A group of rare uterine adnexal tumors comprising non-metastasizing neoplasms arising from the fallopian tube. This includes epithelial tumors (benign serous tumors such as serous adenofibroma and papilloma) and mature teratomas. Patients may be asymptomatic or present with tubal obstruction.


A rare primary immunodeficiency characterized by infantile onset of generalized lymphadenopathy, splenomegaly, and lymphocytosis, with excessive polyclonal expansion of B-cells. Patients present recurrent infections and impaired T-cell and antibody responses, while overt autoimmune manifestations are usually absent. Occurrence of B-cell malignancy later in life has been reported.


A rare, inherited platelet disorder characterized by mild to severe bleeding tendency , macrothrombocytopenia and absent ristocetin-induced platelet agglutination.


Best vitelliform macular dystrophy (BVMD) is a genetic macular dystrophy characterized by loss of central visual acuity, metamorphopsia and a decrease in the Arden ratio secondary to an egg yolk-like lesion located in the foveal or parafoveal region.

Summary:
Epidemiology
The prevalence is estimated to be between 1/5,000 and 1/67,000 in northern Sweden and Denmark respectively. Males are more affected than females (3:1).
Clinical description
Onset of BVMD is in childhood and sometimes in later teenage years (5-13 years). Affected individuals have normal vision at birth. BVMD then progresses through distinct stages that include an asymptomatic previtelliform phase (stage 1) followed by the formation of a yellow, egg yolk-like (vitelliform) lesion in the macula (stage 2). The contents become less homogenous and develop a "scrambled-egg" appearance (stage 2a). The lesion eventually develops a fluid, yellow-colored vitelline substance (pseudohypopyon or stage 3) and finally breaks down, leaving a scar that causes central visual acuity deterioration (20/200). This may be complicated by a subfoveal choroidal neovascular (CNV) membrane (rare in children). Anomalous color discrimination (mainly the protan axis) and metamorphopsia may be observed but patients retain normal peripheral vision and dark adaptation. Some affected individuals remain asymptomatic.
Etiology
BVMD is characterized by atrophy of the retinal pigment epithelium (RPE) affecting photoreceptors with impaired central visual function. In most cases, BVMD is caused by mutations in BEST1 (11q12), encoding for bestrophin-1, a chloride channel expressed in RPE. A defect in this protein leads to accumulation of lipofuscin secondary to abnormal ion exchange.
Diagnostic methods
The clinical diagnosis is based on family history, visual-acuity testing and funduscopy (showing yellow, round deposits of lipofuscin at the center of the macula). Full-field electroretinogram (ERG) is normal. Electro-oculography (EOG) measures standing potential of the eye by recording the Arden ratio (AR; ratio of light peak/dark trough; normal value ≥1.8). AR is usually decreased in BVMD (1.0-1.3). High-resolution optical coherence tomography may identify abnormal accumulation of lipofuscin between photoreceptors and RPE. Diagnosis is confirmed by genetic screening of BEST1.
Differential diagnosis
Differential diagnosis of BVMD includes adult-onset foveomacular vitelliform dystrophy, age-related macular degeneration, autosomal recessive bestrophinopathy, autosomal dominant vitreoretinochoroidopathy, retinitis pigmentosa (see these terms) and Bull's-eye maculopathy.
Antenatal diagnosis
Prenatal diagnosis and preimplantation genetic diagnosis is possible for families in which the disease-causing mutation is known.
Genetic counseling
BVMD is inherited in an autosomal dominant manner with complete penetrance. Age of onset and severity of vision loss show inter- and intrafamilial variability.
Management and treatment
Management is symptomatic and includes use of low vision aids for individuals with significant deterioration in visual acuity. Annual ophthalmologic examination for persons of all ages is recommended. Smoking should be avoided as it increases the risk of neovascular macular degeneration. Photodynamic therapy using verteporfin, direct laser photocoagulation or anti-VEGF agents (bevacizumab) may be options for treating CNV. Transcorneal electrical retinal stimulation may be used to treat BVMD.
Prognosis
BVMD may progress to geographic atrophy and in some cases is complicated by development of CNV. 7-9% of patients never experience vision loss, but have an aberrant EOG with normal ERG.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                            Pr Ian MACDONALD


A rare, genetic organic aciduria affecting ketone body metabolism and the catabolism of isoleucine and characterized by intermittent ketoacidotic episodes associated with vomiting, dyspnea, tachypnoea, hypotonia, lethargy and coma, with an onset during infancy and usually ceasing by adolescence.

Summary:
Epidemiology
The estimated birth prevalence ranges between 1/100,000 to 230,000 worldwide.
Clinical description
Children often appear normal at birth with disease presentation typically between the ages of 5 months to 2 years; however, presentation may occur anywhere between birth and childhood. The onset of symptoms usually occurs in the form of a ketoacidotic crisis, most often brought on by stress, fasting, acute illness and/or infections (i.e. gastroenteritis), and rarely by increased dietary protein intake. An acetone or fruity odor on the breath often signals ketoacidosis. These episodes are associated with vomiting, dyspnea, lethargy and unconsciousness, and can lead to coma and death if not treated. Neurological sequelae (such as developmental delay) following severe episodes are common. Rarely, patients present with signs of metabolic encephalopathy (hypotonia, dysarthria, chorea, developmental delay). The occurrence of developmental delay or neurological manifestations before a first ketoacidotic crisis, however, is rare. The frequency of episodes decreases with age, eventually stopping before adolescence. In between episodes, patients are often asymptomatic.
Etiology
This disease is caused by mutations (over 100 described) in the gene, ACAT1 (11q22.3). This gene encodes the enzyme acetyl-CoA acetyltransferase which, when its activity is reduced or absent, impairs the breakdown of isoleucine and acetoacetyl- CoA, hampering the utilization of ketone bodies and leading to toxic accumulations of isoleucine derived acyl-CoA esters in the body.
Diagnostic methods
Most patients are diagnosed by demonstrating metabolic acidosis and ketosis, by urinary organic acid analysis (2-methyl-3-hydroxybutyrate (the most reliable marker), 2- methylacetoacetate and tiglylglycine), or by acylcarnitine analysis during metabolic decompensation. Diagnosis can be confirmed by cultured fibroblast enzyme assays (reduced potassium-dependent acetoacetyl-CoA thiolase activity) and molecular genetic testing. Computed tomography of the brain may reveal basal ganglia lesions that have been reported in some patients. Newborn screening programs are available in certain countries including the U.S. and Australia.
Differential diagnosis
The differential diagnosis includes sepsis, other organic acidurias, HSD10 disease and succinyl-CoA:3-ketoacid CoA transferase deficiency, and other conditions that cause ketoacidosis in childhood.
Antenatal diagnosis
In families with a known disease causing mutation, prenatal testing is possible by molecular genetic testing or enzyme activity assays using cultured amniocytes.
Genetic counseling
The pattern of inheritance is autosomal recessive. The risk of inheriting the disease is 25% where both parents are unaffected carriers.
Management and treatment
During a ketoacidotic crisis, intravenous fluids with glucose and electrolytes should be administered immediately. Bicarbonate (initially as 1mmol/kg over 10 minutes followed by continuous infusion) should be given to treat acidosis. Carnitine supplementation may be helpful. Dialysis is effective but usually not necessary. Unconscious patients and those with severe dyspnea may require mechanical ventilation. Long-term management involves avoidance of fasting (and intravenous glucose in cases of fever or vomiting) and, in children, a mildly restricted protein intake (1.5-2g/kg/day), avoidance of fat-rich (ketogenic) diet, and L-carnitine therapy in those with low carnitine levels. Avoidance of isoleucine overload might prevent neurological complications, but currently there is no evidence to support this.
Prognosis
The prognosis is often good if detected early and treated properly so as to prevent ketoacidotic attacks.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Toshiyuki FUKAO  - Dr Hideo SASAI


Beta-mannosidosis is a very rare lysosomal storage disease characterized by developmental delay of varying severity and hearing loss, but that can manifest a wide phenotypic heterogeneity.


An extremely rare disorder of methionine cycle and sulfur amino acid metabolism characterized by increased urine excretion of beta-mercaptolactate-cysteine disulfide (due to deficiency of mercaptopyruvate sulfurtransferase activity in erythrocytes), leading to a positive cyanide nitroprusside test. Association with intellectual disability, congenital lens dislocation, and behavioral abnormalities has been reported, however the causal link remains to be established. There have been no further descriptions in the literature since 1981.


Beta-propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood, is a rare form of neurodegeneration with brain iron accumulation (NBIA) characterized by early-onset developmental delay and further neurological deterioration in early adulthood.


Beta-sarcoglycan-related limb-girdle muscular dystrophy R4

A subtype of autosomal recessive limb girdle muscular dystrophy characterized by a childhood to adolescent onset of progressive pelvic- and shoulder-girdle muscle weakness, particularly affecting the pelvic girdle (adductors and flexors of hip). Usually the knees are the earliest and most affected muscles. In advanced stages, involvement of the shoulder girdle (resulting in scapular winging) and the distal muscle groups are observed. Calf hypertrophy, cardiomyopathy, respiratory impairment, tendon contractures, scoliosis, and exercise-induced myoglobinuria may be observed.


Beta-thalassemia associated with another hemoglobin anomaly

Beta-thalassemias associated with hemoglobin (Hb) anomalies result in a variable clinical spectrum, ranging from asymptomatic to severe, depending on the severity of the thalassemia mutation and on the type of the Hb anomaly [hereditary persistence of fetal Hb, delta-beta-thalassemia, Hb C - beta-thalassemia, Hb E - beta-thalassemia and Hb S - beta-thalassemia (see these terms)].


Beta-thalassemia (BT) intermedia is a form of BT (see this term) characterized by mild to moderate anemia which does not or only occasionally requires transfusion.

Summary:
Epidemiology
BT is prevalent in Mediterranean countries, the Middle East, Central Asia, India, Southern China, North Africa and South America. The overall annual incidence of symptomatic cases of beta-thalassemia is estimated at 1/100,000 worldwide and 1/10,000 in the EU. Annual incidence of BT intermedia is not known.
Clinical description
BT intermedia encompasses a wide clinical spectrum with more severe cases presenting between 2 and 6 years of age with anemia, spleen and sometimes liver enlargement, as well as delayed growth and development. In other cases, patients are completely asymptomatic until adult life with only mild anemia. Hypertrophy of erythroid marrow, with the possibility of extramedullary erythropoiesis, is common and leads to characteristic deformities of the bone and face, osteoporosis with pathologic fractures of long bones and formation of erythropoietic masses primarily affecting the spleen, liver, lymph nodes, chest and spine. Less commonly, erythroid marrow hypertrophy may cause neurological problems (spinal cord compression with paraplegia). Patients may also develop leg ulcers and gallstones. An increased predisposition to thrombosis versus BT major has been reported, especially after splenectomy. Although patients are at risk of iron overload, hypogonadism, hypothyroidism and diabetes are not common. Cardiac involvement may also occur as a result of a high-output state and pulmonary hypertension, while systolic left ventricle function is usually preserved.
Etiology
BT intermedia is caused by minor and/or silent mutations in the HBB gene (11p15.5) encoding the beta-chains of hemoglobin (Hb), in the homozygous or compound heterozygous state.
Diagnostic methods
Diagnosis is based on clinical findings, hematological tests (Hb level between 7 and 10 g/dl, mean corpuscular volume (MCV) between 50 and 80 fl and mean corpuscular Hb (MCH)between 16 and 24 pg), hemoglobin analysis and molecular genetic testing.
Differential diagnosis
Differential diagnosis is usually simple but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as myelomonocytic leukemia and aplastic anemia; see these terms).
Genetic counseling
Transmission is commonly autosomal recessive and autosomal dominant forms have rarely been reported (dominant beta-thalassemia; see this term). Genetic counseling provides information for patients and at-risk couples (i.e. both carriers) regarding the mode of inheritance, transmission and clinical phenotype. However, there are not always exact genotype-phenotype correlations and prenatal diagnosis is performed in selected cases.
Management and treatment
Treatment is symptomatic. Supplementary folic acid can be prescribed to prevent deficiency from hyperactive bone marrow. Treatment of extramedullary erythropoietic masses is based on radiotherapy, transfusions, or hydroxycarbamide. Main indications for splenectomy are symptoms of splenic enlargement, worsening of anemia (not explained by transient factors such as infection) sometimes associated with leukopenia and/or thrombocytopenia, delayed growth, and heart disease. Iron overload is controlled with chelation therapy. Suitable anticoagulation therapy must be administered before surgery to prevent thrombosis. Pregnant patients need a multidisciplinary approach including specialists in thalassemia care.
Prognosis
Prognosis is usually good with appropriate monitoring and treatment. Patients do not usually have severe hemosiderosis and are less prone to iron overload-related cardiac problems. Pulmonary hypertension, thromboembolic complications, overwhelming postsplenectomy sepsis, and the development of hepatocarcinoma may however reduce survival.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA


Beta-thalassemia (BT) major is a severe early-onset form of BT (see this term) characterized by severe anemia requiring regular red blood cell transfusions.

Summary:
Epidemiology
The annual incidence of symptomatic cases is estimated at 1/100,000 worldwide and 1/10,000 in the EU. The prevalence of this form is not known.
Clinical description
Onset is during infancy with severe anemia, failure to thrive and progressive pallor. Feeding problems, diarrhea, irritability, recurrent bouts of fever, and progressive enlargement of the abdomen caused by splenomegaly and hepatomegaly may occur. Untreated or poorly transfused patients show growth retardation, pallor, jaundice, poor musculature, genu valgum, leg ulcers, formation of masses due to extramedullary hematopoiesis, and skeletal changes including deformities in the long bones of the legs and typical craniofacial changes such as bossing of the skull, prominent malar eminence, depression of the bridge of the nose, tendency to a mongoloid slant of the eye, and maxillae hypertrophy, which tends to expose upper teeth. In regularly transfused patients, growth and development tend to be normal but complications related to iron overload may develop, including growth retardation and failure or delay of sexual maturation. Later-onset iron overload complications include dilated myocardiopathy, arrhythmias, liver fibrosis and cirrhosis, diabetes mellitus, and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands. Other complications are hypersplenism, venous thrombosis and osteoporosis.
Etiology
BT is caused by point mutations or, more rarely, deletions in the HBB gene (11p15.5), leading to reduced (beta+) or absent (beta0) synthesis of the beta-chains of hemoglobin (Hb). Mutations causing BT major are homozygous or compound heterozygous.
Diagnostic methods
Diagnosis is suspected in infants younger than 2 years of age with severe microcytic anemia, mild jaundice and hepatosplenomegaly. Blood analysis shows reduced Hb levels (< 7 g/dl), mean corpuscular volume (MCV) > 50 < 70 fl, and mean corpuscular Hb (MCH) > 12 < 20 pg, anisopoikilocytosis and presence of erythroblasts in the peripheral blood smear. Hb analysis and molecular genetic analysis provide diagnostic confirmation.
Differential diagnosis
Differential diagnosis is usually simple but may include genetic sideroblastic anemias, congenital dyserythropoietic anemias, and other conditions with high levels of HbF (such as juvenile myelomonocytic leukemia and aplastic anemias; see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible by amniocentesis. Both disease-causing alleles must be identified before prenatal testing can be performed.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling provides information for patients and at-risk couples (i.e. both carriers) regarding the mode of inheritance and transmission. Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified.
Management and treatment
Treatment is based on lifelong transfusions to correct anemia, suppress erythropoiesis, and inhibition of gastrointestinal iron absorption, which occurs in non-transfused patients due to increased, although ineffective, erythropoiesis. Iron chelation should be started once patients have had 10-15 transfusions or when ferritin levels are above 1000 ng/ml. Management should also include treatment of iron overload-related complications (growth deficiency, delayed puberty, hypogonadism, hypopara- and hypothyroidism, diabetes, and osteoporosis). Splenectomy may be required. Bone marrow transplantation (BMT) is at present the only available definitive cure. Recently a first patient was successfully treated with gene therapy.
Prognosis
Patients who do not receive regular transfusions and iron chelation usually die before the 2nd or 3rd decade whereas survival is higher in regularly transfused and chelated patients. Cardiac complications are still the major cause of death.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA


Beta-thalassemia with other manifestations

Beta-thalassemias with other manifestations are a group of beta-thalassemias (see this term) associated with another disorder.

Summary:
Etiology
These forms of beta-thalassemia are not related to defects in the beta-globin gene cluster but to mutations either in the gene encoding the transcription factor TFIIH (beta-thalassemia - trichothiodystrophy) or in the X-linked transcription factor GATA-1 (beta-thalassemia - X-linked thrombocytopenia; see these terms).

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA


Beta-thalassemia - X-linked thrombocytopenia is a form of beta-thalassemia (see this term) characterized by splenomegaly and petechiae, moderate thrombocytopenia, prolonged bleeding time due to platelet dysfunction, reticulocytosis and mild beta-thalassemia.

Summary:
Epidemiology
Prevalence of this form is not known.
Etiology
The disorder is not associated with mutations in the HBB gene (11p15.5), but with mutations in the gene encoding GATA-binding protein-1 (GATA1; Xp11.23) that result in reduced expression of the beta-globin genes.
Genetic counseling
Transmission is X-linked.

                            Last update:
                            May 2011

                            - Expert reviewer(s):
                            Pr Renzo GALANELLO  - Dr Raffaella ORIGA


Beta-thalassemia (BT) is characterized by deficiency (Beta+) or absence (Beta0) of synthesis of the beta globin chains of hemoglobin (Hb).

Summary:
Epidemiology
Exact prevalence is unknown but annual incidence at birth of symptomatic BT is estimated at 1/100,000 worldwide. The disease was initially described in the Mediterranean basin but severe forms of BT frequently occur throughout the Middle East, South East Asia, India and China. Population migrations have lead to global distribution of the disease.
Clinical description
Three main types of BT have been described (minor, intermedia and major; see these terms). 1) Thalassemia minor (BT-minor, BT trait) is the heterozygous form and is usually asymptomatic. 2) Thalassemia major (Cooley anemia; BT-major) is the homozygous form and associates splenomegaly and microcytic and hypochromic anemia resulting from dyserythropoiesis and hemolysis. Onset generally occurs from 6-24 months of age. The severe anemia requires systematic transfusions to maintain Hb levels above the range of 90-100 g/L and to allow normal activity. Long-term transfusion of red cell concentrates results in iron overload which hampers the vital prognosis (mainly due to cardiac involvement) and causes significant morbidity (due to endocrinal and hepatic iron deposition). 3) Thalassemia intermedia (BTI) in which the anemia is less severe and diagnosed later in life compared to BT-major. Patients with BTI may or may not require occasional transfusions. Hypersplenism, cholelithiasis, extramedullary hematopoiesis, thrombotic complications and progressive iron overload are the main clinical features that may complicate the course of BTI. Other forms include BT associated with Hb anomalies (HbE - beta-thalassemia resulting in BTI or less frequently BT-major, HbC - beta-thalassemia, delta-beta-thalassemia and hereditary persistence of fetal Hb with BT resulting in inconstant manifestations of BTI; see these terms). Rare autosomal dominant forms have also been described (dominant beta-thalassemia; see this term). In rare instances, BT trait is associated with trichothiodystrophy or X-linked thrombocytopenia (see these terms).
Diagnostic methods
Diagnosis of BT anemia relies on analysis of Hb by electrophoresis or HPLC. In BT-major, HbA is absent or greatly reduced and HbF predominates. In BT-minor, the levels of HbA2 are increased and the levels Hb are usually normal to low with microcytosis and hypochromia.
Genetic counseling
Transmission is autosomal recessive and around 200 mutations (B0 or B+) have been identified. Genetic counseling is recommended to permit couples who are at risk an informed choice among available options including prenatal diagnosis.
Management and treatment
There are two major treatment options for BT. 1) A combination of regular transfusions and iron chelation therapy with early and regular parenteral deferoxamine administration has led to increased survival during the last 40 years. Availability of new oral iron chelators and monitoring of cardiac iron overload by MRI result in further clinical improvement and current evaluation is ongoing to determine their impact on morbidity and mortality. In 2006, deferasirox, a once-daily orally administered iron chelator, obtained EU marketing authorization as an Orphan drug for first-line treatment of BT-related iron overload. The marketing authorization for deferiprone, another orally active iron chelator, particularly effective in removing heart iron, is restricted to cases in which treatment with deferoxamine fails or is contraindicated. 2) Hematopoietic stem cell transplant is the curative treatment for BT major: results are very favorable for children displaying an HLA-identical familial donor. Recently, a first patient was successfully treated with gene therapy.
Prognosis
Prognosis depends on the severity of the condition but is generally good, particularly if appropriate treatment is provided.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr Isabelle THURET


Beta-ureidopropionase deficiency is a very rare pyrimidine metabolism disorder described in fewer than 10 patients to date with an extremely wide clinical picture ranging from asymptomatic cases to neurological (epilepsy, autism) and developmental disorders (urogenital, colorectal).


A form of congenital muscular dystrophy characterized by a congenital to childhood onset of progressive proximal muscle weakness, joint contractures, and potential respiratory insufficiency in adulthood.

Summary:
Epidemiology
A Northern England study of genetic muscle disease reported an estimated prevalence of Bethlem muscular dystrophy of 1/129,870 people.
Clinical description
Patients present with hypotonia and delayed motor milestones in early childhood; mild hypotonia and muscle weakness may be present at birth and slowly progresses during the patient's lifetime. Proximal muscle weakness and joint contractures of the elbows, Achilles tendons, and long finger flexors are evident by adulthood. More than 2/3rd of the patients aged >50 years require mobility aids outdoors. Respiratory involvement in some patients can result in respiratory insufficiency in aduldhood, necessitating nocturnal non-invasive ventilation (NIV).
Etiology
The disease is caused by mutations in the genes coding for the alpha chains of the extracellular matrix protein collagen VI (COL6A1, COL6A2, and COL6A3) and can be inherited in an autosomal dominant or autosomal recessive manner.
Diagnostic methods
The diagnosis of Bethlem myopathy is established in a proband with characteristic clinical, muscle imaging, and muscle immunohistochemical features and the identification of a heterozygous or biallelic pathogenic variants (PVs) in COL6A1, COL6A2 or COL6A3 by molecular genetic testing. Muscle biopsy shows degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue. Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI. Muscle MRI can be an excellent diagnostic tool to identify characteristic patterns of abnormal muscle signaling.
Differential diagnosis
The differential diagnosis includes intermediate COL6-related dystrophy (COL6-RD), Ehlers-Danlos/myopathy overlap syndrome (including COL12A1-related myopathy), limb-girdle muscular dystrophies (LGMDs) including calpainopathy (also called LGMDR1 and LGMD2A) due to PVs in CAPN, Emery-Dreifuss muscular dystrophy due to PVs in EMD, FHL1, or LMNA, FHL1-related myopathy, LAMA2-related dystropy (the partial merosin deficiency subtype), and TTN-related myopathy (the «contractural» phenotype).
Antenatal diagnosis
Once PVs have been identified in an affected family member, prenatal diagnosis and preimplantation genetic testing are possible.
Genetic counseling
Bethlem muscular dystrophy is usually inherited by an autosomal dominant PV in COL6A1, COL6A2 or COL6A3; in these cases, each child of an affected individual has a 50% chance of inheriting a PV. Less commonly, Bethlem muscular dystrophy can be inherited in an autosomal recessive manner; if both parents are carriers of a disease-causing mutation, they should be informed that there is a 25% risk of having an affected child with each pregnancy. Parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in COL6-RDs and should be considered, given the implications for recurrence risk assessment.
Management and treatment
Currently, there is no curative treatment; however, careful pulmonary surveillance and proactive care improve the quality of life of affected individuals. Non-invasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) may be necessary to support nocturnal ventilation during adulthood. Use of a mechanical insufflator-exsufflator promotes airway clearance. Physical therapy and occupational therapy are important for providing recommendations for joint stretching, swimming, and aquatherapy. Achilles tendon contractures should be managed with splints and/or tendon release surgery.
Prognosis
Proximal weakness and joint contractures develop by adulthood. The disease progression is slow with more than 2/3rd of patients aged >50 years old requiring mobility aids (crutches, canes, wheelchair) outdoors. In some patients, respiratory muscle weakness, particularly of the diaphragm, can result in respiratory insufficiency in aduldhood.

                            Last update:
                            October 2023

                            - Expert reviewer(s):
                            Dr Carsten G. BONNEMANN  - Dr A. Reghan FOLEY


A rare autoimmune encephalitis/neuropathy characterized by disturbances of consciousness, ophthalmoplegia, ataxia, and hyperreflexia. It has common clinical features with Miller Fisher syndrome.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Patients usually present with onset of diplopia and gait disturbance (gait ataxia) followed by disturbances of consciousness and hyperreflexia, typically following upper respiratory or gastrointestinal tract infections. The symptoms are progressive (within 4 weeks of onset). Flaccid symmetrical tetraparesis may also be observed in 60% of the patients, together with deep or superficial sensory impairment, facial weakness, bulbar palsy, internal ophthalmoplegia, blepharoptosis and nystagmus. In the acute phase of disease, BBE may be so severe that there is coma and complete ophthalmoplegia. Brain MRI studies are usually unremarkable.
Etiology
BBE has been reported to occur following upper respiratory or gastrointestinal tract infections. Although the exact pathological mechanism is not fully understood, BBE is associated with the presence of the antiganglioside antibody, anti-GQ1b.
Diagnostic methods
Diagnosis is based on the clinical findings, patient history, cerebrospinal fluid (CSF) analysis (revealing raised protein levels), detection of serum anti-GQ1b IgG antibodies (not present in all patients). MRI studies are usually unremarkable. Electroencephalogram and electromyography are indicative of central nervous system and predominantly in the brainstem.
Differential diagnosis
BBE shows clinical overlap with Miller-Fisher syndrome (MFS), a cranial nerve variant of Guillain-Barré syndrome (GBS), as well as with the axonal forms of GBS (acute motor axonal neuropathy and acute motor-sensory axonal neuropathy) in patients with limb weakness, leading several authors to suggest that BBE, MFS and GBS represent variable manifestations of the same clinical spectrum. The differential diagnosis in patients with BBE should also include acute disseminated encephalomyelitis (ADEM), as well as rare post-infectious neurological disorders.
Management and treatment
Management is based on immunotherapy with intravenous immunoglobulin (IVIg) or plasma exchange.
Prognosis
Although the clinical picture is severe, the disease course is generally monophasic with complete remission of symptoms within 6 months in over half of the patients. Other patients may have mild to severe residual findings.

                            Last update:
                            November 2023

                            - Expert reviewer(s):
                            Pr Satoshi KUWABARA


Biemond syndrome type 2 (BS2) is a rare genetic neurological and developmental disorder reported in a very small number of patients with a poorly defined phenotype which includes iris coloboma, short stature, obesity, hypogonadism, postaxial polydactyly, and intellectual disability. Hydrocephalus and facial dysostosis were also reported. BS2 shares features with Bardet-Biedl syndrome. There have been no further descriptions in the literature since 1997.


A rare progressive autosomal recessive tapetoretinal degeneration disease, occurring in the third decade of life, characterized by small sparkling crystalline deposits in the posterior retina and corneal limbus in addition to sclerosis of the choroidal vessels and manifesting as nightblindness, decreased vision, paracentral scotoma, and, in the end stages of the disease, legal blindness.


A rare congenital nose and cavum anomaly characterized by clefting of the nose ranging from a minimally noticeable groove in the columella to complete clefting of the underlying bones and cartilage (resulting in two half noses) with a usually adequate airway. Bifid nose may be seen in frontonasal dysplasia; other malformations such as hypertelorbitism and midline clefts of the lip may also be associated.


Bifid uvula is a fissure type embryopathy affecting the uvula at the back of the soft palate.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
The cleft in the uvula is median. The clinical forms range from a simple posterior notch to the complete duplication of the uvula. Bifid uvula has no clinical repercussions.
Etiology
This embryopathy appears in the 7th to 12th week of pregnancy following an error in the fusion of the palatine process, which usually involves a fusion that occurs from the front to back of the hard palate, the soft palate and then the uvula. Genetic, environmental and toxic factors are all possible causes.
Diagnostic methods
Although bifid uvula is usually isolated, it can also been seen in syndromic forms. Usually discovered by chance, it is important to eliminate any association with a submucous cleft velum. A submucous cleft velum is a specific form of cleft palate where a cleft in the muscular tissue is covered by the oral and nasal mucosa.
Management and treatment
When bifid uvula is isolated, there are no clinical repercussions and it can be considered as a familial genetic trait. In the isolated forms, once an associated submucous cleft has been ruled out, there is no therapeutic management necessary in the absence of clinical manifestations.

                            Last update:
                            December 2011

                            - Expert reviewer(s):
                            Dr Eva GALLIANI  - Pr Marie-Paule VAZQUEZ


A rare peroxisomal beta-oxidation disorder characterized by deficiency of peroxisomal D-bifunctional protein, type 1 being caused by deficiency of both dehydrogenase and hydratase activities of the enzyme, and types 2 and 3 by hydratase or dehydrogenase deficiency alone, while type 4 is due to compound heterozygous mutations affecting both units and represents a clinically milder phenotype. Types 1-3 are typically fatal in infancy. Patients present with early onset of generalized hypotonia, seizures, severe global developmental delay, craniofacial dysmorphism (large fontanel, high forehead, hypertelorism, epicanthal folds) and elevated plasma very long chain fatty acids. Variable features include hepatomegaly, polymicrogyria, and cerebral white matter abnormalities, among others.


Bilateral acute depigmentation of the iris (BADI) is characterized by acute onset of bilateral iris depigmentation, pigment dispersion in the anterior chamber, and heavy pigment deposition in the anterior chamber angle. Patients typically present with acute and usually severe photophobia, blurred vision, red eye, and ocular discomfort or pain with a usually self-limiting clinical course. Cases often occur after a flu-like illness, upper respiratory tract infection, and after the use of oral moxifloxacin. When associated with iris epithelial depigmentation, iris transillumination defects and atonic/mydriatic pupil, the condition is referred to as bilateral acute iris transillumination (BAIT) which has an increased risk of severe intractable rise in intraocular pressure.


Bilateral frontoparietal polymicrogyria (BFPP) is a sub-type of polymicrogyria (PMG; see this term), a cerebral cortical malformation characterized by excessive cortical folding and abnormal cortical layering, that involves the frontoparietal region of the brain and that presents with hypotonia, developmental delay, moderate to severe intellectual disability, pyramidal signs, epileptic seizures, non progressive cerebellar ataxia, dysconjugate gaze and/or strabismus.


Bilateral microtia-deafness-cleft palate syndrome

A rare genetic, orofacial clefting syndrome characterized by the association of bilateral microtia with severe to profound hearing impairment, and cleft palate.


A rare lethal form of multicystic dysplastic kidney (MCDK), a congenital anomaly of the kidney and urinary tract (CAKUT), in which both kidneys are large, distended by non-communicating multiple cysts and non-functional.

Summary:
Epidemiology
The prevalence and incidence of bilateral MCDK are unknown.
Clinical description
Bilateral MCDK may be suspected antenatally at routine ultrasound scans, with the majority detected around the 20th week of gestation. It is considered a lethal entity, and most pregnancies are terminated. When born, such infants present with features of the Potter sequence (constellation of signs resulting from prolonged in utero oligohydramnios) including severe pulmonary hypoplasia and severe renal failure, limb anomalies and facial dysmorphic features, and generally die shortly after birth.
Etiology
MCDK results from disrupted nephrogenesis but the exact pathogenic mechanism is still unknown. Disturbed formation of nephrons could result from impaired fetal urine flow early in development. Mutations in the HNF1B gene (17q12), coding for hepatocyte nuclear transcription factor 1beta, are known to cause unilateral MCDK and have only rarely been reported for bilateral cases. MCDK is also linked to gestational diabetes and to the use of some medications during pregnancy, such as anti-epileptic drugs.
Diagnostic methods
Diagnosis is mainly based on prenatal ultrasound showing large hypoechogenic, non-communicating cysts within an irregularly outlined kidney with no visible renal pelvis. A tiny remnant kidney can be observed if the cysts have involuted. In addition, oligo/anhydramnios is present as a sign of poor functional renal development.
Differential diagnosis
Differential diagnoses include bilateral pelviureteric junction obstruction, in which the largely dilated calices may appear to be cysts. Posterior urethral valves may result in oligo/anhydramnios, and the megaureter may be mistaken for renal cysts.
Antenatal diagnosis
Ultrasonographic screening can detect MCDKs from midway through gestation.
Genetic counseling
Both sporadic and familial cases have been observed. In familial cases, transmission is autosomal dominant with a recurrence risk of 50%.
Management and treatment
As the absence of functional renal tissue results in anhydramnios with pulmonary hypoplasia (Potter sequence), which is generally lethal shortly after birth, most pregnancies with bilateral MCDK will be terminated. When children with bilateral MCDK survive the early postnatal period, renal replacement therapy will be needed.
Prognosis
Bilateral MCDK is considered a lethal entity.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr M.F. [Michiel] SCHREUDER | ERKNet*

                                * European Reference Network


Bilateral polymicrogyria is a rare cerebral malformation due to abnormal neuronal migration defined as a cerebral cortex with many excessively small convolutions. It presents with developmental delay, intellectual disability, seizures and various neurological impairments and may be isolated or comprise a clinical feature of many genetic syndromes. It may also be associated with perinatal cytomegalovirus infection.


Bilateral striopallidodentate calcinosis (BSPDC, also erroneously called Fahr disease) is characterized by the accumulation of calcium deposits in different brain regions, particularly the basal ganglia and dentate nucleus, and is often associated with neurodegeneration.

Summary:
Epidemiology
The prevalence of BSPDC is not known, however it is very rare and fewer than 200 cases have been reported. BSPDC is more common in men (male:female ratio 2:1).
Clinical description
BSPCD can be asymptomatic. Symptomatic forms usually manifest in the fourth decade of life, whereas calcification may be found in the second decade. Patients present with progressive movement disorders, including parkinsonism, chorea, tremor, dystonia, athetosis and orofacial dyskinesia, ataxia and neuropsychiatric disorders including difficultly with concentration and memory, personality and/or behavior changes, and dementia. The first manifestations often include clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements or muscle cramping. Seizures occur frequently. Urinary incontinence may occur.
Etiology
The causative gene or genes are not known. Linkage to chromosome 14q has been established in one family. Calcium is the major element deposited on the basal ganglia and accounts for the radiologic appearance of the disease. It is thought that the calcifications observed are a marker of the disease rather than a cause of the clinical symptoms.
Diagnostic methods
Single proton emission computed tomography (SPECT) reveals markedly decreased perfusion to the basal ganglia bilaterally with decreased perfusion to the cerebral cortices. Diagnosis is based on CT or MRI evidence of bilateral, almost symmetric, calcifications of one or more of the following areas: basal ganglia, dentate nuclei, thalamus and cerebral white matter. Diagnosis is further based on normal childhood growth and development and the absence of parathyroid or other known neurologic disorders. Electroencephalogram, nerve conduction studies, and pattern shift visual-evoked potentials studies are usually normal and brainstem auditory-evoked potentials may vary from normal to minor abnormalities.
Differential diagnosis
Differential diagnoses include hypoparathyroidism and pseudohypoparathyroidism, which can usually be excluded by normal serum levels of parathyroid hormone, Kenny-Caffey syndrome type 1, neurodegeneration with iron accumulation, Cockayne syndrome and Aicardi-Goutières syndrome (see these terms).
Antenatal diagnosis
Genetic counseling may be offered.However, there is currently no possibility of antenatal diagnosis.
Genetic counseling
It can be familial or sporadic. Over 30 families with the familial form have been reported. The familial form of idiopathic basal ganglia calcification is inherited in an autosomal dominant manner.
Management and treatment
There is no specific treatment available. Treatment based on amelioration of manifestations, including pharmacologic treatment for anxiety, depression, obsessive-compulsive behaviors and dystonia, may be attempted.
Prognosis
Prognosis is not fully understood due to a lack of longitudinal studies. However, while asymptomatic cases have been observed in individuals younger than 25 years old, it is possible that symptoms may appear with increasing age.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Pr Bala MANYAM


Bile acid CoA ligase deficiency and defective amidation is an anomaly of bile acid synthesis (see this term) characterized by fat malabsorption, neonatal cholestasis and growth failure.

Summary:
Epidemiology
Prevalence is unknown. Only 8 cases have been reported.
Clinical description
Patients present with a history of neonatal cholestasis, fat and fat-soluble vitamin malabsorption (rickets or bleeding secondary to hypoprothrombinemia) and growth failure.
Etiology
Several mutations in the bile acid-CoA ligase gene have been found in most patients with this defect.
Genetic counseling
The mode of transmission of these mutations is not known.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Pr James HEUBI


Biliary atresia with splenic malformation syndrome (BASM) designates the association of biliary atresia (see this term) and splenic abnormalities (mainly polysplenia and less frequently asplenia, double spleen). Cardiac defect, situs inversus and a preduodenal portal vein can also be present. It represents the embryonal or syndromic form of biliary atresia. It affects newborns or infants and is characterized by jaundice, pale stools, dark urine, failure to thrive, hepatomegaly, coagulopathy, anemia and often palpable spleen.


Biotin-thiamine-responsive basal ganglia disease

A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness. Imaging may reveal bilateral lesions in the basal ganglia. The disease usually becomes symptomatic in childhood and is life-threatening if left untreated, but symptoms can be reversed and progression prevented by treatment with high doses of biotin and thiamine.


A late-onset form of multiple carboxylase deficiency, an inborn error of biotin metabolism that, if untreated, is characterized by seizures, breathing difficulties, hypotonia, skin rash, alopecia, hearing loss and delayed development.

Summary:
Epidemiology
Prevalence of clinical biotinidase deficiency (BD) is estimated to be 1/61,000. Carrier frequency in the general population is approximately 1/120.
Clinical description
Symptoms of BD deficiency typically appear within the first few months of life, but later onset has also been reported. Individuals with untreated profound deficiency (less than 10 % of mean normal serum biotinidase activity) have variable clinical findings including seizures, hypotonia, eczematoid rash, alopecia, ataxia, hearing loss, fungal infections, and developmental delay. Metabolically, untreated children can exhibit ketolactic acidosis, organic acidemia (-uria) and mild hyperammonemia. Individuals with untreated partial BD (10% to 30% of mean normal biotinidase activity) may be asymptomatic, but during periods of stress, such as illness, fever or fasting, may develop symptoms similar to those of individuals with profound BD. Multiple adults with optic neuropathy and/or peripheral neuropathy, that is often mistakenly diagnosed as multiple sclerosis, have been shown to have profound biotinidase deficiency.
Etiology
BD deficiency is caused by mutations in the BTD gene (3p25) resulting in reduced or absent biotinidase activity. This enzyme recycles free, non-protein bound, biotin which is required for multiple biotin-dependent metabolic processes. There are more than 150 known mutations of the BTD gene that cause BD.
Diagnostic methods
The disorder is detected through newborn screening when available. Other cases are diagnosed by clinical signs and symptoms and confirmed by demonstration of deficient serum biotinidase activity. Molecular mutation analysis of the BTD gene is also possible.
Differential diagnosis
The symptoms of BD overlap with those of other metabolic diseases, including holocarboxylase synthetase deficiency, isolated carboxylase deficiency, nutritional biotin deficiency, zinc deficiency and essential fatty acid deficiency. Testing for biotinidase deficiency should be considered in all individuals thought to have multiple sclerosis.
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is possible and can be performed by enzymatic analysis or by mutation analysis when the mutation is known. However, because of the treatability of the disorder, prenatal testing is not considered by most families.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child for each pregnancy. Siblings of patients with BD should be tested for the deficiency even if they do not exhibit symptoms.
Management and treatment
Supplementation with oral biotin in the free, non-protein bound, form is the primary treatment and improves symptoms in symptomatic patients, and prevents symptoms in those identified by newborn screening or before symptoms have developed. Once some features, such as optic atrophy, hearing loss, or developmental delay develop, they may not be reversible with biotin treatment. Treatment with biotin should be maintained lifelong. There are no known, serious adverse effects of biotin therapy. Patients and their families should be warned about the importance of treatment compliance. Periodic ophthalmological, neurological and metabolic evaluations are recommended. Raw eggs should be avoided because of their avidin content (biotin-binding substance), but cooking inactivates the binding effect of avidin.
Prognosis
The prognosis for individuals diagnosed with BD is very good, provided they are treated before symptoms occur and are compliant with biotin therapy. In adult patients presenting with optic neuropathy and/or peripheral neuropathy, improvement in symptoms is likely with early intervention. However, if such individuals remain symptomatic for too long a period, their symptoms may be irreversible.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Dr Barry WOLF


A rare, genetic bone disorder characterized by the presence of two non-fused talar bone fragments, with the posterior fragment located at the level of the posterior talar process. Patients may present with foot and/or ankle pain (exercise-induced or not), repetitive ankle sprains, chronic ankle ligamentous laxity, restricted ankle motion (i.e. plantar flexion, eversion, and inversion), and mild swelling.


Birdshot chorioretinopathy is a posterior uveitis characterized by multiple cream-colored, hypopigmented choroidal lesions in the fundus and a strong association with HLA-A29 and clinically presenting with blurred vision, floaters, photopsia, scotoma and nyctalopia.

Summary:
Epidemiology
The disease is more common in North European descents with a female preponderance. It accounts for 6%-8% of cases of posterior uveitis. Prevalence in North Carolina is estimated to be 1/700,000.
Clinical description
The age of onset is usually the fifth or sixth decade of life. Patients often present with gradual deterioration of vision, floaters, photopsia, scotoma, nyctalopia, metamorphopsia and poor color and contrast sensitivity. Decreased visual acuity in early disease is attributed to macular edema. Persistent inflammation and optic disc edema can lead to optic atrophy and subsequent permanent visual loss. In majority of the patients, the disease is chronic and progressive while 20% of patients develop a limited disease with spontaneous remission. A systemic involvement including essential hypertension, cerebrovascular accidents, hearing loss, vitiligo (see this term) and psoriasis is rarely observed.
Etiology
Etiology is unknown but an organ -specific T-cell - driven autoimmune process is implicated, with both choroid and retina being independent targets and sites of inflammation. The Th17 system has also been implicated but this remains unconfirmed. A strong association with HLA-A29 is noted.
Diagnostic methods
The diagnosis is based on clinical findings, supportive flourescein angiography and HLA testing (<50% positive predictive value, as 8% of general population are HLA-A29+), The visual fields may show blind spot enlargement, central/ paracentral scotomas or constriction of the peripheral vision. Fundoscopy reveals characteristic multifocal, hypopigmented, ovoid, cream-colored lesions (50-1500 µm) at the level of the choroid and retinal pigment epithelium in the postequatorial fundus displaying a nasal and radial distribution. Angiography (Indocyanine green (ICG), flourescin) reveals multiple hypofluorescent spots (birdshot lesions), vascular leakage, macular edema, disc edema, optic atrophy and neovascularization (in later stages).
Differential diagnosis
The differential diagnoses are those diseases that produce white dots in choroid and retina; they include white dot syndromes, vogt-Koyanagi-Harada disease, infectious etiologies (Lyme disease, tuberculosis, toxoplasmosis) and primary intraocular lymphoma (masquerade syndromes) (see these terms).
Genetic counseling
More than 95 percent of patients with birdshot chorioretinopathy are HLA-A29 positive. However, the disease is not considered heritable.
Management and treatment
Electroretinography, flourescin angiography and perimetry are important in the follow-up of patients with Birdshot retinopathy. While periocular, ocular, intravitreal and systemic corticosteroids may be effective in the short-term management of vitritis and macular edema, they are of inconsistent efficacy in the long run. Early introduction of corticosteroid-sparing immune modulatory treatment (cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, tacrolimus, human immunoglobulin G) is advocated, as extended treatment is anticipated in most patients. For refractory cases, daclizumab and infliximab has been helpful.
Prognosis
Preservation of central vision until late in the disease and induction of long-term remission are possible with treatment, however the long-term visual prognosis of this disorder remains guarded.

                            Last update:
                            May 2014

                            - Expert reviewer(s):
                            Dr Simon TAYLOR


A rare inherited cancer-predisposing syndrome characterized by skin lesions, benign and malignant kidney tumors, and pulmonary cysts that may be associated with pneumothorax.

Summary:
Epidemiology
The prevalence of Birt-Hogg-Dubé syndrome (BHD) is estimated at 1/200,000 but the exact incidence is unknown. More than 500 families affected by BHD have been reported so far.
Clinical description
Numerous pleural and subpleural cysts are present in more than 80% of adult BHD patients. They can cause single or recurrent spontaneous pneumothorax, mainly between 20-40 years old. The estimated prevalence of pneumothorax is about 22-38%. The lifetime risk for malignant renal cell carcinoma is estimated to be 20%, with a mean age at diagnosis around 50 years old. The kidney tumors in BHD patients can be multifocal and bilateral and range from benign oncocytomas to malignant renal cell carcinomas including chromophobe, clear cell or papillary subtypes. Chromophobe/oncocytoma hybrid renal cell cancer tumors are characteristic for BHD. Possible associations of BHD with additional tumor types, including colon cancer, thyroid cancer, parotic gland tumors and malignant melanoma, have been reported. The typical skin lesions are fibrofolliculomas that often start to appear between 20-40 years of age and tend to increase in number. Fibrofolliculomas are typically located on the face (especially paranasal and on the forehead) and in the retroauricular regions and on the neck / upper trunk and present as multiple small (2-5 mm) whitish papules. Histopathologically, they are characterized by sharply demarcated intradermal tumors due to a proliferation of collagen and epithelial strands from the upper part of the follicle epithelium protruding into surrounding thickened, basophil, fibro-mucinous stroma. Patients also might develop trichodiscomas and acrochordons.
Etiology
BHD syndrome is transmitted in an autosomal dominant fashion. The causative gene, FLCN, is located on chromosome 17p11.2. The FLCN gene encodes folliculin, a protein involved in different important cell functions, including autophagy, regulation of transcription factors, amino acid sensing and lysosomal signaling.
Diagnostic methods
Clinical diagnosis relies on recognition of typical combinations of clinical manifestations, such as multiple lung cysts, fibrofolliculomas and/or chromophobe/oncocytoma hybrid renal cell cancer tumors. The diagnosis can be confirmed by detection of pathogenic variants in the FLCN gene.
Differential diagnosis
Sporadic pulmonary lymphangioleiomyomatosis (LAM) also can present with multiple lung cysts.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The disorder is autosomal dominant, genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
So far there are no consensus recommendations for clinical surveillance. Provisional recommendations: BHD patients should receive abdominal/pelvic MRI to screen for renal tumor(s) every 1-2 years, starting at 20 years of age. Pneumothoraces are treated as usual; regular screening of the lung by CT is not recommended. Fibrofolliculomas are benign lesions but can be a cosmetic concern for the patients. The definitive treatment for solitary or very prominent lesions is surgical removal. Ablative laser treatment or dermabrasion are treatment options for more extensive areas, but lesions may recur and patients must be aware that scarring can be a possible side effect. Patients with BHD should be screened and pulmonary, renal, and gastrointestinal findings should be managed. Coloscopy every three years, starting at age 40 years and annual ultrasound screening of thyroid and parotid glands should be considered.
Prognosis
The prognosis for patients with BHD depends mainly on early detection and treatment of renal cell cancer. Recurrent pneumothoraxes might affect quality of life and multiple fibrofolliculomas might be perceived disfiguring by the patient.

                            Last update:
                            November 2023

                            - Expert reviewer(s):
                            Dr Elke SATTLER  - Pr Ortrud STEINLEIN


Björnstad syndrome is characterized by congenital sensorineural hearing loss and pili torti.

Summary:
Epidemiology
Less than fifty cases have been reported so far.
Clinical description
The hearing loss usually becomes evident very early in life, often in the first year. Pili torti, a condition in which the hair shaft is flattened and twisted, makes the hair very brittle and patients develop hair loss in the first two years of life.
Etiology
Björnstad syndrome is caused by mutations in the BCS1L gene. Mutations in this gene also cause GRACILE syndrome (see this term).
Genetic counseling
Björnstad syndrome is transmitted as an autosomal recessive condition.

                            Last update:
                            September 2007

                            - Expert reviewer(s):
                            Dr Pascal REYGAGNE


A congenital genitourinary malformation belonging to the spectrum of the exstrophy-epispadias complex (EEC) and is characterized by an evaginated bladder plate, epispadias and an anterior defect of the pelvis, pelvic floor and abdominal wall.

Summary:
Epidemiology
The prevalence at birth for the EEC is reported at 1/10,000. As epispadias (E), classic bladder exstrophy (CEB) and cloacal exstrophy (EC) are now recognized clinical variants of the same spectrum, accurate epidemiological data on E/EC/CEB are no longer available. However, CEB appears to be more frequent in the white population. Most studies report a male-to-female ratio of around 2.4:1, but ratios as high as 6:1 have also been reported.
Clinical description
CEB is evident from birth, with the reddish bladder mucosa being visible in the lower abdomen and mucosal polyps sometimes present on the surface. Urine drips from the ureteric orifices on the bladder surface. Other findings include pubic diastasis of various degrees with divergent rectus muscles and inguinal hernias. In males, the penis is short and broad with dorsal chordee. The urethral plate covers the whole dorsum of the penis from the open bladder to the glandular grove. Both corpora cavernosa are located beneath the urethral plate and the colliculus seminalis and the ductus ejaculatorii are visible as tiny openings in the area where the prostate is presumably dorsally located. Females present with a bifid clitoris next to the open urethral plate. The vaginal opening appears narrow and the perineum is shortened due to the anterior displacement of the vagina and anus. Women with CEB have a predisposition for vaginal or uterine prolapse. Spinal anomalies occur in about 7% of cases but gastrointestinal anomalies are rare in CEB.
Etiology
CEB results from early abnormal development of the intra-abdominal wall and bladder during rupture of the cloacal membrane. Though the underlying cause remains still unknown, a developmental field defect with both genetic and environmental factors is likely to play a role.
Diagnostic methods
Diagnosis is clinical. However, during follow-up, laboratory and imagining studies (such as ultrasound of the urogenital system, pelvic MRI or X-ray, voiding cystography and urodynamics) are useful to determine renal function and assess bladder capacity and detrusor function.
Management and treatment
Management is primarily surgical, with the main aims of obtaining secure abdominal wall closure, achieving urinary continence with preservation of renal function, and, finally, adequate cosmetic and functional genital reconstruction. Currently, several methods for bladder reconstruction with creation of an outlet resistance and epispadias repair (either as a staged or a one-stage approach) during the newborn period are favored worldwide. Removal of the bladder template with complete urinary diversion to a rectal reservoir can be an alternative.
Prognosis
After reconstructive surgery of the bladder, continence rates of about 80% are expected during childhood. Though spontaneous voiding is the main issue, additional surgery might be needed to optimize bladder storage and emptying function. In cases of definite reconstruction failure, urinary diversion should be undertaken. In puberty, genital and reproductive function constitute increasingly important issues for both sexes. Psychosocial and psychosexual outcome reflect the importance of long-term care (from birth into adulthood) from a multidisciplinary team of experts for parents and children with EEC to facilitate an adequate quality of life.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Pr Anne-Karoline EBERT  - Dr Michaël LUDWIG  - Pr Heiko REUTTER  - Pr Wolfgang RÖSCH


Blake pouch cyst is a non-syndromic, usually benign, cystic malformation of the posterior fossa characterized by a midline outpouching of the superior medullary velum into the cisterna magna that results from failure of the rudimental fourth ventricular tela choroidea to regress during embryogenesis. Patients can be asymptomatic or present in childhood or adulthood with clinical manifestations of hydrocephalus, such as headache, hypotonia, vertigo, syncope, vomiting, blurred or double vision, nystagmus, papilledema, and delayed gait development.


Blastic plasmacytoid dendritic cell neoplasm

A rare and highly aggressive myeloid malignancy characterized by predominant cutaneous involvement with concomitant or subsequent bone marrow, lymph node and visceral involvement, as well as central nervous system (CNS) disease. It derives from the precursors of plasmacytoid dendritic cells (pDC).

Summary:
Epidemiology
US incidence ranges from 500 to 1000 cases per year; global point prevalence is estimated at 12/100,000. Incidence is higher in patients aged ≥ 60 years and in males; ~10% of cases occur in children.
Clinical description
BPDCN affects patients of all ages but is most common in the elderly. Median age at onset is 60-70 years. It is characterized by skin and bone marrow involvement, but may involve lymph nodes, peripheral blood, liver, spleen and the CNS. The most common clinical presentation is asymptomatic solitary or multiple skin lesions (either isolated purplish nodules, isolated bruise-like papules, or disseminated purplish nodules/macules/papules). Some patients may present with leukemia.
Etiology
BPDCN derives from the precursors of pDC. There is no single cytogenetic or molecular change characteristic of BPDCN.
Diagnostic methods
Diagnosis requires biopsy of the affected area(s) with morphologic assessment and immunophenotyping. Skin biopsy shows a diffuse, monomorphous infiltrate of medium-sized blast cells resembling lymphoblasts or myeloblasts with massive dermis. Immunohistochemical diagnostic criteria are expression of CD123 (in all cases), CD4 and/or CD56, or one other pDC marker; or expression of any three pDC markers (CD123, TCF4, TCL1, CD303, CD304, CD4, CD56) and no expression of CD3, CD14, CD19, CD34, lysozyme, and myeloperoxidase.
Differential diagnosis
The differential diagnosis includes acute myeloid leukemia (AML), chronic myelomonocytic leukemia, nasal-type extranodal NK/T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma, and cutaneous T cell lymphoma.
Management and treatment
Tagraxofusp, a CD123-directed therapy, is the only drug approved for patients aged ≥2 years with newly diagnosed and relapsed/refractory BPDCN in the USA, or for adults with newly diagnosed BPDCN in Europe. Tagraxofusp, typical chemotherapy regimens for acute myeloid leukemia and acute lymphocytic leukemia, or lymphoma induction chemotherapies, are recommended as first-line treatment by the NCCN AML guideline. However, the chemotherapy regimens are associated with more toxicities, as well as lower survival rates and are not FDA/EMA-approved. Intrathecal chemotherapy should be considered for patients with documented CNS disease at diagnosis. Management strategies should vary according to patients' age and fitness. Off protocol approaches and participation in clinical trials can be considered in young/fit patients. Hematopoietic stem cell transplantation (HSCT) offers the best chance of long-term disease-free survival and should be considered in first remission for all eligible patients.
Prognosis
Historically, prognosis is poor. Median overall survival (OS) ranges from 8 to 12 months following chemotherapy and is 15.7 months following tagraxofusp. Median OS is longer in patients who were bridged to HSCT.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Dr Naveen PEMMARAJU


Blau syndrome (BS) is a rare systemic inflammatory disease characterized by early onset granulomatous arthritis, uveitis and skin rash. BS now refers to both the familial and sporadic (formerly early-onset sarcoidosis) form of the same disease. The proposed term pediatric granulomatous arthritis is currently questioned since it fails to represent the systemic nature of the disease.

Summary:
Epidemiology
Exact prevalence is unknown. From a Danish registry, the annual incidence was estimated to be 1/1,670,000/ year for children <5 years of age.
Clinical description
Skin rash (of tiny red/tan dots) is usually the first manifestation and appears as early as the age of 1 month on the face and then spreads to the trunk. Patients can have intermittent episodes of skin lesions that resolve without treatment. Joint manifestations usually begin before the age of 10 with painless cyst-like swellings on the back of feet and wrists. Symmetric arthritis (with boggy inflammatory synovitis and tenosynovitis) of the wrists, ankles, knees and sometimes elbows follows. Camptodactyly due to hypertrophic tenosynovitis is often described as the disease progresses. Severe handicap is not usually experienced until the age of 40-50. An insidious granulomatous iridocyclitis and posterior uveitis (see this term) can evolve into a severe destructive panuveitis. Over time, characteristic iris nodules, focal synechiae, cataract, increased intraocular pressure and characteristic clumpy keratic precipitates at the limbus ensue. Posterior involvement includes vitritis, multifocal choroiditis, retinal vasculopathy and optic nerve edema. Significant visual loss is observed in 20-30% of the affected individuals. The spectrum of clinical manifestations includes fever, malignant systemic and pulmonary hypertension, granulomatous large-vessel vasculitis and granulomatous inflammation of the liver, kidneys and lung.
Etiology
BS is due to an inherited or de novo mutation in the NOD2 gene (16q12), responsible for alterations in the innate immune response, inflammation and cell death. From transfection studies, it has been proposed that NOD2 mutations cause activation of nuclear factor kappa B which is in turn an up-regulator of pro-inflammatory cytokine transcription.
Diagnostic methods
Diagnosis relies greatly on the demonstration of noncaseating granulomatous inflammation with epithelioid cells and multinucleated giant cells on a skin, synovial or conjunctival biopsy, and genetic testing for mutations in the NOD2 gene.
Differential diagnosis
Differential diagnoses include polyarthritis and systemic juvenile idiopathic arthritis (JIA; see this term), granulomatous inflammation associated with primary immunodeficiencies, and systemic granulomatous vasculitis. In patients with granulomatous inflammation, chronic infections especially with mycobacteria and fungi must be excluded.
Antenatal diagnosis
Antenatal diagnosis and prenatal genetic testing is rarely performed.
Genetic counseling
BS is an autosomal dominant disorder in the familial form and genetic counseling is advised.
Management and treatment
There is no evidence-based data on the optimal treatment of BS. Moderate to low-dose daily corticosteroid therapy is effective in controlling uveitis and joint disease but the side effects of prolonged use may become unacceptable. Methotrexate at a dosage of 10-15 mg/m2 once weekly is effective in suppressing disease activity and allowing corticosteroid tapering. The introduction of anti-TNF monoclonal antibody agents (infliximab and adalimumab) may constitute a major therapeutic advance in the treatment of BS; however, the effect on uveitis activity may be less convincing.
Prognosis
BS is a chronic and progressive disease with a variable and often unpredictable spectrum of severity. In cases with expanded manifestations, life expectancy may be reduced. Uveitis has a poor prognosis.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Carlos ROSE  - Pr Carine WOUTERS


Bleeding diathesis due to a collagen receptor defect

A rare, genetic coagulation disorder characterized by a mild to moderate bleeding tendency due to impaired platelet activation and aggregation in response to collagen, or impaired platelet-vessel wall interaction, resulting from a collagen receptor defect. Patients manifest with ecchymoses, epistaxis, menorrhagia, and/or post-traumatic and post-surgery bleeding complications. Laboratory analysis reveals prolonged bleeding time and, occasionally, mild thrombocytopenia.


Bleeding diathesis due to thromboxane synthesis deficiency

A rare, genetic, isolated constitutional thrombocytopenia disease characterized by impaired platelet aggregation resulting from a defect in thromboxane synthesis or signaling, manifesting with mild to moderate mucocutaneous, gastrointestinal or surgical bleeding (e.g. easy bruising, prolonged epistaxis, excessive bleeding after a tooth extraction).


Bleeding disorder due to CalDAG-GEFI deficiency is a rare hematologic disease due to defective platelet function and characterized by mucocutaneous bleeding starting in infancy (around 18 months of age), presenting with prolonged and severe epistaxis, hematomas and bleeding after tooth extraction. Massive menorrhagia and chronic anemia have also been reported.


P2Y12 defect is a rare hemorrhagic disorder characterized by mild to moderate bleeding diathesis with easy bruising, mucosal bleedings, and excessive post-operative hemorrhage due to defect of the platelet P2Y12 receptor resulting in selective impairment of platelet responses to adenosine diphosphate.

Summary:
Epidemiology
To date, 14 patients have been described in the world literature.
Clinical description
P2Y12 defect is a congenital disorder that manifests by mildly to severely prolonged bleeding time, easy bruising, mucosal bleeding (epistaxis, gastric mucosa bleeding, gum bleeding, etc.), menorrhagia, and bleeding complications after trauma and minor or major surgery.
Etiology
P2Y12 defect is caused by mutations in the  P2RY12 gene (3q24-q25) which result in the premature truncation of the P2Y12 receptor or in the synthesis of a dysfunctional P2Y12 receptor. ADP activates platelets through its interaction with two G protein-coupled receptors, P2Y1 and P2Y12. The P2Y1 receptor mediates mobilization of ionized calcium and is responsible for ADP-induced shape change andweak and transient aggregation, while the P2Y12 receptor is responsible for the completion and amplification of the response to ADP and to all platelet agonists including thromboxane A2, thrombin, and collagen. P2Y12 receptor thus plays a central role in the formation and stabilization of a thrombus.
Genetic counseling
Transmission of P2Y12 deficiency is autosomal recessive. Genetic counseling should be offered to at-risk couples (where both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Pr Marco CATTANEO


Bleeding disorder in hemophilia A carriers

A rare bleeding disorder in association with carrier mutations in the F8 gene (Xq28) encoding coagulation factor VIII (FVIII), with a biological activity of FVIII ≥40 IU/dL and characterized clinically by abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. Spontaneous hemorrhages may occur occasionally. Heavy menstrual bleeding is the most frequent type of bleed in the carriers.


Bleeding disorder in hemophilia B carriers

A rare bleeding disorder in association with carrier mutations in the F9 gene (Xq27.1) encoding coagulation factor IX (FIX), with a biological activity of FIX ≥40 IU/dL and characterized clinically by abnormal bleeding as a result of minor injuries or following trauma, surgery or tooth extraction. Spontaneous hemorrhages may occur occasionally. Heavy menstrual bleeding is the most frequent type of bleed in the carriers.


A rare ectodermal dysplasia syndrome characterized by the association of lower eyelid ectropion, upper eyelid distichiasis, euryblepharon, bilateral cleft lip and palate, and conical teeth.

Summary:
Epidemiology
Over 50 cases have been described in literature to date.
Clinical description
Blepharocheilodontic syndrome (BCD) syndrome is characterized by eyelid malformations, cleft lip with or without cleft palate (CLP), and dental anomalies. CLP is usually bilateral and eyelid malformations are typical (ectropion of the lower eyelids, euryblepharon, and lagophthalmia). Patients harbor variable expression of ectodermal dysplasia, with constant dental anomalies corresponding to conical teeth and tooth agenesis. Additional variable features have been reported, including congenital hypothyroidism due to thyroid gland hypoplasia or aplasia, imperforate anus, neural tube defect, and syndactyly. Patients have normal intellectual development. Significant interindividual and intrafamilial variability have been reported, as well as incomplete penetrance. Diffuse gastric cancer and lobular breast cancer have been reported in two families so far. To date, the risk of cancer in BCD syndrome is not precisely known, since cancers were not reported in the other reported families.
Etiology
BCD syndrome is due to either heterozygous CDH1 or CTNND1 variants. CDH1 encodes the E-cadherin, a transmembrane glycoprotein. CTNND1 encodes the Delta-Catenin, a protein linked to the cytoplasmic domain of E-cadherin. Both proteins are involved in a cell-cell adhesion complex, critical for establishing and maintaining polarized and differentiated epithelia during development. Recurrent missense CDH1 variants have been identified in BCD syndrome, probably impairing ion calcium binding. Variations in CTNND1 correspond predominantly to truncating variants, but missense variants have also been reported. BCD-related to CDH1 and CTNND1 variants are clinically indistinguishable, although the latter usually shows a milder phenotype. CDH1 variants also cause hereditary diffuse gastric cancer (HDGC), and diffuse gastric cancer and lobular breast cancer have been reported in two BCD families with CDH1 variants. Since cancers have not been reported in other reported families to date, the risk of cancer development is not precisely known. No HDGC-related cancer has been reported in patients with CTNND1 variants.
Diagnostic methods
The syndrome is suspected on the association of CLP, typical eyelid malformations and ectodermal dysplasia features. Molecular genetic testing approaches include targeted sequencing of the entire CDH1 and CTNND1 coding regions.
Differential diagnosis
BSD presents with a unique constellation of features and there are no relevant differential diagnoses.
Antenatal diagnosis
Prenatal testing is possible if the pathogenic variant has been identified in an affected family member. However if the pathogenic variant is identified in the fetus, the severity of the condition is not predictable.
Genetic counseling
BCD syndrome is usually sporadic, but large families have been described. The disorder is autosomal dominant and patients harboring BCD syndrome features and carrying a CDH1 variant or a CTNND1 variant have 50% risk to transmit the pathogenic variant to their offspring. Due to intrafamilial variability and incomplete penetrance, prediction of the severity is difficult.
Management and treatment
Management of BCD syndrome is supportive and symptomatic. CLP management is surgical, dental, and orthodontic. Early orthodontic follow-up should be proposed. Blepharoplasty is required for ankyloblepharon and for severe eyelid anomalies. Lagophthalmos can lead to corneal abrasion. Ophthalmologic evaluation is recommended to assess eye movement and possible tearing reduction. Congenital hypothyroidism is usually diagnosed through neonatal screening and treated with thyroid replacement therapy. Assessment of risk of cancer is challenging. Currently, there are no clear guidelines for surveillance or prophylactic total gastrectomy.
Prognosis
The prognosis and functional consequences are variable and dependent on the associated anomalies. In families carrying a CDH1 variant and with a positive familial history of CDH1-related cancers, or fitting criteria for hereditary diffuse gastric cancer (HDGC), prognosis can be worsened by the occurrence of cancer.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Dr Jamal GHOUMID | ITHACA* - Pr Florence PETIT | ITHACA*

                                * European Reference Network


Blepharonasofacial syndrome is a rare otorhinolaryngological malformation syndrome characterized by a distinctive mask-like facial dysmorphism, lacrimal duct obstruction, extrapyramidal features, digital malformations and intellectual disability.

Summary:
Epidemiology
Blepharonasofacial syndrome has been reported in 3 families to date.
Clinical description
The facies has a mask-like appearance due to weakness of facial muscles, and lacrimal duct obstruction is characteristic. Clinical features also include telecanthus (with temporal displacement of lacrimal puncta), bulky nose, broad nasal bridge, sometimes a hypoplastic midface, longitudinal cheek furrows, trapezoidal upper lip and malformation of the ears. Intellectual disability, cutaneous syndactyly, torsion dystonia, increased deep tendon reflexes, Babinski sign, poor coordination, and joint laxity are also observed.
Etiology
Inheritance is thought to be either autosomal or X-linked dominant.

                            Last update:
                            January 2014


Blepharophimosis-intellectual disability syndrome, MKB type

A rare, X-linked, syndromic, intellectual disability disorder affecting only boys and characterized by global development delay with little or no speech, urogenital abnormalities, including scrotal hypoplasia, micro penis, and cryptorchidism, autistic behavior, and facial dysmorphism. Most typical facial features are ptosis, blepharophimosis, a bulbous nasal tip, a long philtrum, and maxillar hypoplasia with full cheeks. Other variable features include microcephaly, hearing loss, dental anomalies, and hyperextensible joints.


Blepharophimosis-intellectual disability syndrome, Ohdo type

A multiple congenital malformation syndrome characterized by blepharophimosis, ptosis, dental hypoplasia, hearing impairment and intellectual disability.

Summary:
Epidemiology
So far, less than 30 patients have been reported worldwide.
Clinical description
Abnormal ears, microcephaly, and growth retardation have been reported occasionally. Male patients may show cryptorchidism and scrotal hypoplasia.
Genetic counseling
Most reported cases are sporadic, except the original cases of Ohdo who described two affected sisters and a first cousin, favoring autosomal recessive inheritance. Autosomal dominant, X-linked- and mitochondrial inheritance have also been suggested.

                            Last update:
                            May 2009


Blepharophimosis-intellectual disability syndrome, SBBYS type

A rare, genetic, multiple congenital anomalies syndrome characterized by the association of a typical facial phenotype with microcephaly associated with congenital hypothyroidism, skeletal involvement (polydactyly, long thumb(s) and long first toe(s), and patellar hypoplasia/agenesis), and some degree of global developmental delay, hypotonia and intellectual disability. Facial features include an immobile mask-like face, severe blepharophimosis and ptosis, tear duct abnormalities, a broad nasal bridge, bulbous nasal tip, small mouth, thin upper lip, hypoplastic teeth and small, low set ears. Renal and genital anomalies, usually cryptorchidism, are often present in affected males. Congenital heart defects and growth delay are variably present.

Summary:
Epidemiology
Although the prevalence of the disorder is unknown, it is thought to be less than 1/1,000,000. To date, 122 individuals with molecularly diagnosed blepharophimosis-intellectual disability syndrome, SBBYS type (SBBYS), have been reported.
Clinical description
Clinical diagnosis is typically based on the striking facial gestalt associated with microcephaly. Skeletal anomalies include long thumbs and great toes, patellar hypoplasia/agenesis, polydactyly (both pre and postaxial), camptodactyly, clinodactyly, brachydactyly, syndactyly, club feet , flexion contractures of the knees and/or hips, and anomalies of the spine, and/or ribs. Individuals generally have developmental delay/intellectual disability, which can be mild. Language disorder, autism spectrum features, anxiety, aggressiveness, attention problems, agenesis or hypoplasia of the corpus callosum, optic nerve hypoplasia and other brain abnormalities have also been reported. Congenital heart malformations (50% of cases), ocular anomalies and bilateral mixed hearing loss are also often present. Renal anomalies (e.g. hydronephrosis or multiple renal cysts), anal and genital anomalies including cryptorchidism, hypospadias, clitoromegaly and/or hypoplasia of the labia minora or majora, are reported in more than 40% of cases. In a minority of cases, thyroid agenesis/hypoplasia, hypothyroidism, intestinal malrotation, dental anomalies, feeding and respiratory difficulties, gastroesophageal reflux, poor growth, short stature, cleft palate, and Pierre Robin sequence are observed. SBBYS is allelic with genitopatellar syndrome and an intermediate phenotype has been described; thus, the disorder may present as part of a spectrum.
Etiology
The syndrome is caused by heterozygous variants in KAT6B (10q22) encoding a highly conserved acetyltransferase that is part of the MYST family, and regulates the expression of multiple genes.
Diagnostic methods
Diagnosis is based on clinical examination, brain imaging and molecular studies (specific gene testing if the specific clinical suspicion has been raised, otherwise broader genomic tests).
Differential diagnosis
Differential diagnosis include other genetic syndromes that associates intellectual disability with one or more of the key features of this disorder.
Antenatal diagnosis
Polyhydramnios, increased nuchal translucency and/or cystic hygroma, renal anomalies can be observed during pregnancy but are non-specific. Genetic diagnosis can be proposed to families in which the pathogenic variant has already been identified in an affected relative.
Genetic counseling
Transmission is autosomal dominant. Most of the cases described are de novo, so the empirical risk of recurrence is low, 1-2%. Three families have been described in which the pathogenic variant has been inherited from a parent with a mild phenotype. The recurrence risk in these cases is 50%. To date, no cases of germinal mosaicism have been reported but this cannot be excluded.
Management and treatment
Management requires a lifelong multidisciplinary approach with specific regular follow-up based on the patient's clinical manifestations (pediatric, neuropsychiatric, cardiological, ophthalmological, audiometric, orpthopedic, and genetic examinations). Occupational, physical, speech (in particular non-verbal methods of communication), feeding and educational therapies must be tailored to the patient's needs. Bowel malrotation is a potentially dangerous medical complication. Particular attention should be paid to monitoring feeding and growth, as feeding problems tend to occur early.
Prognosis
Whilst there is limited data regarding life expectancy, adult patients are reported and there are no known reasons to suspect reduced life expectancy. Autonomy depends on the degree of involvement and the severity of the psychomotor developmental delay.

                            Last update:
                            January 2021

                            - Expert reviewer(s):
                            Dr Livia GARAVELLI | ITHACA* - Dr Gabriele TRIMARCHI | ITHACA*

                                * European Reference Network


Blepharophimosis-intellectual disability syndrome, Verloes type

A rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by congenital microcephaly, severe epilepsy with hypsarrhythmia, adducted thumbs, abnormal genitalia, and normal thyroid function. Hypotonia, moderate to severe psychomotor delay, and characteristic facial dysmorphism (including round face with prominent cheeks, blepharophimosis, large, bulbous nose with wide alae nasi, posteriorly rotated ears with dysplastic conchae, narrow mouth, cleft palate, and mild micrognathia) are additional characteristic features.


Blepharophimosis-intellectual disability syndrome/genitopatellar overlap syndrome

A rare developmental defect during embryogenesis characterized by the presence of major features of both blepharophimosis-intellectual disability syndrome and genitopatellar syndrome. These major features may include blepharophimosis, ptosis, hypomimia, skeletal features like patellar a/hypoplasia and renal and/or genital malformations.


Blepharophimosis-ptosis-epicanthus inversus syndrome plus

A rare disorder of the ocular adnexa characterized by an extended phenotype of blepharophimosis, ptosis, epicanthus inversus and telechantus syndrome (BPES). When BPES is caused by a microdeletion encompassing other genes in addition to the causative gene FOXL2, the patient has additional features including intellectual disability, external genital anomaly, spastic diplegia, and speech delay. Acquired microcephaly can also be observed.


A rare ophthalmic disorder characterized by blepharophimosis, ptosis, epicanthus inversus, and telecanthus, that can appear associated with (type 1) or without primary ovarian insufficiency (POI; type 2).

Summary:
Epidemiology
The worldwide prevalence is unknown.
Clinical description
A congenital disorder characterized by a complex bilateral eyelid malformation including blepharophimosis, ptosis, epicanthus inversus and telecanthus. Other ophthalmic manifestations that are usually associated include lacrimal duct anomalies, amblyopia, strabismus, refractive errors and a lateral displacement of the inferior lacrimal puncta. Additional features include a broad nasal bridge, low-set ears, and a short philtrum. Affected females may develop POI, and are thus considered to have BPES type 1. Females without POI are classed as BPES type 2.
Etiology
The disorder is caused by an intragenic mutation (80%), gene deletion (10-12%), deletions of regulatory elements outside of the FOXL2 gene (3q23)(<5%), and translocations involving the FOXL2 region. FOXL2 encodes a forkhead transcription factor that contains a typical DNA-binding forkhead domain and a polyalanine tract of 14 residues strictly conserved in mammals. FOXL2 is expressed in peri-ocular tissues as well as in the fetal and adult ovaries.
Diagnostic methods
Diagnosis is based on presence at birth of the 4 major eyelids features with or without POI (amenorrhea for greater than 6 months, less than age 40 years and follicle stimulating hormone concentration greater than 40 IU/L). The clinical diagnosis is confirmed by the identification of a genetic defect in the FOXL2 gene or its regulatory region.
Differential diagnosis
The differential diagnoses includes those conditions in which ptosis or blepharophimosis are major features. However, this disorder can be relatively easily distinguished from most of these conditions as its facial appearance is very typical.
Antenatal diagnosis
Genetic prenatal testing may be possible where the pathogenic variant has been previously identified in an affected family member.
Genetic counseling
Whilst the disorder can occur sporadically (de novo), the pattern of inheritance is typically autosomal dominant and genetic counseling for affected families should be offered. Penetrance for the eyelid phenotype is complete and presence of POI varies between families. Germline mosaicism has been described as well as a recessive mutation (one family) involving a polyalanine expansion of intermediate length.
Management and treatment
The surgical management is traditionally performed in two stages and involves a medial canthoplasty for correction of the blepharophimosis, epicanthus inversus, and telecanthus at ages 3 to 5 years, followed about a year later by ptosis correction. However, when ptosis is severe, surgical repair is recommended before age 3 years. Ophthalmologic follow-up is important for management of the oculoplastic surgery. All female patients should be assessed and followed up for POI. Management of POI is multidisciplinary ( requiring a geneticist, endocrinologist, gynaecologist) should include counseling of the patient and relatives. Egg donation may be considered as a reproductive option. In the case of a detectable ovarian reserve, therapeutic counseling can lead to fertility preservation.
Prognosis
Prognosis is good and patients have a normal lifespan.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Pr Elfride DE BAERE  - Dr Hannah VERDIN


A rare syndrome characterised by the association of blepharophimosis and ptosis, V-esotropia, and weakness of extraocular and frontal muscles with syndactyly of the toes, short stature, prognathism, and hypertrophy and fusion of the eyebrows.


A rare, genetic, lens position anomaly disease characterized by bilateral congenital blepharoptosis, ectopia lentis and high grade myopia. Additional reported manifestations include abnormally long eye globes and signs of levator aponeurosis disinsertion. There have been no further descriptions in the literature since 1982.


A focal dystonia involving symmetrical benign essential blepharospasm (BEB) and oromandibular dystonia.


This syndrome associates progressive visual loss with scoliosis or kyphoscoliosis and arachnodactyly of the fingers and toes.

Summary:
Epidemiology
The syndrome has been described in four patients (three males and one female) from the same family.
Clinical description
The male patients presented with the complete phenotype while the female patient suffered only from blindness.
Etiology
No mutations were found in the FBN1, TGFBR1 and TGFBR2 genes which are associated with other syndromes presenting similar clinical findings (i.e. Marfan syndrome; see this term).
Genetic counseling
Transmission seems autosomal dominant.

                            Last update:
                            October 2009


Blomstrand lethal chondrodysplasia (BLC) is a neonatal osteosclerotic dysplasia characterized by advanced endochondral bone maturation, very short limbs, dwarfism and prenatal lethality.

Summary:
Epidemiology
To date, less than 10 cases have been described in the literature.
Clinical description
BLC is a congenital disorder characterized by a low birth weight, facial dysmorphism (widely spaced and protruding eyes (which typically show cataract), depressed nasal bridge, short columella, long philtrum, macroglossia, protruding tongue, severe micrognathia), short trunk, narrow thorax and severe rhizo-meso-acromelic shortness of the limbs. Other anomalies also observed include tooth and mammary gland development defects, hypoplastic lungs, aorta coarctation, and bowel malrotation. Two forms of BCL, have been described: type I which is the severe, classical form and type II which has less severe features (such as absence of short trunk or, severely shortened arms but moderately shortened legs).
Etiology
BLC is caused by inactivating homozygous or compound heterozygous mutations in PTH1R (3p22-p21.1) which encodes the parathyroid hormone (PTH)/parathyroid-hormone-related peptide (PTHrP) receptor (PTH1R). These mutations result in the decrease in binding or response to PTH and PTHrP.
Diagnostic methods
Diagnosis is based on the clinical and radiological characteristics which show generalized increase in bone density with advanced ossification, severe shortness of the long bones with wide metaphyses and club-shaped distal ends, long narrow thorax, calcified hyoid bone and laryngeal cartilage and underdeveloped viscerocranium. Histopathological examination shows an important acceleration of the endochondral ossification in tubular bones, narrow cartilages of the epiphyses and large epiphyseal ossification centers. Diagnosis is confirmed by the genetic screening of PTH1R.
Differential diagnosis
Differential diagnosis includes primary failure of tooth eruption (see this term) and other lethal short limbed dwarfisms.
Antenatal diagnosis
Prenatal diagnosis is achieved by sonographic examination showing polyhydramnios, hydrops fetalis and a fetus with very short limbs, nuchal edema, macroglossia, a protuberant abdomen, internal anomalies and markedly advanced endochondral bone formation.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.
Prognosis
Both forms of BLC are lethal either prenatally or shortly after birth.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Pr Harald JÜPPNER  - Dr Caroline SILVE