hemorrhagic fever with high mortality in untreated individuals. The second, chronic phase, termed verruga peruana, can persist for months or years and manifests with endothelial cell-derived, blood-filled tumors developing on the surface of the skin.


Bartsocas-Papas syndrome is a rare, inherited, popliteal pterygium syndrome (see this term) characterized by severe popliteal webbing, microcephaly, a typical face with short palpebral fissures, ankyloblepharon, hypoplastic nose, filiform bands between the jaws and facial clefts, oligosyndactyly, genital abnormalities, and additional ectodermal anomalies (i.e. absent hair, eyebrows, lashes, nails). It is often fatal in the neonatal period, but patients living until childhood have been reported.


A form of Bartter syndrome characterized by a later age at onset than the other types of Bartter syndrome, typically presenting beyond the first year of life with failure to thrive, hypokalemic and hypochloremic metabolic alkalosis, increased levels of plasma renin and aldosterone and low to normal blood pressure.

Summary:
Epidemiology
Exact prevalence is not known.
Clinical description
The disease is characterized by a milder clinical picture with a wide phenotypic heterogeneity when compared to other types of Bartter syndrome. Only one third of the patients present with maternal polyhydramnios which usually does not lead to prematurity. Patients usually present in the first year of life with failure to thrive, poor weight gain or polyuria with polydipsia. Fatigue, muscle weakness, cramps and carpopedal spasms may occur in some patients. Hypokalemia and hypochloremic metabolic alkalosis are common. Urinary calcium excretion is variable, only a few patients develop medullary nephrocalcinosis. In a subset of patients, the clinical picture and the biochemical abnormalities may resemble Gitelman syndrome, another salt losing tubulopathy caused by mutations in the sodium chloride cotransporter, SLC12A3, of the distal convoluted tubule. Indeed, the biochemical hallmarks of hypomagnesmia with hypocalciuria may also be detected in some patients with this type of Bartter syndrome.
Etiology
Mutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, have been identified as the underlying molecular defect. ClC-Kb is closely related to ClC-Ka, and both channels are expressed in thick ascending limb of the loop of Henle (TAL), ClC-Ka is exclusively expressed in the loop of Henle, whereas ClC-Kb is also expressed in distal convoluted tubule (DCT), thereby explaining the pronounced DCT features (similar to Gitelman syndrome) in some patients with this type of Bartter syndrome.
Diagnostic methods
Diagnosis is based on the clinical picture, blood gas analysis, plasma and urine electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium), renin and aldosterone levels. Urinary calcium excretion rates variably range from low to normal or slightly increased. Only genetic testing provides the definite diagnosis.
Differential diagnosis
The differential diagnosis includes Gitelman syndrome, pseudo-Bartter syndrome (e.g. in cystic fibrosis), HNF1B-nephropathy, and EAST syndrome. From late adolescence, also diuretic abuse, surreptitious vomiting, and surreptitious laxative use need to be ruled out.
Antenatal diagnosis
Prenatal diagnosis is technically feasible after genetic counseling and may be considered on an individual basis.
Genetic counseling
Transmission is autosomal recessive. Genetic counselling should be offered to any patient with Bartter syndrome and to parents with an affected child. In at-risk couples (both individuals are carriers of a disease-causing mutation) there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment includes oral salt and potassium supplements next to liberal salt and fluid intake. In addition, non-steroidal anti-inflammatory drugs (e.g. indometacin or celecoxib) are helpful in the majority of patients. Potassium-sparing diuretics should only be used with caution. In stressful situations (intercurrent illness, surgical procedures, trauma) blood electrolyte levels may change rapidly, requiring prompt and vigorous treatment.
Prognosis
Reliable long term outcome data are still lacking. Life expectancy may be reduced in severe cases. Quality of life may be compromised. During follow-up, proteinuria may occur, some patients develop chronic renal failure but rarely need renal replacement therapy.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Pr Martin KONRAD | ERKNet*

                                * European Reference Network


A form of Bartter syndrome characterized by maternal polyhydramnios, premature delivery, salt loss, polyuria and sensorineural deafness, associated with hypokalemic and hypochloremic metabolic alkalosis, increased levels of plasma renin and aldosterone, and low to normal blood pressure. Urinary calcium excretion rates are variable, and nephrocalcinosis is typically absent.

Summary:
Epidemiology
It is the least common of all recessive types of Bartter syndrome.
Clinical description
A severe type of antenatal Bartter syndrome that typically manifests prenatally with maternal polyhydramnios (due to fetal polyuria) usually evident by the end of second trimester, often leading to preterm labor and prematurity. Postnatally, patients present with polyuria, isosthenuria/hyposthenuria and are at high risk of dehydration, hypovolemic hypotension and shock. Virtually all patients are found to have complete sensorineural deafness. Recurrent vomiting, muscle cramps, spasms and failure to thrive are observed. Progression to renal failure is frequent. Hypokalemic and hypochloremic metabolic alkalosis, and in some cases hypomagnesemia, are noted (hypercalciuria is an inconsistent finding and only transient).
Etiology
The disorder is caused by a defect in chloride reabsorption in the thick ascending limb of the loop of Henle and the early distal convoluted tubule as a consequence of inactivating mutations of the BSND gene (1p32.3), encoding for the protein Barttin (Bartter syndrome type 4A), which is required for the location and proper function of the basolateral chloride channels ClC-Ka and ClC-Kb. Alternatively, the disorder may be caused by digenic mutations in CLCNKA (1p36.13) and CLCNKB (1p36.13) which inactivates the 4 alleles of the 2 genes (Bartter syndrome type 4B). ClC-Ka is highly expressed in the inner ear and contributes to maintaining the high potassium ion concentration in the endolymph necessary for normal hearing, and for which functional disruption leads to nerve deafness.
Diagnostic methods
Diagnosis is based on the clinical picture, blood gas analysis, plasma and urine electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium), renin and aldosterone levels. Urinary calcium excretion rates are variably ranging from low to normal or slightly increased. Objective hearing assessment is mandatory to identify sensorineural hearing loss. Only genetic testing provides the definite diagnosis.
Differential diagnosis
The most important differential diagnoses include congenital chloride diarrhea, pseudohypoaldosteronism type 1, and pseudo-Bartter syndrome (e.g. in cystic fibrosis).
Antenatal diagnosis
Prenatal diagnosis is technically feasible after genetic couseling and may be considered on an individual basis.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to any patient with Bartter syndrome and to parents with an affected child. In at-risk couples (both individuals are carriers of a disease-causing mutation) there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Especially in the perinatal period, treatment includes vigorous salt and fluid replacement therapy. Non-steroidal anti-inflammatory drugs (e.g. indomethacin or celecoxib) are the second mainstay of therapy. Beyond the neonatal period, next to liberal salt intake, long-term enteral salt and potassium supplements are necessary in most patients. In stressful situations (intercurrent illness with fever, gastroenteritis) blood electrolyte levels may change rapidly, requiring prompt and vigorous intravenous treatment. With respect to deafness, timely intervention ensuring that the child has access to developing receptive and expressive language is of paramount importance.
Prognosis
The perinatal course is critical because of the complications of severe prematurity. Life expectancy may be reduced in severe cases and chronic renal failure may develop in a subset of children. Reliable long term outcome data are still lacking.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Pr Martin KONRAD | ERKNet*

                                * European Reference Network


A form of antenatal Bartter syndrome characterized by early maternal polyhydramnios, excessive renal salt loss with secondary metabolic alkalosis in the neonatal period that completely disappears within the first months of life.


Bartter syndrome is a group of rare renal tubular disease characterized by impaired salt reabsorption in the thick ascending limb of Henle's loop and clinically by the association of hypokalemic alkalosis, hypercalciuria/nephrocalcinosis, increased levels of plasma renin and aldosterone, low blood pressure and vascular resistance to angiotensin II.

Summary:
Epidemiology
Annual incidence is estimated at 1/1000,000 in Europe.
Clinical description
Five distinct genotypes have been described, with four distinct clinical variants: an antenatal/infantile Bartter syndrome (most patients with genotypes I and II; see this term), characterized by polyhydramnios, premature delivery, polyuria, dehydration, hypercalciuria and nephrocalcinosis; an infantile Bartter syndrome with deafness (genotype IV, see this term), with congenital sensorineural deafness; classic Bartter syndrome (mostly patients with genotype III, but also some patients with genotype I and II; see this term), manifesting as polyuria-polydipsia in infancy-childhood through adulthood, dehydration and a variable delay in the height-weight growth curve; and autosomal dominant hypocalcemia with Bartter syndrome (patients with genotype V, see this term), associating chronic hypocalcemia and tubular salt wasting, hypokalemia and alkalosis.
Etiology
Bartter syndrome results from a defect in sodium, potassium and chloride reabsorption at the level of Henle's loop. They are caused by homozygous or compound heterozygous mutations in four genes encoding proteins involved in tubular fluid reabsorption in the thick ascending part of Henle's loop: SLC12A1 gene (15q15-21), encoding the sodium-potassium-chloride cotransporter NKCC2 in type I Bartter syndrome; KCNJ1 gene (11q24) encoding the potassium channel ROMK in type II; CLCNKB gene (1p36), encoding a basolateral chloride channel, in type III; and BSND gene (1p32.3), encoding barttin, the beta-subunit for the basolateral chloride channels, CLCNKA and CLCNKB in type IV. A final variant (type V) is associated with heterozygous activating mutations of the CASR gene (3q21.1), encoding the calcium sensing receptor.
Diagnostic methods
Diagnosis is based on the clinical picture, as well as in plasma and urine electrolytes (sodium, potassium, chloride, bicarbonate, magnesium, calcium), renin and aldosterone levels. Calcium levels in the urine may be normal to markedly increased. Hypocalcemia is observed in Bartter syndrome type V. Genetic testing provides the definite diagnosis.
Differential diagnosis
The differential diagnosis includes pseudo-Bartter syndrome (diuretic abuse, surreptitious vomiting), Gitelman syndrome, cystic fibrosis and celiac disease (see these terms).
Antenatal diagnosis
Diagnostic testing of amniocytes might be indicated for mothers of affected children, or potential heterozygous carriers (close relatives of affected individuals).
Genetic counseling
Four of the genetic variants (types I,II,III,IV) of Bartter syndrome are transmitted following an autosomal recessive pattern whereas variant (type V) is transmitted as an autosomal dominant trait.
Management and treatment
Treatment includes oral potassium supplements, non-steroidal anti-inflammatory drugs (e.g. indomethacin) and possibly potassium-sparing diuretics. In stressful situations (intecurrent diseases, surgical procedures, trauma) blood electrolyte levels may change rapidly, requiring prompt and vigorous intravenous treatment.
Prognosis
Life expectancy may be reduced in severe cases but renal failure is rare. Quality of life may be poor, growth rate reduced, and hospitalization rate high.

                            Last update:
                            September 2014

                            - Expert reviewer(s):
                            Dr Giacomo COLUSSI


A rare, genetic intellectual disability syndrome characterized by severe global developmental delay with intellectual disability, microcephaly, growth retardation, ocular defects such as congenital cataract, and nevus flammeus simplex on the forehead. Cardiac, urogenital, and skeletal abnormalities, as well as seizures are present in most patients. Dysmorphic craniofacial features include sparse hair, downslanting palpebral fissures, hypertelorism, broad and overhanging nasal tip and short philtrum, among others.

Summary:
Epidemiology
To date, 22 patients have been described with common clinical features and biallelic variants in MED25.
Clinical description
Patients present with some common clinical features. From infancy, almost all have severe global developmental delay with inability to walk and speech, and is followed by intellectual disability (ID). Dysmorphic craniofacial features include sparse hair, high forehead, high frontal hairline, sparse eyebrows, epicanthus, hypertelorism, broad and overhanging nasal tip, short philtrum, exaggerated cupid's bow, retrognathia/micrognathia and nevus flammeus simplex of the forehead. Microcephaly, short stature and feeding difficulties are also reported in some patients, and mandibular prognathia has been reported in various adult individuals from the same family. Other common features that have been described and include 2-3 toe syndactyly, congenital heart diseases (septal defects), urogenital and ocular anomalies (cataract, microcornea, microphthalmia), hypotonia and seizures. Cleft palate, hearing loss, hypospadias, kyphosis / scoliosis, camptodactyly, adducted thumb, tapered fingers with ulnar deviation, overlapping fingers / toes and hyperconvex nails have been described more rarely. Brain imaging abnormalities such as thin corpus callosum, ventriculomegaly and cerebral atrophy are common. Polymicrogyria has recently been reported as a distinctive neuro-radiological finding.
Etiology
The syndrome is caused by homozygous variants in the MED25 gene (19q13.33), coding for a component of the mediator complex. This complex is required for transcription of most RNA polymerase II-dependent genes.
Diagnostic methods
Diagnosis is based on clinical examination, brain imaging, cytogenetic and molecular studies.
Differential diagnosis
Differential diagnosis include other genetic syndromes characterized by intellectual disability accompanied by eye and brain abnormalities.
Antenatal diagnosis
Prenatal diagnosis is possible where a known pathogenic variant has previously been 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
Management requires a lifelong multidisciplinary approach and includes physical, occupational and speech therapy, in particular non-verbal methods of communication. Treatment is symptomatic and supportive. Antiepileptic drugs may be used to control seizures. Particular attention should be paid to monitoring feeding and growth, particularly as feeding problems tend to occur early on.
Prognosis
Some adult patients are reported; however, current data is limited with regard to life expectancy. Prognosis depends on disease severity.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Benedetta CAVIRANI | ITHACA* - Dr Livia GARAVELLI | ITHACA*

                                * European Reference Network


Bathing suit ichthyosis (BSI) is a rare variant of autosomal recessive congenital ichthyosis (ARCI; see this term) characterized by the presence of large dark scales in specific areas of the body.

Summary:
Epidemiology
Less than 20 patients are reported in the literature.
Clinical description
This particular skin aspect appears after the sheading of a collodion membrane observed at birth. Contrarily to other forms of ARCI, the members (in exception of the folds) and the face are not affected by ichthyosis. Scales are present on warmer skin areas such as the trunk, the scalp, and the axillary region. On affected areas, the patient present with large dark scales similar to those observed in lamellar ichthyosis (LI).
Etiology
BSI is caused by specific thermo-sensitive mutations in the TGM1 gene (encoding transglutaminase 1, involved in the cornification of the stratum corneum). Affected skin areas (warmer areas), show a clearly reduced enzyme activity in contrast to healthy skin areas that demonstrate an almost normal enzyme activity. Transmission is autosomal recessive.

                            Last update:
                            January 2012

                            - Expert reviewer(s):
                            Pr Juliette MAZEREEUW-HAUTIER


A rare paraneoplastic syndrome characterized by acral psoriasiform lesions typically involving the ears, nose, fingers and nails of the hands and feet, but may also extend to cheeks, elbows, knees and trunk, with occasional pruritus. In a majority of cases the cutaneous lesions precede the symptoms/diagnosis of malignancy (generally involving the upper aerodigestive tract, but also other squamous cell malignancies).

Summary:
Epidemiology
To date, approximately 150 cases have been described in the literature. The syndrome most commonly affects males over 40 years of age (mean age of onset: 61 years), and < 10% of cases affect women.
Clinical description
Patients present with symmetrical, acral, erythemato-squamous psoriasiform eruptions. The most common sites of involvement are the ears, nails, nose, fingers, hands, and feet. Isolated involvement of the helices of the ears, or involvement of the tip of the nose, the distal fingertips, or nails (usually the first sign of the disease), is typical in the early stages of the disease. Lesions may extend to the cheeks, elbows, knees and trunk as the disease progresses. The lesions can be asymptomatic but pain and pruritus can occur in about 20% of cases. Histological findings are not specific and include psoriasiform epidermal hyperplasia, hyperkeratosis with parakeratosis, and perivascular lymphocytic infiltrates in the dermis. In 70% of the cases, the cutaneous lesions precede the symptoms or diagnosis of the malignancy, which is most often a squamous cell carcinoma involving the upper aerodigestive tract.
Etiology
The pathogenesis of Bazex syndrome remains unclear. It may be caused by the production of epidermal growth factor by tumor cells or by cross-reactivity between epidermal and tumor antigens.
Diagnostic methods
Diagnosis is based on clinical and histological findings. Complete evaluation of the upper aerodigestive tract should be performed to identify the underlying malignancy.
Differential diagnosis
Differential diagnoses include psoriasis, allergic contact dermatitis, photosensitivity, dermatomyositis, drug eruption, cutaneous lupus erythematosus and mycosis.
Management and treatment
The dermatosis may respond to acitretin alone or to a combination of acitretin and UVA phototherapy. Oral and topical steroids have also been reported as effective for the treatment of lesions. Cutaneous lesions regress with the treatment of the underlying malignancy, whereas nail lesions may persist. Recurrence of skin lesions in a successfully treated patient implies a recurrence of the malignancy.
Prognosis
Prognosis is related to the underlying neoplasm.

                            Last update:
                            April 2024

                            - Expert reviewer(s):
                            Pr Arda ISIK


Bazex-Dupré-Christol syndrome is a rare genodermatosis with a predisposition to early-onset basal cell carcinomas.

Summary:
Epidemiology
So far, 143 cases have been reported, mostly from France and Belgium.
Clinical description
The disease manifests during the neonatal period or during infancy. It is characterized by hypotrichosis, hypohidrosis, milia and basal cell carcinomas of early onset. Follicular atrophoderma is frequent and most common on the dorsum of the hands and feet, the extensor surfaces of the elbows and knees, and the face. Hypotrichosis affects the scalp and sometimes the eyebrows. The milia papules and basal cell carcinomas are located predominantly on the face. Basal cell carcinomas develop in 40% of patients, usually during the 2nd or 3rd decade of life. Additional common features include basal cell hamartomas, trichoepitheliomas and, in very rare cases, atopy, keratosis pilaris, ichthyosis, arachnodactyly with joint hyperlaxity, osteochondritis, deafness and learning difficulties.
Etiology
The gene has been mapped to the long arm of the X chromosome, within the Xq24-q27.1 region. UBE2A (Xq24), encoding a protein involved in repair of UV-damaged DNA, has been proposed as a candidate gene.
Differential diagnosis
The differential diagnosis should include Gorlin syndrome, which also leads to multiple basal cell carcinomas of early onset, and X-linked dominant chondrodysplasia punctata (see these terms) in which follicular atrophoderma may also be observed. Rombo syndrome and generalized basaloid follicular hamartoma syndrome (see these terms) should also be included in the differential diagnosis.
Genetic counseling
Transmission is X-linked dominant.
Management and treatment
Management involves photoprotection and early detection of basal cell carcinomas. Surgical intervention, and sometimes cryosurgery or topical imiquimod, are indicated for basal cell carcinomas. Radiotherapy is contraindicated.

                            Last update:
                            October 2008

                            - Expert reviewer(s):
                            Dr Jean-Noël DAUENDORFFER  - Pr Philippe SAIAG


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

Summary:
Epidemiology
Becker muscular dystrophy (BMD) primarily affects males; in Europe the estimated prevalence ranges between 1:16,700-1:18,500 male births.
Clinical description
Onset is usually in childhood, typically after 7 years of age, but can be later. Presenting features in children include toe walking gait and or exercise-related cramps with or without myoglobinuria. Some patients may present following anesthetic induced acute rhabdomyolysis. In older patients, cardiomyopathy may be the presenting feature. As the condition progresses, muscle weakness leads to functional difficulties (difficulty climbing stairs or rising from a chair). Rarely, cardiomyopathy may be the presenting feature. Clinical examination reveals muscle pseudohypertrophy of the calf muscles and there may be atrophy of more proximal muscles such as the quadriceps. There is symmetrical and proximal muscle weakness, with the lower limbs being more severely affected than the upper limbs. There may be joint contractures, especially of the tendo- Achilles. The facial, ophthalmic and bulbar muscles are not involved. The condition is slowly progressive and about 40% of affected patients will eventually become wheelchair-dependent. In wheelchair dependent patients, restrictive respiratory insufficiency occurs due to weakness of the intercostal muscles and diaphragm. Cardiac involvement leads to dilated cardiomyopathy, which can be disproportionate to skeletal muscle involvement.
Etiology
BMD is caused by dystrophin deficiency due to in-frame deletions, mutations or duplications in the DMD gene (Xp21.2).
Diagnostic methods
Diagnosis is suspected on the basis of the clinical picture, family history and laboratory findings (raised serum creatine kinase to 10-100 times the normal level). The diagnosis is confirmed with DNA testing for variants in the DMD gene. Muscle biopsy shows a dystrophic picture with reduced dystrophin staining.
Differential diagnosis
Differential diagnosis includes the limb girdle muscular dystrophies, Duchenne muscular dystrophy, malignant hyperthermia and metabolic muscle diseases. In some cases the distinction between a mild variant of BMD and X-linked dilated cardiomyopathy can be difficult.
Antenatal diagnosis
If the diagnosis has been confirmed by genetic testing of carriers, then antenatal, genetic diagnosis is possible.
Genetic counseling
BMD is an X-linked recessive disease and genetic counseling is recommended. Male siblings of a proband have a 50% risk of being affected; female siblings have a 50% risk of being carriers. Whilst carriers are typically asymptomatic, a small percentage manifest milder forms of the disease (symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers). Male offspring of an affected male do not inherit the disease, female offspring are obligate carriers.
Management and treatment
Management includes multidisciplinary care with physiotherapy to reduce joint contractures and prolong walking. Night time ankle-foot orthoses are prescribed for children to reduce tendo- achilles contractures. Cardiac surveillance and monitoring of respiratory function are very important to improve outcome. Early treatment of cardiomyopathy with ACE (angiotensin-converting enzyme) inhibitors and or beta-blockers is recommended, and referral for cardiac transplantation is appropriate for severely affected patients. Patients with respiratory insufficiency should have pneumococcal and flu vaccines. Respiratory insufficiency should be treated with nocturnal BiPAP (bilevel positive airway pressure) and cough augmentation.
Prognosis
BMD is slowly progressive with wide phenotypic variability. Despite childhood onset, independent walking is never lost before 16 years of age. Life-expectancy for patients can be normal but may be significantly shortened by dilated cardiomyopathy or respiratory failure.

                            Last update:
                            June 2020

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


A rare, syndromic, benign, epidermal nevus syndrome characterized by the association of a Becker nevus (i.e. circumscribed, unilateral, irregularly shaped, hyperpigmented macules, with or without hypertrichosis and/or acneiform lesions, occuring predominantly on the anterior upper trunk or scapular region) with ipsilateral breast hypoplasia or other, typically hypoplastic, skeletal, cutaneous, and/or muscular defects, such as pectoralis major hypoplasia, supernumerary nipples, vertebral defects, scoliosis, limb asymmetry, odontomaxillary hypoplasia and lipoatrophy.


Beckwith-Wiedemann syndrome (BWS) is a genetic disorder characterized by overgrowth, tumor predisposition and congenital malformations.

Summary:
Clinical description
Patients tend to grow at an increased rate during the 2nd half of pregnancy and in the first few years of life; adult heights are typically in the normal range. Abnormal growth may also manifest as hemihyperplasia and/or macroglossia (leading to difficulties in feeding, speech and infrequently, sleep apnea). Hypoglycemia is reported in 30-50% of neonates. A recognizable facial gestalt is common and often normalizes by adulthood. In addition to macrosomia, macroglossia, hemihyperplasia and hypoglycemia, characteristic findings may include omphalocele/umbilical hernia/diastasis recti, embryonal tumor, anterior earlobe crease(s) and posterior helical pit(s), nevus flammeus or other vascular malformations, visceromegaly involving abdominal organs, fetal adrenocortical cytomegaly (pathognomonic), renal abnormalities, positive family history, and rarely cleft palate. Cardiac malformations are found in 9-34% of cases and about half of these have spontaneously-resolving cardiomegaly. Cardiomyopathy is rare. Patients are highly predisposed to embryonal malignancies primarily in the first 8 years of life with a risk estimate of 7.5% (range of 4 - 21%).
Etiology
BWS is caused by various epigenetic and/or genetic alterations that dysregulate imprinted genes on chromosome 11p15.5. Molecular subgroups are associated with different recurrence risks and different clinical findings (e.g. tumor risks).
Diagnostic methods
Generally, diagnosis is supported by the presence of at least three characteristic clinical findings, however embryonal tumor development may occur with 'milder' presentations. Positive molecular tests may confirm the diagnosis; however a negative result does not rule out BWS.
Differential diagnosis
Differential diagnoses include Simpson-Golabi-Behmel, Costello, Perlman, and Sotos syndromes, and mucopolysaccharidosis type VI (see these terms).
Antenatal diagnosis
Prenatal testing by chorionic villus sampling or amniocentesis can be offered, especially if a cytogenetic or genomic abnormality has been identified; methylation alterations are more reliably detected via amniocentesis at present. Amniocentesis may also be indicated for BWS-associated findings detected on fetal ultrasound (e.g. fetal omphalocele). In the absence of a known molecular defect, screening can be undertaken by measurement of maternal serum alpha-fetoprotein and targeted ultrasound screening.
Genetic counseling
The disease occurs sporadically (85%), but familial transmission is reported (15%). Genetic counseling is recommended and recurrence risk estimation and cascade genetic testing should take into account family history and the molecular subgroup of the affected family member.
Management and treatment
Management typically involves standard supportive medical and surgical strategies. Tumor surveillance should be initiated if BWS is suspected/diagnosed and in a clinically unaffected monozygotic twin of a patient, but should not be guided by genotype/phenotype correlations at this time. Screening for hypoglycemia should be undertaken in the neonatal period if there are suggestive or diagnostic prenatal findings, and even for clinically unaffected newborns at increased risk based on family history.
Prognosis
At the severe end of the spectrum, patients are at risk of early death due to complications arising from hypoglycemia, prematurity, cardiomyopathy, macroglossia, or tumors. In patients who survive childhood, prognosis is generally good.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Pr Chéryl SHUMAN  - Pr Rosanna WEKSBERG


Beemer-Ertbruggen syndrome is a lethal malformation syndrome reported in 2 brothers of first-cousin parents that is characterized by hydrocephalus, cardiac malformation, dense bones, and unusual facies with down-slanting palpebral fissures, bulbous nose, broad nasal bridge, micrognathia and a long upper lip. There have been no further descriptions in the literature since 1984.


Behavioral variant of frontotemporal dementia (bv-FTD) is a form of frontotemporal dementia (FTD; see this term), characterized by progressive behavioral impairment and a decline in executive function with frontal lobe-predominant atrophy.


A rare, chronic, relapsing, multisystemic vasculitis characterized by mucocutaneous lesions, as well as articular, vascular, ocular and central nervous system manifestations.

Summary:
Epidemiology
Behçet disease (BD) is most often reported in populations along the Silk Road, with highest prevalence reported in Turkey at >1/1,000, versus 1/10,000 in Japan. European cases are more often described in Mediterranean countries.
Clinical description
Onset most commonly occurs in adults (mean 30 years of age), but pediatric cases have been reported. Relapsing episodes of round oral aphthae with sharp erythematous and elevated borders (1-3 cm diameter) may be accompanied by genital aphthae (>50% of cases); cutaneous features may include pseudo-folliculitis and erythema nodosum. Ocular disorders (posterior uveitis, retinal vasculitis) occur in over 50% of BD patients. Arthralgia and/or non-erosive, asymmetric, arthritis affecting mainly large articulation (knees, ankles ect.) are frequent (45%) and can occur as an initial symptom. Vasculitis in BD is more frequent in the venous system where thromboses in femoro-iliac, superior and inferior vena cava and cerebral territories may occur. Rarer arterial thromboses and aneurysms primarily affect the pulmonary and aorta vessels. Neurological manifestations (neuro-BD) are frequent (>20%), and may include headache, fever, pyramidal signs with hemiparesis, cranial nerve damage, meningitis, behavioral changes and sphincter dysfunction. Aphthoid and/or ulcerative lesions may affect the whole digestive tract but mainly the ileo-caecum and ascending colon, potentially leading to hemorrhages and perforations.
Etiology
Of unknown origin, genetic predisposition in BD may allow certain infectious (in particular Streptococcus sanguis) and/or environmental insults to trigger symptoms involving sporadic inflammatory attacks reminiscent of auto-inflammatory disorders due to cross reactions with oral mucosa antigens. HLAB5101 antigen is associated to BD in 50-60% of patients. NF-kB activation and aberrant cytokine levels (eg- IL-6, TNF-a, IL-8, IL-12, IL-17 and IL-21) have been implicated in the pathogenesis of BD. A familial, autosomal dominant form of BD, A20 haploinsufficiency, is linked to mutations in TNFAIP3(6q23.3).
Diagnostic methods
The diagnosis of BD is essentially clinical and is based on the international classification criteria, which are sensitive and specific. The presence of recurrent oral ulceration (at least 3 times over 12 months; 2 points), genital ulceration (2 points), uveitis (2 points), skin lesions (1 point), cardiovascular (1 point), neurologic (1 point) and/or pathergy reaction (1 point). Behçet disease is retained with 4 or more points. Other elements may contribute to the diagnosis. Isolated severe visceral involvement (e.g. vena cava, cerebral and/or subhepatic vein thrombosis, pulmonary aneurysms, neurological involvement and/or retinal vasculitis) can be inaugural and should evoke BD; therefore, systematic request of an expert opinion is recommended. A family history of BD also increases the probability of diagnosis. Searching for the HLA-B51 haplotype is not a strong diagnostic element, but can be useful in situations of diagnostic uncertainty.
Differential diagnosis
Differential diagnosis depends on upon the manifestations, herpes ulcerations, spondylo-arthropathies, infectious uveitis, relapsing polychondritis, sarcoidosis, antiphospholipid syndrome, Takayasu arteritis, Crohn's disease, infectious meningo-encephalitis or multiple sclerosis may be considered.
Management and treatment
Anti-inflammatory steroids are the basis of treatment; however, corticodependance and relapses may occur upon discontinuation. Concurrent administration of immunosuppresive drugs (e.g. azathioprine, cyclophosphamide, methotrexate or mycophenolate mofetil), are also prescribed but their action is delayed. Anti-TNF and alpha-interferon (2a or 2b) are efficient, particularly in severe uveitis, and antiplatelet or anticoagulation treatments are discussed in case of vascular thrombosis. Colchicine relieves mucocutaneous symptoms. Apremilast has been recently approved in refractory oral ulceration of BD. Efficacy is dependent upon rapid initiation and patient compliance.
Prognosis
In the absence of treatment, the prognosis is severe due to ocular involvement leading potentially to blindness, the risk of lethal arterial rupture, large vessel thrombosis and neurological symptoms potentially causing encephalopathy or cerebral hypertension that may lead to a loss of autonomy. Intensive care coupled with close multidisciplinary follow-up, and adapted immunosuppressive treatment has been shown to reduce morbidity and mortality.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr David SAADOUN


Bencze syndrome or hemifacial hyperplasia with strabismus is a malformation syndrome involving the abnormal growth of the facial skeleton as well as its soft tissue structure and organs, and is characterized by mild facial asymmetry with unaffected neurocranium and eyeballs, as well as by esotropia, amblyopia and/or convergent strabismus, and occasionally submucous cleft palate. Transmission is autosomal dominant. There have been no further descriptions in the literature since 1979.


Benign adult familial myoclonic epilepsy (BAFME) is an inherited epileptic syndrome characterized by cortical hand tremors, myoclonic jerks and occasional generalized or focal seizures with a non-progressive or very slowly progressive disease course, and no signs of early dementia or cerebellar ataxia.

Summary:
Epidemiology
Worldwide prevalence is unknown but an estimated prevalence of 1/35,000 was reported in Japan.
Clinical description
BAFME usually presents in the second decade of life (but age of onset can range from age 11-50) with a minor cortical hand tremor. The tremor consists of continuous, arrhythmic fine twitching in the hands that is exacerbated by fatigue or emotional stress. There is no progression of severity in these tremors until after the age of 70. Myoclonus usually appears around the same age as the cortical tremor and consists of erratic, arrhythmic, segmental jerks of the upper limbs heightened by posture and action. Rare tonic-clonic seizures are also a manifestation of BAFME (peak age of onset being 30), occurring after the appearance of tremors and myoclonus and often precipitated by photic stimulation, emotional stress and sleep deprivation. Some patients from families mapped on chromosome 2p11.1-q12.2 present with drug-resistant complex partial seizures and focal EEG abnormalities. At an advanced age, a worsening of the myoclonus is possible as well as difficulty walking and mild ataxia.
Etiology
BAFME has been mapped to at least 4 different chromosomal loci. The identified chromosomal loci linked to BAFME are: 8q23.3-q24.11 in Japanese families (BAFME type 1), 2p11.1-q12.2 in Italian families (BAFME type 2), 5p15.31-p15.1 in a French family (BAFME type 3) and 3q26.32-q28 in a Thai family (BAFME type 4). In addition, a consanguineous Egyptian family with focal epilepsy, neuropsychiatric features, borderline cognitive level, and myoclonus, resembling BAFME but inherited in an autosomal recessive manner was recently described. A homozygous deletion in the CNTN2 (1q32.1) gene encoding contactin 2 was found to be responsible.
Diagnostic methods
Diagnosis is based on clinical and electrophysiological findings. Electroencephalographic (EEG) findings include a photomyoclonic response along with abnormality of polyspikes and waves. Patients also display extremely enlarged cortical components of somatosensory evoked potentials and an enhanced C-reflex. Jerk-locked average analysis reveals positive-negative, biphasic spikes preceding myoclonus.
Differential diagnosis
BAFME must be differentiated from epilepsy syndromes with prominent myoclonus features. Patients may easily be misdiagnosed as having juvenile myoclonic epilepsy (JME; see this term) due to the occurence of myoclonic jerks and generalized tonic-clonic seizures. However, JME differs clinically from BAFME by the absence of cortical tremor, the mainly proximal myoclonic jerks, and seizures typically occurring at awakening. The absence of ataxia and dementia, the adult onset, and the usually benign outcome of epilepsy differentiates BAFME from progressive myoclonic epilepsies.
Genetic counseling
BAFME is transmitted autosomal dominantly and penetrance is high. Genetic counseling is possible when a family member has the disease and presymptomatic diagnosis may be done in young patients from families mapped on any of the 3 loci, based on electrophysiological findings.
Management and treatment
Cortical tremor (unlike essential tremor) usually has a poor response to beta blockers but improves with antiepileptic drugs. As alcohol aggravates these tremors, it should be avoided. Valproate, levetiracetam, and benzodiazepines are most beneficial in the treatment of cortical tremors and myoclonus due to their combined antiepileptic and antimyoclonic effects. In some cases, epilepsy may be difficult to treat.
Prognosis
BAFME has no effect on life expectancy. With successful treatment, patients are often relieved from their symptoms.

                            Last update:
                            February 2012

                            - Expert reviewer(s):
                            Dr Pasquale STRIANO


A rare non-Langerhans cell histiocytosis characterized by multiple small yellowish-red or brown papules initially erupting predominantly in the head and neck region. The histopathological hallmark of these eventually self-healing lesions is a dermal proliferation of histiocytes with intracytoplasmic comma-shaped bodies, coated vesicles, and desmosome-like structures. Birbeck granules are absent. The disease typically occurs in young children.


Benign concentric annular macular dystrophy (BCAMD) is a progressive autosomal dominant macular dystrophy characterized by parafoveal hypopigmentation followed by a retinitis pigmentosa-like phenotype (nyctalopia and peripheral vision loss) with a bulls eye configuration.


Benign epithelial tumor of salivary glands is a rare neoplastic disease characterized by the presence of a tumor located in the parotid, sublingual, submandibular and/or minor salivary glands, which presents with a wide spectrum of clinical features depending on the location, size and type of salivary gland involved, usually manifesting as a slow-growing, painless, commonly solitary mass, rarely associated with facial nerve palsy or nasal/airway obstruction.


Benign familial mesial temporal lobe epilepsy is a rare epilepsy characterized by seizures with viscerosensory or experential auras, onset in adolescence or early adulthood and good prognosis. It is defined as at least 24 months of seizure freedom with or without antiepileptic medication.


A rare epilepsy typically characterized by isolated focal motor and somatosensory seizures. Less frequently other focal seizure types, with or without secondary generalization, have been described. The seizures usually happen when the patient is awake and take a benign course. The condition is transitory, interictal examinations are normal, and there is usually no family history of epilepsy.


A rare, genetic, movement disorder characterized by early-onset, very slowly progressive choreiform movements that may involve variable parts of the body, typically aggravated by stress or anxiety, in various members of a family. Additional variable manifestations include hypotonia, often resulting in psychomotor delay (including gait disturbances) and dysarthria, as well as myoclonus, dystonia, behavioral symptoms (ADHD, obsessive-compulsive disorder), learning difficulties (particularly in writing) and spasticity with hyperreflexia and/or flexor/extensor plantar reflexes.


A rare neonatal epilepsy syndrome characterized by seizures without specific underlying etiology, occurring during the first days of life in infants with an otherwise normal neurological state and no family history of neonatal convulsions. The most commonly partial and clonic seizures usually last for one to three minutes. Repeated seizures may lead to status epilepticus lasting up to 20 hours. Overall, remission rates are high and neurological outcome is favorable.


Benign infantile focal epilepsy with midline spikes and waves during sleep is a rare infantile epilepsy syndrome characterized by age of onset between 4 and 30 months, partial sporadic seizures presenting with motion arrest, staring, cyanosis and, less common, automatisms and lateralizing signs, and characteristic interictal sleep EEG changes consisting of a spike followed by a bell-shaped slow wave in the midline region.


Benign infantile seizures associated with mild gastroenteritis is a rare infantile epilepsy syndrome characterized by benign afebrile seizures in previously healthy infants and children (age range 1 month to 6 years) with mild acute gastroenteritis without any central nervous system infection, severe dehydration, or electrolyte imbalances. In most cases the seizures are tonic-clonic with focal origin on EEG, occur between day 1 and 6 following onset of acute gastroenteritis, cease within 24 hours and do not persist after the illness.


A rare renal tumor characterized by a benign epithelial (metanephric adenoma), biphasic (metanephric adenofibroma) or renal stromal (metanephric stromal tumor) neoplasm. Metanephric adenoma mostly occurs in the fifth to sixth decade of life with distinct female predominance. It may be asymptomatic or present with abdominal pain, hematuria, and/or polycythemia. Metanephric adenofibroma has been described from infancy to young adulthood, potentially causing polycythemia or hematuria. Metanephric stromal tumor typically presents in infancy or childhood as an abdominal mass, sometimes manifestations of extrarenal vasculopathy such as hypertension or hemorrhage.


Benign nocturnal alternating hemiplegia of childhood is a rare neurologic disease characterized by recurrent attacks of nocturnal screaming or crying followed or accompanied by unilateral or sometimes bilateral hemiplegia. Disorder is not associated with neurological or developmental impairments but may be associated with mild behavioral abnormalities.


Benign paroxysmal tonic upgaze of childhood with ataxia is a rare paroxysmal movement disorder characterized by episodes of sustained, conjugate, upward deviation of the eyes and down beating saccades in attempted downgaze (with preserved horizontal eye movements) which is accompanied by ataxic symptomatology (unsteady gait, lack of balance and movement coordination disturbances) in an otherwise healthy individual. Bilateral vertical nystagmus is associated. Symptoms generally disappear spontaneously within 1-2 years after onset.


Benign paroxysmal torticollis of infancy

A rare, transient paroxysmal dystonia characterized by onset of recurrent episodes of torticollic posturing of the head between infancy and early-childhood.

Summary:
Epidemiology
To date, more than 150 cases have been described in the literature; however, the disease is likely under reported. The condition appears to be slightly more frequent in females.
Clinical description
Onset typically occurring between 2 and 8 months of age but may occur anywhere between birth and early childhood with episodes occurring between every few weeks and every few months. The duration of the torticollis varies between patients, but usually lasts from a few hours to a few days (although persistence for over one week has been reported). The torticollic episodes (in particular those of shorter duration) may by associated with other symptoms including vomiting, pallor, sweating, apathy or irritability, an unsteady gait, an upwardly-diverted gaze, abnormal truncal posture (tortipelvis) and contraction of the posterior neck muscles (retrocollis). The frequency and duration of the torticollic episodes decreases with age and episodes usually stop completely by 5 years of age.
Etiology
There is some clinical and genetic evidence pointing to benign paroxysmal torticollis as one of the infantile migraine precursors. In some cases disease-causing mutations have been identified in the CACNA1A (19p13.13). In one case, a mutation in PRRT2  (16p11.2) has been identified. Both CACNA1A and PRRT2 have been linked to other diseases such as familial hemiplegic migraine.
Diagnostic methods
Diagnostic criteria include i) recurrent attacks in infants and small children ii) head tilt to either side that remits spontaneously after minutes to days iii) one of the following symptoms: pallor, irritability, malaise, vomiting and ataxia which may coexist during attacks iv) normal neurological examination between attacks v) not attributed to another disorder. As the disorder is benign and transient, extensive investigations should be avoided, although some diagnostic tests (brain ultrasound, computerized tomography, magnetic resonance imaging, studies of toxics or drugs and otorhinolaryngological examination), all giving normal results, may be required mainly in the first episode to exclude other causes of torticollis.
Differential diagnosis
The differential diagnosis (mainly in the first episode) should include intoxication, undesirable secondary effects of drugs, craniocervical junction abnormalities such as atlanto-axial instability, Arnold-Chiari malformation, epilepsy, vertigo, Sandifer's syndrome and posterior fossa tumors in cases with associated symptoms.
Genetic counseling
The disorder usually occurs sporadically; however, a few families with autosomal dominant inheritance have been reported.
Management and treatment
As the disease is self-limiting and resolves spontaneously by mid-childhood, no treatment is usually required. There is no approved medication for this disease.
Prognosis
Prognosis is excellent.

                            Last update:
                            September 2019

                            - Expert reviewer(s):
                            Pr Emilio FERNANDEZ-ALVAREZ  - Dr Esther VAZQUEZ-LOPEZ


Benign partial epilepsy of infancy with complex partial seizures is a rare infantile epilepsy syndrome characterized by complex partial seizures presenting with motion arrest, decreased responsiveness, staring, automatisms and mild clonic movements, with or without apneas, normal interictal EEG and focal, mostly temporal discharges in ictal EEG. Most often, seizures occur in clusters and have a good response to treatment. Psychomotor development is normal.


Benign partial epilepsy with secondarily generalized seizures in infancy is a rare infantile epilepsy syndrome characterized by seizures presenting with motion arrest and staring. They are followed by generalized tonic-clonic convulsions with normal interictal EEG and focal paroxysmal discharges, followed by generalization in ictal EEG. Seizures usually occur in clusters and are responsive to treatment. Psychomotor development is normal.


Benign recurrent intrahepatic cholestasis (BRIC) is a hereditary liver disorder characterized by intermittent episodes of intrahepatic cholestasis, generally without progression to chronic liver damage. BRIC is now believed to belong to a clinical spectrum of intrahepatic cholestatic disorders that ranges from the mild intermittent attacks in BRIC to the severe, chronic and progressive cholestasis seen in progressive familial intrahepatic cholestasis (PFIC; see this term).

Summary:
Epidemiology
The prevalence of BRIC is unknown.
Clinical description
The first cholestatic episode can occur at any age but onset within the first two decades of life is most common. Patients present with bouts of intense pruritus and jaundice that may last for several weeks or months before resolving spontaneously. Associated manifestations include fatigue, loss of appetite, dark urine and pale stools. Hepatomegaly is also a common finding. Between episodes patients show no symptoms and the interval between attacks varies from months to years. The factors triggering the onset of the cholestasis remain unclear but viral infections, pregnancy and oral contraceptives have all been implicated. Two forms of BRIC have been described (BRIC1 and BRIC2) (see these terms). Clinically, these forms are very similar; however, patients with BRIC1 can display extrahepatic features such as hearing loss, pancreatitis and diarrhea, whereas cholelithiasis is a common manifestation of BRIC2. Patients with BRIC2 also have an increased risk for hepatobiliary malignancy.
Etiology
BRIC1 is allelic to PFIC1 (see this term) and is caused by mutations in the ATP8B1 gene (18q21) encoding a P-type ATPase expressed at the canalicular membrane of hepatocytes as well as in other epithelia. BRIC2 is allelic to PFIC2 (see this term) and is caused by mutations in the ABCB11 gene (2q24) encoding the liver-specific bile salt export pump (BSEP). The disease-causing mutations in BRIC are generally missense mutations.
Diagnostic methods
Diagnosis is based on the clinical history (at least 2-3 episodes of cholestasis), serum biochemistry (low to normal serum gamma GT activity and cholesterol, elevated serum total bile acids and high levels of conjugated bilirubin during episodes), cholangiography (showing normal intra- and extrahepatic bile ducts), liver histology (revealing intrahepatic cholestasis with normal liver structure) and immunohistochemical analysis (absent or reduced BSEP staining in majority of BRIC2 patients). Molecular genetic testing confirms the diagnosis and discriminates between subtypes.
Differential diagnosis
Differential diagnoses include drug-induced cholestatic disease as well as intrahepatic cholestasis of pregnancy, primary biliary cirrhosis and primary sclerosing cholangitis (see these terms). BRIC can be differentiated from PFIC on the basis of the disease course and liver histology.
Antenatal diagnosis
Prenatal testing is available for families in which the disease-causing mutations have already been identified.
Genetic counseling
Both BRIC1 and BRIC2 are inherited in an autosomal recessive manner, although a BRIC family with seemingly autosomal dominant inheritance has been reported.
Management and treatment
Management is mainly symptomatic: rifampicin and cholestyramine can be used to reduce pruritus and to induce remission of a cholestatic episode in some patients. Plasmapheresis/MARS (Molecular Adsorbents Recirculation System) has also been shown to be of benefit in some cases. For individuals that are unresponsive to medical therapy, endoscopic nasobiliary drainage is generally effective. Partial external biliary diversion is also used to improve quality of life and prevent disease progression. Liver transplantation may eventually be indicated for patients with frequent and severe episodes.
Prognosis
The prognosis is generally good with a tendency for a reduction in the frequency of attacks with age. However, progression from BRIC to PFIC and cirrhosis has been reported in the literature, indicative of a clinical continuum.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Pr R.H.J. [Roderick] HOUWEN  -  W.L. [Wendy] VAN DER WOERD


Benign Samaritan congenital myopathy is a rare, genetic, skeletal muscle disease characterized by severe neonatal hypotonia with respiratory insufficiency, delay in motor milestones, and dysmorphic features including bitemporal narrowing, epicanthal folds and hypertelorism. Affected individuals show gradual improvement in hypotonia and muscle weakness within the first two years of life resulting in minimal clinical manifestations in adulthood.


A rare benign peripheral nerve sheath tumor characterized by a usually encapsulated space-occupying lesion composed of differentiated neoplastic Schwann cells. It most commonly arises from peripheral nerves in the head and neck region and extensor aspects of the extremities, but also from spinal and cranial nerves, especially the vestibular nerve. The tumor may be asymptomatic or cause symptoms related to a mass effect. It grows slowly and only rarely undergoes malignant transformation.