Bloom syndrome is a rare disorder associated with pre- and postnatal growth deficiency, a telangiectatic erythematous rash of the face and other sun-exposed areas, insulin resistance and predisposition to early onset and recurrent cancer of multiple organ systems.

Summary:
Epidemiology
Bloom syndrome (BSyn) overall prevalence is unknown, but in the Ashkenazi Jewish population it is estimated at approximately 1/ 48,000 births. A founder mutation, known as BLMash is present in approximately 1 in 100 persons of Ashkenazi Jewish background. There are also founder mutations in the Slavic and Hispanic populations.
Clinical description
Individuals with BSyn show proportionate growth deficiency of prenatal onset (average birth weight 1757 g) and continuing throughout life (average adult height of 149 cm for men and 138 cm for women). Dolichocephaly, narrow face, prominent nose and ears, and malar and mandibular hypoplasia can be observed. Subcutaneous adipose tissue is sparse. Telangiectatic erythema appears during the first 1-2 years of life on the face (in particular the cheek), dorsum of the hands and other sun-exposed areas. Café-au-lait macules and hypopigmented skin lesions are common. Children with BSyn characteristically feed slowly, have a decreased appetite and eat a limited variety of foods. Despite nutritional interventions, weight gain is modest and children are rarely in the normal range for growth. One major feature of Bsyn is a greatly increased predisposition to cancers in a distribution corresponding to the general population but occurring at a much younger age. Survivors of a first cancer may have multiple cancers in their lifetime. Most men with BSyn have azoospermia or severe oligospermia, while women are often fertile but may begin menopause prematurely.
Etiology
Bloom syndrome is inherited as an autosomal recessive trait. The BLM gene codes for a RecQ helicase that forms a complex with two other proteins, DNA topoisomerase IIIα and RMI.BLM heterozygotes are healthy and without any clinical features of the disorder.
Diagnostic methods
The diagnosis of BSyn is suspected clinically by identification of characteristic features and is confirmed by identification of biallelic pathogenic variants of the BLM gene on molecular genetic testing.
Differential diagnosis
The differential diagnosis of Bloom syndrome includes Fanconi anemia, Silver-Russell syndrome, Rothmund-Thomson syndrome, ataxia-telangiectasia, and Nijmegen breakage syndrome. Three other disorders also may be of interest in a differential diagnosis. RECQ-mediated genome instability 1, RECQ-mediated genome instability 2, Microcephaly, growth restriction, & increased sister-chromatid exchange 2.
Antenatal diagnosis
Prenatal diagnosis of at-risk pregnancies is possible by cytogenetic (SCE) or molecular genetic testing (BLM sequencing and deletion/duplication) of fetal cells obtained by amniocentesis or chorionic villus sampling. Molecular genetic testing is preferred.
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 that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management is symptomatic. Increased calorie density formulas and foods may promote weight gain and increased growth. Although growth hormone treatment may improve linear growth, many clinicians caution against its use because of reports of early onset of cancer in some treated children. Standard antibiotic regimens are used to treat infections. If the serum levels of immunoglobulins are low and the patient is experiencing repeated infections, some have been treated with intravenous or subcutaneous immunoglobulins. Skin protection, including covering exposed skin and use of a broad-spectrum sunscreen with at least 30 SPF is crucial to reduce the sun-sensitive skin rash. Health supervision recommendations for persons with Bloom syndrome have been published, including recommendations for cancer surveillance. Due to hypersensitivity of patients to chemotherapy, reduced dosage and/or duration of therapy is recommended, usually beginning with 50% of the weight-based dosage. Caution should be exercised with use of ionizing radiation or alkylating agents, particularly busulfan, cyclophosphamide or melphalan.
Prognosis
The high occurrence of cancer reduces life expectancy. The median overall life expectancy is approximately 30 years, with cancer and related complications as the leading cause of death.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Dr Christopher CUNNIFF  -  Maeve FLANAGAN


Blount disease is characterized by disturbed growth of the inner portion of the upper tibial extremity, progressively leading to bowlegged deformity with bone angulation just below the knee (tibia varus). In 60% of cases, the condition affects both legs.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Clinically, patients with Blount disease present with bowing and length discrepancy in the lower limbs and a medial prominence of the proximal tibia. Obesity and early walking are predisposing factors for the development of the disorder.
Etiology
The underlying causes are controversial: it seems to be a multifactorial disease, but the contribution of genetic factors is unknown.
Diagnostic methods
Blount disease can only be diagnosed in children over 2 years of age, as tibia varus can occur physiologically.
Management and treatment
A severe untreated deformity can lead to early degenerative arthritis of the knee. Management must be adapted to each child: an orthopaedic therapeutic program is often the first management option, but in more severe cases associated with pain, surgery may be indicated to correct the deformity.

                            Last update:
                            October 2006

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Blue cone monochromatism (BCM) is a recessive X-linked disease characterized by severely impaired color discrimination, low visual acuity, nystagmus, and photophobia, due to dysfunction of the red (L) and green (M) cone photoreceptors. BCM is as an incomplete form of achromatopsia (see this term).

Summary:
Epidemiology
The prevalence is estimated to be 1/100,000 worldwide.
Clinical description
BCM manifests in early infancy and predominantly affects males, with severely impaired color vision and low visual acuity (only rod and blue cone function is preserved). Additionally, photophobia, myopia, and pendular nystagmus are commonly observed. Nystagmus may wane with time.
Etiology
The disorder is caused by mutations in the red and green opsin gene cluster OPN1LW and OPN1MW (Xq28) and thus affect the corresponding cones. These mutations include deletions of the locus control region that is critical for expression of both genes. These deletions may also extend to parts of or the whole opsin gene cluster. Genomic rearrangements (unequal crossing-over) can result in single red and/or red/green hybrid genes carrying deleterious point mutations. The c.607T>C p.C203R missense mutation is commonly observed, but other missense and nonsense mutations have also been reported.
Diagnostic methods
The diagnosis of BCM is achieved by clinical ophthalmological examination, electrophysiological (i.e. electroretinography/ ERG) and psychophysical testing (i.e. color vision, dark adaptometry), where BCM patients show no response to red and green light but normal response to blue light. Mutation screening can confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes achromatopsia, Leber congenital amaurosis, various types of cone dystrophies (see these terms) and cerebral achromatopsia.
Antenatal diagnosis
Prenatal diagnosis may be offered by specialized laboratories for at-risk couples. The use of prenatal diagnostic testing in BCM will vary depending on national customs and ethics.
Genetic counseling
BCM is inherited in an X-linked manner. Genetic counseling is mandatory. A carrier female has a 50% risk of transmitting the mutated allele to her offspring. Penetrance is complete with little variability in disease expression.
Management and treatment
There is no specific therapy available. Management is symptomatic and includes regular ophthalmological follow-up examinations. Patients should be informed about the possibility of using filtering glasses or contact lenses (red tinted or brown) to reduce photophobia and to improve contrast sensitivity. Low-vision aids include high-powered magnifiers for reading.
Prognosis
BCM is usually a stationary disease, yet in rare cases, macular degeneration can occur in older patients.

                            Last update:
                            August 2013

                            - Expert reviewer(s):
                            Dr Susanne KOHL


A rare inborn error of metabolism characterized by early-onset diarrhea, fever, recurrent hypoglycemia, hypercalcemia with nephrocalcinosis, metabolic acidosis, and indicanuria due to bacterial degradation of malabsorbed tryptophan with excessive indole production which, upon oxidation to indigo blue, causes bluish discoloration of urine spots in the diaper of the affected infant.


A rare vascular malformation disorder with cutaneous and visceral lesions frequently associated with serious, potentially fatal bleeding and anemia.

Summary:
Epidemiology
More than 200 cases have been published so far, but prevalence is unknown.
Clinical description
Multifocal venous malformations most commonly involve the skin and gastrointestinal tract (GIT), but can also affect the brain, kidneys, lungs, eyes, bones and other organs. Hemostatic abnormalities due to consumption coagulopathy and thrombocythemia have also been described. The lesions are generally present in childhood but can develop later in life. They are usually blue colored and easily compressible with light palpation. The main clinical manifestation is acute or chronic bleeding from the multiple GIT vascular malformations, with the small intestine usually being involved. The acute bleeding presents as hematemesis, melena, or rectal bleeding. Unless treated radically, patients with BRBN develop anemia from chronic gastrointestinal bleeding and require lifelong treatment with iron and blood transfusions. Malignant transformation of the lesions has not been reported so far. Infrequent complications of the gastrointestinal malformations are volvulus, intussusception and intestinal infarction.
Etiology
The cause of the syndrome is still unknown. Although most cases show no apparent hereditary pattern, autosomal dominant expression has been reported in several families. A gene mutation has been mapped to the short arm of chromosome 9 and might be involved in these familial cases.
Diagnostic methods
Diagnostic methods include: blood counts, endoscopy, ultrasound, CT, MRI, and histopathology.
Differential diagnosis
Differential diagnoses include vascular tumors, either benign (hemangiomas) or malignant (Kaposi's sarcoma, angiosarcoma); vascular anomalies associated with congenital or systemic diseases (Klippel-Trenaunay-Weber, Ehlers-Danlos, the CREST variant of scleroderma, and Osler-Weber-Rendu syndrome) and acquired and sporadic lesions (angiodysplasias, gastric antral vascular ectasia, radiation-induced vascular ectasias, and Dieulafoy's lesions) (see these terms).
Management and treatment
Cutaneous lesions do not usually bleed: surgery, sclerotherapy or embolization provide a good cosmetic result. In the absence of massive GIT bleeding, a conservative treatment is sufficient (iron supplementation and/or blood transfusions). Corticosteroids, antifibrinolytic agents, high-dose intravenous gamma globulin and interferon alpha are of poor effect. Long-term use of octreotide has been found to reduce blood loss from BRBN and other vascular gastrointestinal lesions. Intra-operative enteroscopy is the accepted ultimate diagnostic and/or therapeutic procedure, allowing immediate resolution of pathological findings by endoscopic coagulation or surgical full-thickness wedge excision. It is recommended to start with capsule wireless endoscopy to specify the indication for the procedure. Capsule endoscopy may also be a useful tool for monitoring the effects of therapy.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Marcela KOPACOVA


BNAR syndrome is a very rare multiple congenital anomaly syndrome characterized by a bifid nose (see this term) (with bulbous nasal tip but not associated with hypertelorism) with or without the presence of anal defects (i.e. anteriorly placed anus, rectal stenosis or atresia) and renal dysplasia (unilateral or bilateral renal agenesis, see these terms) and without intellectual disability. BNAR syndrome is phenotypically related to Fraser syndrome and oculotrichoanal syndrome (see these terms).


A rare vascular anomaly characterized by congenital, progressive, circumscribed venous malformations (phlebectasias) primarily involving the upper and/or lower extremities, either on one side or bilaterally. The malformed vessels are visible beneath the skin. Veins of all sizes are affected. Pain, swelling, muscle wasting, and ulceration may occur.


Body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency

A rare genetic skin disease characterized by severe skin laxity affecting the trunk and limbs.


A rare multiple congenital anomalies syndrome characterized by intrauterine growth retardation (IUGR), postnatal failure to thrive, severe feeding difficulties, microcephaly/trigonocephaly, facial dysmorphism, a recognizable upper limb posture and severe developmental delay. The upper limb posture consists of internal rotation of the shoulders, flexion of the elbows, ulnar deviation of wrists and/or metacarpophalangeal joints.

Summary:
Epidemiology
To date 46 cases have been described, less than half of which were molecularly confirmed as carrying a heterozygous pathogenic variation in ASXL1.
Clinical description
Bohring-Opitz syndrome (BOS) is characterized by IUGR, severe neonatal feeding difficulties, and microcephaly/trigonocephaly, cleft lip/palate and hirsutism. Facial dysmorphism is characterized by glabellar/frontal nevus flammeus, synophrys, proptosis, hypertelorism, depressed wide nasal bridge, anteverted nares, full cheeks, and micrognathia. The posture of upper limbs, common in all patients at birth, is characterized by internal rotation of the shoulders, flexion of the elbows, ulnar deviation of wrists and/or metacarpophalangeal joints. Most patients exhibit truncal hypotonia and hypertonic extremities at birth. Seizures and obstructive sleep apnea/sleep disturbances can occur during infancy. Other abnormalities can involve the following organs: brain (corpus callosum defects), eyes (retinal and optic nerve abnormalities, high myopia), heart (bradycardia, septal defect), gastrointestinal tract (cycling emesis, gastroesophageal reflux disease) as well as the joints (contractures, congenital hip/radial head dislocations).
Etiology
BOS is due to a heterozygous pathogenic variation in ASXL1 (20q11.21), which acts as a chromatin modulator.
Diagnostic methods
Clinical diagnosis can be confirmed by sequencing of ASXL1 or by intellectual disability-related next generation sequencing panel including the gene. If sequencing is negative, multiplex ligation-dependent probe amplification may be used.
Differential diagnosis
A BOS-like phenotype related to KLHL7 has been described which has several features in common with BOS (including a similar upper limb posture) but is clinically distinguished by the absence of trigonocephaly, synophrys, high myopia and cycling emesis. Other diseases sharing several features with BOS but lacking the BOS posture include C syndrome, Shashi-Pena syndrome, Bainbridge-Ropers syndrome and Cornelia de Lange syndrome.
Antenatal diagnosis
Prenatal diagnosis is possible on chorionic villi or amniotic fluid where the pathogenic variant has been previously identified in the family. Prenatal genetic counseling should therefore be offered to parents of patients with ASXL1 variants to discuss the genetic risks and reproductive options.
Genetic counseling
The disorder is autosomal dominant; however, most cases are de novo. Genetic counseling should be offered to all at-risk couples since germinal mosaicism may occur.
Management and treatment
Management requires an early multidisciplinary approach. Seizures are drug-responsive. An increased risk of Wilms tumor is reported. An abdominal ultrasound every 3-4 months is suggested in the first 8 years of life.
Prognosis
The rate of infant mortality is high. In patients who survive infancy, feeding difficulties and recurrent infections become less severe. Older patients may have some purposeful limb movements, however, their resting state returns to BOS posture. Intellectual disability ranges from severe to profound.

                            Last update:
                            September 2021

                            - Expert reviewer(s):
                            Dr Stefania BIGONI | ITHACA* - Pr Alessandra FERLINI | ITHACA*

                                * European Reference Network


Bolivian hemorrhagic fever (BHF), caused by the Machupo virus (MACV), is a severe acute viral hemorrhagic fever characterized by fever, myalgia, and arthralgia followed by hemorrhagic and neurological manifestations.


A rare lethal bone dysplasia characterized at birth by low birth weight, a rhizomelic dwarfism, bent femora and short chest producing asphyxia. The initial cases could have been diagnosed as Desbuquois syndrome, or a recessive Larsen syndrome. There has been no further description in the literature since 1988.


Bonnemann-Meinecke-Reich syndrome is a syndrome of multiple congenital anomalies characterized by an encephalopathy which predominantly occurs in the first year of life and presenting as psychomotor delay. Additional features of the disease include moderate dysmorphia, craniosynostosis, dwarfism (due to growth hormone deficiency), intellectual disability, spasticity, ataxia, retinal degeneration, and adrenal and uterine hypoplasia. The disease has been described in only two families, with each family having two affected siblings. An autosomal recessive inheritance has been suggested. There have been no further descriptions in the literature since 1991.


Boomerang dysplasia (BD) is a rare lethal skeletal dysplasia characterized by severe short-limbed dwarfism, dislocated joints, club feet, distinctive facies and diagnostic x-ray findings of underossified and dysplastic long tubular bones, with a boomerang-like bowing.

Summary:
Epidemiology
The prevalence of BD is unknown.
Clinical description
Affected neonates are stillborn or die rapidly after birth and present clinically with severe short-limbed dwarfism, dislocated hip, knee and elbow joints, club feet and proviso born alive have severe cardio respiratory failure. Facial dysmorphism includes midface hypoplasia and cleft palate. Boomerang dysplasia clinically differs from AOI and AOIII because of the boomerang shaped bowing of the femur and occasionally observed encephalocele and omphalocele.
Etiology
BD results from missense mutations or small in-frame deletions in the FLNB gene reported in exons 2-5, normally expected to translate full length but biochemically abnormal filamin B protein.
Diagnostic methods
Diagnosis can be confirmed from skeletal radiographs, chondro-osseous histopathology and genetic testing. Distinctive radiographic findings are similar to AOI but, BD presents with a more severe deficiency in mineralization, with non-ossification of certain segments of limbs and vertebrates, and a boomerang-like shape of some long tubular bones.
Differential diagnosis
Comprises other skeletal dysplasias with severe short-limbed dwarfism such as achondrogenesis, campomelic dysplasia, Ellis-van Creveld syndrome, achondroplasia, metatropic dysplasia, Roberts syndrome, short rib-polydactyly syndrome and thanatophoric dysplasia. Additional differential diagnosis includes diseases associated with impaired ossification such achondrogenesis, hypophosphatasia, and osteogenesis imperfecta (see these terms).
Antenatal diagnosis
The prenatal diagnosis of BD is difficult to ascertain by ultrasound. Ultrasound shows thoracic hypoplasia, limb shortening, delayed ossification of spine and appendicular segments and possibly joint dislocations, similar to AOI and AOIII. Boomerang-shape morphology some long tubular bones may be diagnosed prenatally by 3D-CT scan.
Prognosis
Prognosis is poor, as the condition is lethal in utero.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Pr Stephen ROBERTSON


A rare otomandibular dysplasia syndrome characterized by branchial arch anomalies (branchial clefts, fistulae, cysts), malformations of the ear associated with hearing impairment (malformations of the auricle with pre-auricular pits, conductive or sensorineural hearing impairment), and renal malformations (urinary tree malformation, renal hypoplasia or agenesis, renal dysplasia, renal cysts).

Summary:
Epidemiology
Worldwide, the prevalence of Branchiootorenal (BOR) syndrome in the general population is unknown; however, in the pediatric population it is estimated to be 1/40,000.
Clinical description
The expression of the disease varies widely from one family to another and among individuals of the same family. Some individuals do not present with renal abnormalities or a urinary tract malformation.
Etiology
The causative gene, EYA1, is located on the long arm of chromosome 8. Point mutations and deletions in EYA1 have been identified in approximately 40-75% of affected individuals. In a smaller proportion of patients, mutations in the SIX1 and SIX5 genes have been identified, the products of which interact with EYA1 to form transcription factor complexes.
Diagnostic methods
The diagnosis of BOR syndrome might be suspected clinically in an individual with second branchial arch anomalies, auricular malformations, preauricular pits or tags, deafness and/or renal anomalies. Especially if there are other affected family members. By genetic testing, the diagnosis can be validated in around half of the patients.
Differential diagnosis
The main differential diagnosis is branchio-oculo-facial syndrome (BOFS), caused by TFAP2A variants, which is characterized by branchial defects, highly variable ocular defects and characteristic craniofacial features which can include ear anomalies. Moreover, renal anomalies can occur in patients with BOFS. Other differential diagnosis include hypoparathyroidism-sensorineural deafness-renal disease (HDR) syndrome, due to GATA3 variants, which is distinguished by the presence of hypoparathyroidism in the majority of patients; and otofaciocervical syndrome. Moreover, hearing loss is a common symptom in many genetic disorders.
Antenatal diagnosis
Prenatal diagnosis is possible if the pathogenic variant has previously been identified in a family member. Although, the variable expressivity of the syndrome makes it impossible to predict the severity of the disease in the fetus.
Genetic counseling
The disorder is inherited in an autosomal dominant manner; most patients have an affected parent whilst some cases occur sporadically. Genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. The penetrance is thought to be complete while there is a great intrafamilial and interfamilial variability in the presence, severity and type of anomalies.
Management and treatment
Management of affected patients includes excision of branchial fistulae or cysts, hearing aids and education programs appropriate for the hearing impaired, and follow-up by a nephrologist. Dialysis or renal transplantation may be required.
Prognosis
Most patients with BOR syndrome receiving appropriate treatment are able to lead normal, active lives. The prognosis of BOR syndrome patients primarily depends on the severity of the renal involvement. Pregnancies where the fetus has severe renal impairment can end in a miscarriage. Later in life, the renal disease might progress to end-stage renal disease.

                            Last update:
                            May 2022

                            - Expert reviewer(s):
                             Ariane SCHMETZ  - Pr Dagmar WIECZOREK | ITHACA*

                                * European Reference Network


Borjeson-Forssman-Lehmann syndrome (BFLS) is a rare X-linked obesity syndrome characterized by intellectual deficit, truncal obesity, characteristic facial features, hypogonadism, tapered fingers and short toes.

Summary:
Epidemiology
The prevalence is unknown. Approximately 50 patients have been reported, from 24 families and sporadic cases.
Clinical description
BFLS is found mainly in boys, but several mild to moderately symptomatic females have been reported within known families, and as isolated cases. There is a wide variability in manifestations. At birth, large ears and small genitalia are occasionally evident. The head circumference is variable and hypotonia, leading to poor feeding, is seen in all infants. Developmental delay is often noted before the age of one. In late childhood, truncal obesity is apparent. Fingers are malleable and tapered and feet are usually broad with flexed, short toes. Most have short stature but some are of normal height. In adolescence, gynecomastia develops and genitalia usually remain small. Characteristic coarse facial features also appear in adolescence and include deep-set eyes, narrow forehead, supraorbital ridges, ptosis and large, fleshy earlobes, all of which become more pronounced in adulthood. Intellectual disability can range from mild to severe and is not progressive. Patients are usually sociable and friendly but some experience anxiety, depression and challenging or hypersexual behavior. Less common findings reported include acute precursor T-cell acute lymphoblastic leukemia, Legg-Calvé-Perthes disease (LCPD), cleft lip/palate (see these terms), hypopituitarism, hearing impairment, epilepsy and mild to generalized polyneuropathy. Females are mainly asymptomatic but in rare cases can exhibit learning problems along with some of the physical features seen in males.
Etiology
BFLS is caused by mutations in the PHF6 gene, located on Xq26, encoding PHF6, a protein involved in cell growth and proliferation. In general, mutations that result in loss or reduction of PHF6 expression result in more severe clinical symptoms. Loss-of-function mutations and skewed X-inactivation are thought to explain the rare occurrence of symptomatic females. Although most cases are inherited within families, several isolated cases have been reported, where the etiology is unknown.
Diagnostic methods
BFLS is suspected on clinical examination when the characteristic symptoms are present. A family history showing X-linked recessive inheritance as well as skewed X-chromosome inactivation in obligate female carriers is a strong additional indicator of BFLS.  PHF6 mutation screening can confirm a diagnosis.
Differential diagnosis
Differential diagnoses include Coffin-Lowry, Klinefelter, Prader-Willi, Bardet-Biedl, or Wilson-Turner syndromes (see these terms).
Antenatal diagnosis
When a PHF6 mutation is known to exist in a parent, antenatal diagnosis is possible.
Genetic counseling
Inheritance is X-linked and genetic counseling is possible to explain X-linkage to families and identify carrier females. Very few patients with BFLS reproduce, but asymptomatic female carriers can pass on the mutation to their children.
Management and treatment
There is no cure for BFLS. Treatment and management is symptomatic. Special education is started early and followed throughout adolescence and adulthood. A healthy diet is recommended. Adults require variable degrees of supervision which may include institutionalization in severe cases. Testosterone replacement therapy and/or a bilateral mastectomy may be considered for the treatment of gynecomastia. If seizures are present, antiepileptic drugs are prescribed. Symptomatic treatment for LCPD and hearing impairment is available. A social network is important as BFLS patients benefit from strong social relationships.
Prognosis
BFLS is not life threatening but due to the intellectual disability encountered, quality of life is limited and life-long supervision is often necessary.

                            Last update:
                            April 2013

                            - Expert reviewer(s):
                            Dr Mark CORBETT  - Dr Jozef GECZ  - Dr Matt HUNTER


Bosley-Salih-Alorainy syndrome (BSAS) is characterized by variable horizontal gaze dysfunction, profound and bilateral sensorineural deafness associated commonly with severe inner ear maldevelopment, cerebrovascular anomalies (ranging from unilateral internal carotid artery hypoplasia to bilateral agenesis), cardiac malformation, developmental delay and occasionally autism. The syndrome is caused by homozygous mutations in the HOXA1 gene (7p15.2) and is transmitted in an autosomal recessive manner. The syndrome overlaps clinically and genetically with Athabaskan brain dysfunction syndrome (ABDS,). However unlike ABDS, BSAS does not manifest central hypoventilation.


Bothnia retinal dystrophy is a rare form of retinal dystrophy, seen mostly in Northern Sweden, presenting in early childhood with night blindness and progressive maculopathy with a decrease in visual acuity, eventually leading to blindness by adulthood. Retinal degeneration, without obvious bone spicule formation, accompanied by affected visual fields and the typical presence of retinitis punctata albescens (see this term) in the posterior pole are also noted.


Botulism is a rare acquired neuromuscular junction disease, characterized by descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), including four clinical forms with different modes of acquisition.

Summary:
Epidemiology
Estimated global prevalence is less than 1/1,000,000. Annual incidence in Western countries is estimated at 1/2,000,000.
Clinical description
The incubation period usually lasts 12 to 36 h, sometimes up to 5-8 days depending on the disease form. The typical clinical picture includes symmetrical cranial nerve palsies followed by symmetrical descending flaccid motor paralysis, with cholinergic dysautonomia. Initial symptoms include blurry vision (accommodation defects, diplopia) with bilateral ptosis, followed by dysautonomic symptoms (dry mouth and eyes, mydriasis, dysphagia, dysarthria, urinary retention and constipation). In the severe forms, paralysis concerns the neck, shoulder, and proximal muscles, followed by involvement of the muscles of the distal upper extremities, the diaphragm and respiratory muscles, which may result in respiratory compromise or arrest. The sensory system and intellectual functions remain unaffected.
Etiology
Clinical manifestations are common to all forms, whatever the mode of acquisition. Foodborne botulism (see this term) caused by consumption of foods contaminated with BoNTs (homemade or traditional canned-foods, ham, pork products, etc) is the most frequent form of botulism in adults. Intestinal colonization by Clostridium botulinum and in situ toxin production is observed in young infants (infant botulism) and certain adults with risk factors (adult intestinal botulism; see these terms). Wound (or inoculation) botulism, through infection of wounds, is rare and mainly occurs in injection drug users; inhalational botulism and iatrogenic botulism have also been reported (see these terms). Botulism is due to BoNTs produced by C. botulinum and, very rarely, by certain related Clostridia, rod-shaped, strictly anaerobic and sporulating bacteria, i.e neurotoxigenic strains of C. baratii and C. butyricum. There are seven types of BoNTs (A to G) with different antigenic properties. Types A, B, E and, more rarely F, are associated with human botulism. At the site of absorption or adsorption, BoNT diffuses via the blood to the presynaptic membrane of skeletal and autonomic cholinergic nerves. BoNT binds to and enters peripheral cholinergic terminals and causes a block of acetylcholine release, with ensuing flaccid paralysis.
Diagnostic methods
Diagnosis is essentially clinical in the first stage; the electromyography (EMG) pattern is characterized by brief, small, abundant potentials (BSAPs). Confirmation is based on BoNT detection in serum, stools, and/or food samples. The detection of BoNT-producing Clostridium in cultures from stools and food or wound samples also supports the diagnosis.
Differential diagnosis
Differential diagnosis, depending on the disease form, in adults or infants, includes myasthenia, Guillain-Barré syndrome (and Miller Fisher syndrome), Lambert-Eaton syndrome (see these terms), bacterial and chemical food poisoning or chemical intoxication.
Management and treatment
Treatment is symptomatic. Management is based on supportive care and respiratory assistance with recovery in severe cases, in an intensive care unit (ICU). Anti-toxin therapy is effective when it is administrated at the onset of symptoms. In Europe, the formulation currently available for adults is trivalent (anti-A, B, E). A heptavalent (anti-A to G) product is also available. In the USA, bivalent (anti A, B) and monovalent (anti-E) antitoxins are distributed; for infant botulism, a human derived botulinum immune globulin (BIG-IV, anti-A-B) is available.
Prognosis
Prognosis varies depending on the different forms of botulism, but is generally correlated with the rapidity of diagnosis and medical assistance. Death resulting from respiratory failure is rare when the patients receive appropriate medical assistance.

                            Last update:
                            January 2011

                            - Expert reviewer(s):
                            Dr Michel POPOFF


A rare spotted fever rickettsiosis caused by infection with the tick-borne bacterium Rickettsia conorii, characterized by the onset of fever after an incubation period of about a week, followed by a centripetally spreading maculopapular rash, which may evolve into a petechial form. Accompanying symptoms are headaches, myalgia and/or arthralgia, among others. The typical ''tache noire'' may be observed at the site of the tick bite for several days. The disease is endemic in Africa, Southern Europe, and India.


A rare developmental defect during embryogenesis characterized by moderate to severe prenatal and postnatal growth retardation, microcephaly, a distinctive facial appearance, profound psychomotor delay, hip and knee contractures and rockerbottom feet.

Summary:
Epidemiology
Bowen-Conradi syndrome (BCS) birth prevalence is estimated at 1 per 355 within the Hutterite population living in small farming colonies in the Prairie provinces and Great Plains of North America with a carrier frequency as high as 1/10 in the Hutterite population. Outside this population, BCS is considered very rare and has only been reported clinically in 9 patients worldwide to date. To date, there are no non-Hutterite patients reported with biallelic EMG1 pathogenic variants.
Clinical description
Prenatally BCS is characterized by intrauterine growth retardation and often a breech presentation. BCS patients fail to thrive, experience severe feeding problems and seldom live past infancy. Distinctive malformations of the head and craniofacial region describe microcephaly at birth, micrognathia and a prominent nose with a noticeable lack of glabellar angle. BCS patients have a severe psychomotor delay, stiff joints, campodactyly or clinodactyly of the little finger and rockerbottom feet. Finger, hip and knee flexion contractures are frequently present. Less common BCS features described include cryptorchidism, seizures, cleft lip with or without cleft palate, congenital heart defect, hypospadias, renal, brain, or other malformations.
Etiology
In the Hutterite population, BCS is over-represented secondary to a founder effect, and is due to a missense mutation in the EMG1 gene located to 12p13.3, leading to disturbances in ribosomal biosynthesis.
Diagnostic methods
Diagnosis is typically made postnatally based on clinical manifestations and can then be confirmed with molecular testing. The diagnosis can first be identified on antenatal ultrasound; however the findings (particularly in a non-Hutterite infant) are non-specific and would likely not suggest BCS. In a Hutterite fetus, even in the absence of a positive family history, findings such as microcephaly, contractures, and rocker-bottom feet would be strongly suggestive of BCS.
Differential diagnosis
Differential diagnosis includes trisomy 18, COFS syndrome and fetal akinesia deformation sequence. Other conditions with microcephaly and severe growth and developmental delay such as chromosome breakage disorders, DNA damage repair disorders, microcephalic primordial dwarfisms and certain forms of carbohydrate deficient glycoprotein syndromes may also show some overlap.
Antenatal diagnosis
In cases with a family history, prenatal diagnosis is available and possible by amniocentesis or chorionic villus sampling and DNA analysis. Targeted mutation analysis of the Hutterite mutation is available prenatally (although rarely pursued) and in some instances carrier testing of both Hutterite parents of a presumed affected pregnancy can strengthen the possibility of diagnosis
Genetic counseling
BCS transmission is autosomal recessive. With the discovery of the causative mutation in the Hutterite population, carrier testing is available. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is merely symptomatic. Feeding is significantly compromised, and most infants require tube feeding. No curative treatment is presently available. The natural history is similar to aneuploidy syndromes such as trisomy 18 and the discussion of palliative care is appropriate.
Prognosis
Prognosis is extremely poor. Most children die within the first 2 years of life (range 1 day-9 years). Those who survive beyond 1 year of age show extreme growth failure.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr A.Micheil INNES


A rare and crippling chondrodysplasia, reported mainly in the Maputaland region in northern Kwazulu Natal, South Africa, characterized by a bilateral and uniform arthropathy of the joints that primarily and most severely affects the hip but that can also affect many other joints (i.e. knees, ankles, wrists, shoulders, elbows), and that manifests with pain and stiffness that progressively limits joint movement, eventually compromising a patient's ability to walk. Severe short staure and brachydactyly have been reported in a few patients with MJD.


A rare, congenital limb malformation characterized by shortened or underdeveloped middle phalanges of all digits, that are sometimes fused with the terminal phalanges. The proximal phalanges of the thumbs and big toes are also shortened. Short stature in adulthood has been reported in association.


A rare, congenital limb malformation characterized by shortening (hypoplasia or aplasia) of the middle phalanges of the index finger and, sometimes, of the fifth finger. On radiographs, the middle phalanx of the index fingers often appear triangular and in severely affected cases, the index finger is curved radially. The lower limb phenotype is generally milder.


A rare congenital limb malformation characterized by short middle phalanges of the 2nd and 5th fingers and absence of the middle phalanges of toes 2 to 5. Occasionally, the 4th digit may be affected and manifests with an abnormally shaped middle phalanx which causes radial deviation of the distal phalanx. Other hand/foot malformations, such as syndactyly, polydactyly, reduction defects and symphalangism, may be associated.


A rare primary bone dysplasia disorder characterized by brachymesophalangy with mesomelic short limbs, and carpal and tarsal bone abnormalities. In general, the affected individuals are of slightly short stature and normal intelligence. The syndrome has been described in a kindred with seven affected members from three generations. Transmission appears to be autosomal dominant.


A rare dysostosis with brachydactyly characterized by variable combinations of features of brachydactyly types A2 (such as delta-shaped middle phalanx of the second finger or toe) and D (short, broad distal phalanx of the thumb) and other types of brachydactyly (symphalangism), as well as unique features (dislocatable thumbs, lateral deviation of second toes with elevation of first toes). There have been no further descriptions in the literature since 1989.


A rare congenital limb malformation syndrome characterized by hypoplasia or aplasia of the terminal parts of fingers 2 to 5, with complete absence of the fingernails. The thumbs are always intact but frequently show flattening, splitting or duplication of the distal phalanges. Digits on the radial side of the hand are less severely affected than those on the ulnar side. The feet are similarly affected but less severely. Soft tissue syndactyly, symphalangism, carpal and/or tarsal fusions and shortening of metacarpals and/or metatarsals may be present.


A rare subtype of brachydactyly type B characterized by hypoplasia or aplasia of the distal phalanges of digits 2-5 with or without nail dysplasia, in association with fusion of the middle and distal phalanges, a broad or bifid thumb, and occasionally distal and proximal symphalangism or syndactyly. The feet are less severely affected than the hands.


A clinical subtype of brachydactyly type B characterized by hypoplasia/aplasia of distal and/or middle phalanges in fingers and toes II-V (frequently severe in fingers/toes IV-V, milder in fingers/toes II-III) in association with proximal, and occasionally distal, symphalangism, fusion of carpal/tarsal bones and partial cutaneous syndactyly. Additional reported features include proximal placement of thumbs, sensorineural hearing loss and farsightedness.


A rare congenital limb malformation characterized by hypoplastic middle phalanges of fingers 2, 3, and 5, with relative sparing of finger 4, as well as hyperphalangy most commonly affecting fingers 2 and 3, shortening of the first metacarpal with short thumb, and ulnar deviation of fingers 2 and 3. The severity of the malformation is highly variable.


Brachydactyly type E (BDE) is a congenital malformation of the digits characterized by variable shortening of the metacarpals with more or less normal length phalanges, although the terminal phalanges are often short.

Summary:
Epidemiology
BDE is very rare.
Clinical description
Occasionally, the metatarsals are also short. Hyperextensibility of the hand joints is a striking feature. Axial triradius may occur. Affected individuals may be of moderately short stature.
Etiology
BDE may be due to mutations in the PTHLH gene (12p12.1-p11.2) or HOXD13 (2q31-q32).
Antenatal diagnosis
It is inherited as an autosomal dominant trait with variable expressivity.

                            Last update:
                            October 2010


A rare genetic brachydactyly syndrome characterized by the association of brachydactyly type E with hypertension (due to vascular or neurovascular anomalies) as well as the additional features of short stature and low birth weight (compared to non-affected family members), stocky build and a round face. The onset of hypertension is often in childhood.


Brachydactyly-elbow wrist dysplasia syndrome is a rare, genetic bone development disorder characterized by dysplasia of all the bony components of the elbow joint, abnormally shaped carpal bones, wrist joint radial deviation and brachydactyly. Patients typically present with slight flexion at the elbow joints (with impossibilty to perform active extension) and usually associate a limited range of motion of the elbow, wrist and finger articulations. Camptodactyly and syndactyly have also been reported.


A rare autosomal dominant heart-hand syndrome that is characterized by bisymmetric brachydactyly accompanied by long thumbs, joint anomalies (restriction of motion at the shoulder and metacarpophalangeal joints) and cardiac conduction defects. Additional features include small hands and feet, clinodactyly, narrow shoulders with short clavicles, pectus excavatum and mild shortness of the limbs, cardiomegaly and murmur of pulmonic stenosis. There have been no new reports since 1981.


Brachydactyly-mesomelia-intellectual disability-heart defects syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, intellectual disability, thin habitus with narrow shoulders, mesomelic shortness of the arms, craniofacial dysmorphism (e.g. long lower face, maxillary hypoplasia, beak nose, short columella, prognathia, high arched palate, obtuse mandibular angle), brachydactyly (mostly involving middle phalanges) and cardiovascular anomalies (i.e. aortic root dilatation, mitral valve prolapse).


A rare multiple congenital anomalies/dysmorphic syndrome characterized by brachydactyly, nystagmus, and cerebellar ataxia. Intellectual deficit and strabismus have also been reported. There have been no further descriptions in the literature since 1934.


Brachydactyly-preaxial hallux varus syndrome

A rare congenital limb malformation characterized the association of hallux varus with short thumbs and first toes (involving the metacarpals, metatarsals, and distal phalanges; the proximal and middle phalanges are of normal length) and abduction of the affected digits. Intellectual deficit was observed in all reported individuals. There have been no further reports since 1994.


Brachydactyly-short stature-retinitis pigmentosa syndrome is a rare, genetic, congenital limb malformation syndrome characterized by mild to severe short stature, brachydactyly, and retinal degeneration (usually retinitis pigmentosa), associated with variable intellectual disability, developmental delays, and craniofacial anomalies.


Brachydactyly-syndactyly, Zhao type is a recently described syndrome associating a brachydactyly type A4 (short middle phalanges of the 2nd and 5th fingers and absence of middle phalanges of the 2nd to 5th toes) and a syndactyly of the 2nd and 3rd toes. Metacarpals and metatarsals anomalies are common.

Summary:
Epidemiology
This syndrome has been described in two families.
Etiology
It is caused by HOXD13 mutations in 2q31-q32
Genetic counseling
Brachydactyly-syndactyly, Zhao type is inherited as an autosomal dominant trait.

                            Last update:
                            October 2010


A rare malformation syndrome that is characterized by short stature, hypoplastic fifth digits with tiny dysplastic nails, facial dysmorphism with coarse features including a wide mouth and broad nose, and mild intellectual disability. It has been suggested that Coffin-Siris syndrome and BOD syndrome are perhaps allelic variants.


A rare genetic spondylodysplastic dysplasia characterized by short trunk/short stature, generalized platyspondyly with rounding of vertebral bodies. The vertebral bodies show less elongation compared to patients with other types of the disorder. Precocious calcification of the cerebral falx and non-specific minor facial anomalies may be associated. There have been no new reports since 1989.


An exceedingly rare form of brachyolmia, characterized by mild platyspondyly, broad ilia, elongated femoral necks with coxa valga, scoliosis, and short trunked short stature associated with amelogenesis imperfecta of both primary and permanent dentition.


Brachyolmia is a rare, clinically and genetically heterogeneous group of bone disorders characterized by short trunk, mild short stature, scoliosis and generalized platyspondyly without significant abnormalities in the long bones.

Summary:
Epidemiology
The prevalence of brachyolmia is not known, but the disorder is probably under-recognized. Fewer than 100 cases have been reported to date. Cases have been reported in various ethnic groups. However, most cases with the Hobaek/Toledo type reported so far were of Turkish origin.
Clinical description
Four types of brachyolmia have been described: autosomal recessive brachyolmia, Hobaek/Toledo type, autosomal recessive brachyolmia-amelogenesis imperfecta syndrome, autosomal dominant brachyolmia, and autosomal recessive brachyolmia, Maroteaux type (see these terms). The age of onset is generally in childhood with short stature becoming more evident with age. The clinical manifestations are generally mild to moderate, with minor physical functional repercussions. Some patients report non-specific back pain. The disorder is not associated with intellectual disability. AR brachyolmia, Hobaek/Toledo type is characterized by short-trunked short stature with platyspondyly and scoliosis. Corneal opacities and precocious calcification of costal cartilage occur in rare cases. In AR brachyolmia-amelogenesis imperfecta syndrome, short-trunked short stature is associated with platyspondyly and enamel abnormalities. AD brachyolmia is a more severe form with significant short-trunked short stature, platyspondyly and kyphoscoliosis. Lastly, presumably autosomal recessive brachyolmia, Maroteaux type is a vague entity that has not been well characterized but may involve short trunk/short stature, generalized platyspondyly and rounding vertebral bodies.
Etiology
Mutations in the PAPSS2 gene (10q24) have been found in patients with AR brachyolmia, Hobaek/Toledo type, and in the TRPV4 gene (12q24.1) in patients with AD brachyolmia. Precise pathogenesis is not well understood.
Diagnostic methods
Clinical and radiological findings are used to diagnose brachyolmia. Molecular genetic testing can also be used to confirm the diagnosis.
Differential diagnosis
The differential diagnosis includes other genetic skeletal dysplasia syndromes, particularly mild spondyloepiphyseal dysplasia, including mild type 2 collagenopathy and mild Morquio disease (see this term).
Antenatal diagnosis
Prenatal diagnosis is available on molecular grounds, when a mutation (or mutations) was ascertained in a familial case.
Genetic counseling
Brachyolmia follows either an autosomal recessive or rarely an autosomal dominant pattern of inheritance. Genetic counseling based on the mode of inheritance should be provided to affected families.
Management and treatment
No specific treatment is currently available for this disease.
Prognosis
The prognosis for patients with brachyolmia is generally very good.

                            Last update:
                            March 2015

                            - Expert reviewer(s):
                            Dr Gen NISHIMURA


Brachytelephalangic chondrodysplasia punctata (BCDP) is a form of non-rhizomelic chondrodysplasia punctata, a primary bone dysplasia, characterized by hypoplasia of the distal phalanges of the fingers, nasal hypoplasia, epiphyseal stippling appearing in the first year of life, as well as mild and non-rhizomelic shortness of the long bones.

Summary:
Epidemiology
The prevalence of BCDP is not available. A birth prevalence estimate of 1/500,000 newborns has been put forward. The genetic BCDP due to ARSE alterations is pan-ethnic and occurs almost exclusively in males. Another part of BCDP, phenocopies of the genetic ones due to environmental and maternal causes, are also described in both, males and females.
Clinical description
First signs of the disease are often found antenatally by ultrasound imaging, including nasal spine hypoplasia and epiphyseal abnormal calcifications. Stippled epiphyses are usually seen in the tarsus, knee, and distal phalanges, but may be more generalized, including epiphyses of the long bones, vertebrae, hips, hyoid and tracheal cartilage. At birth, the diagnosis is apparent with facial dysmorphism, quite similar to that of maxillonasal dysplasia (or Binder syndrome), i.e. severe nasomaxillary hypoplasia with flattened nasal base, reduced nasal tip protrusion but normal ala of the nose, and short columella. Usually this does not affect birth respiratory function. Typical radiological features of BCDP are hypoplastic pyramidal-shaped distal phalanges with the apices pointing proximally, slightly irregular metaphyses, relatively larger epiphyses, and punctuate calcifications (tracheal, vertebral and tarsal/carpal stippling seen in newborns disappearing in infancy and childhood). Anterior thoracolumbar vertebral body deformities, posterior scalloping and coronal cleft are also sometimes found. Affected individuals do not show asymmetry of the limbs or hypotonia. Relative micromelia without short stature usually develops postnatally and affected adults have a final normal stature. Delay in odontoid ossification may lead to cervical instability in the first months. Less common features include ichthyosis and delayed psychomotor development in cases associated with deletion of ARSE locus. In general, BCDP falls into the mildest end of chondrodysplasia punctata (CDP) spectrum with a good long-term prognosis.
Etiology
The causative gene of BCDP is ARSE (Xp22) encoding the arylsulfatase E protein essential for the correct composition of cartilage and bone matrix during development. ARSE mutations have been identified in only 50% of male patients, and it was proposed that the remainder might represent phenocopies due to maternal-fetal vitamin K deficiency and maternal autoimmune diseases.
Diagnostic methods
Diagnosis can be challenging due to the extensive heterogeneity and variability of both phenotypical and genetic features. Radiographs taken shortly after birth may show only a few calcifications of tarsal and long bones epiphysis. Extensive epiphyseal calcifications (usually ankle and distal phalanges), vertebral stippling and distal phalangeal hypoplasia with proximal apices may also been reported. Calcifications can also occur in the larynx, trachea, and main stem bronchi. X-rays may also reveal vertebral abnormalities. Diagnosis can be confirmed in a male patient with identification of a hemizygous pathogenic variant in ARSE.
Differential diagnosis
The differential diagnosis includes other types of chondrodysplasia punctata, warfarin embryopathy, pseudowarfarin embryopathy, vitamin K malabsorption embryopathy, lupus erythematosus embryopathy, hydantoin embryopathy, Keutel syndrome, and maxillonasal dysplasia.
Antenatal diagnosis
Prenatal testing for at-risk pregnancies is possible if the ARSE pathogenic variant has been previously identified in the family.
Genetic counseling
The pattern of inheritance of BCDP is X-linked. Genetic counseling can inform parents that the risk of transmitting the pathogenic variant for a mother is 50% in each pregnancy. Affected males pass the pathogenic variant to all of their daughters and none of their sons.
Management and treatment
Treatment is supportive. All patients with CDP should be explored for clinical signs of spinal cord compression. In rare cases, respiratory difficulty can require in the first weeks monitoring, nasal stents, and feeding tube. Severe maxillary hypoplasia or maxillary retrognathia may require reconstructive surgery in older individuals. Instability of the cervical spine should be screened within the first year, leading to positioning and manipulation prevention measures. Rarely, it may require a cervical collar or spinal fusion.
Prognosis
Prognosis is good, as most patients have been reported to have a benign course. However, in some cases cervical canal stenosis with cervical cord compression may lead to serious morbidity and early mortality.

                            Last update:
                            June 2018

                            - Expert reviewer(s):
                            Dr Geneviève BAUJAT


A rare developmental anomaly characterized by brachytelephalangy, distinct craniofacial features (prominent square forehead, telecanthus, small nose, malar hypoplasia, smooth philtrum and thin upper lip) and, relative to other family members, short stature. These features may be associated with anosmia and hypogonadotropic hypogonadism (Kallman syndrome). There have been no further descriptions in the literature since 1986.


Braddock syndrome is a rare malformation syndrome with multiple congenital abnormalities, described in 2 siblings, that is characterized by VACTERL -like association in combination with pulmonary hypertension, laryngeal webs, blue sclerae, abnormal ears, persistent growth deficiency and normal intellect.


A rare genetic retinal disorder characterized by childhood-onset of markedly delayed visual adaptation to both dark and light conditions, marked difficulties tracking moving objects, and mild photophobia. Visual acuity is variably reduced, while color vision is unaffected.


A rare, inherited disorder characterized by widespread calcifications of basal ganglia and cortex, developmental delay, small stature, retinopathy and microcephaly. The absence of progressive deterioration of the neurological functions is characteristic of the disease.

Summary:
Epidemiology
The syndrome has been described in eight children from two interrelated families.
Etiology
Brain calcification, Rajab type is associated with a genetic locus on chromosome 2.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            October 2009


A rare infantile-onset neurometabolic disease characterized by dystonia, parkinsonism, nonambulation, autonomic dysfunction, developmental delay and mood disturbances.

Summary:
Epidemiology
The prevalence is unknown. It has been described in 8 patients from one Saudi Arabian family to date.
Clinical description
Disease onset presents in infancy with hypotonia, loss of acquired head control and persistent crying and eye deviation. Motor development is delayed and later manifestations include severe parkinsonism, dystonia, ataxia, oculogyric crises, sleep and mood disturbances, temperature instability, excessive diaphoresis, ptosis and postural hypotension. Symptoms show no diurnal variation, do not improve with intake of vitamin B12 or folinic acid and worsened after administration of L-dopa.
Etiology
Brain dopamine-serotonin vesicular transport disease is caused by a mutation in the SLC18A2 gene (10q25), encoding the vesicular monoamine transporter 2 (VMAT2) which is responsible for the transport of dopamine and serotonin into synaptic vesicles. Mutations in this gene lead to the impairment of VMAT2 and consequently to problems with motor control, autonomic functioning and mood regulation.
Genetic counseling
It is inherited in an autosomal recessive manner, and genetic counseling is recommended.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


Brain malformation-congenital heart disease-postaxial polydactyly syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by intrauterine growth retardation, multiple congenital malformations (such as brain malformations including ectopic neuropituitary gland, hypoplastic adenopituitary, and hypoplastic cerebellar vermis, cardiac and renal anomalies, and postaxial polydactyly), abnormal hair structure with temporal balding, and dysmorphic facial features with hypoplastic nasal bridge, anteverted nostrils, dysplastic ears, long and smooth philtrum, narrow upper lip, and prominent, asymmetric lower lip. Postnatal growth retardation and severe developmental delay have also been reported.


Brain malformations-musculoskeletal abnormalities-facial dysmorphism-intellectual disability syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay, intellectual disability and mild to moderate facial dysmorphism in association with variable brain malformations (including abnormal gyration patterns, ventriculomegaly, white matter abnormalities, hypoplasia of the corpus callosum and cerebellar hemispheres), musculoskeletal abnormalities (including hemivertebrae, scoliosis or kyphosis, contractures, and joint laxity), ocular involvement (strabismus, hypermetropia and cortical visual impairment) and hypotonia. Additional clinical manifestations may include seizures, short stature urogenital malformations, heart defects and gastrointestinal malformations.

Summary:
Epidemiology
To date, approximately 30 patients with this syndrome has been described.
Clinical description
All affected individuals have mild to moderate facial dysmorphisms, including facial asymmetry, midface retraction, low-set ears, downslanting palpebral fissures, deep-set eyes, horizontal eyebrows, a broad and/or depressed nasal bridge, and a short philtrum. Developmental delay and intellectual disability are observed in all affected individuals, whilst other manifestations are variably present. Significant brain abnormalities are observed in the majority of individuals scanned and may include abnormal gyration patterns, ventriculomegaly, white matter abnormalities, hypoplasia of the corpus callosum and cerebellar hemispheres. Musculoskeletal involvement is observed in over three-quarters of individuals and may include joint laxity, scoliosis, or kyphosis, hemivertebrae, cubitus valgus, contractures, small hands and feet, and/or abnormal ribs. Eye and/or vision abnormalities are observed in approximately 70% of patients; whilst strabismus is commonly observed, other features may include hyperopia, cortical visual impairment, and optic atrophy. Short stature is observed in half of individuals. Congenital malformations are less frequently present (≤ 30% of individuals) and may include heart defects (ventricular/atrial septal defect and patent ductus arteriosus), urogenital malformations (single kidney, horseshoe kidney, and kidney dysplasia), intestinal atresia, high-arched or cleft palate, and craniosynostosis. Immunoglobulin deficiency and abnormal coagulation has been reported in several patients. Neurological features include hypotonia (75% of individuals) and seizures (55%).
Etiology
The disorder is due to a heterozygous de novo SON mutation (21q22.11), which encodes for a protein required for proper RNA splicing.
Diagnostic methods
Diagnosis is with whole exome sequencing.
Differential diagnosis
As the clinical phenotype is heterogeneous, the differential diagnosis include the whole group of multiple congenital anomalies/dysmorphic syndrome characterized by developmental delay and intellectual disability associated with brain malformations.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Whilst the disease is autosomal dominant, all reported cases have occurred sporadically.
Management and treatment
A multidisciplinary team approach should be considered, including a pediatrician, clinical geneticist, and psychiatrist. Referral to other specialists (e.g. orthopedic surgeon, ophthalmologist, neurologist) is indicated when specific problems are suspected. Screening of congenital defects (urogenital and heart defects) is recommended after diagnosis. Seizures should be treated according to standard procedures.
Prognosis
The eldest described patient was 34 years of age.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Dr J.M.T. [Jos] DRAAISMA | ITHACA*

                                * European Reference Network


Brain-lung-thyroid syndrome is a rare disorder characterized by congenital hypothyroidism (CH), infant respiratory distress syndrome (IRDS) and benign hereditary chorea (BHC; see these terms).

Summary:
Epidemiology
Prevalence is unknown but to date about 50 cases have been reported in the literature.
Clinical description
The clinical spectrum varies from the complete triad of brain-lung-thyroid syndrome (50%), to brain and thyroid disease (30%), or isolated BHC (13%), which is the mildest expression of the syndrome. In addition, the severity of symptoms varies widely, even in families with the same disease-causing mutation. The thyroid form can present with overt or, more commonly, subclinical hypothyroidism / hyper-thyrotropinemia at birth, in infancy or in early childhood. There is significant correlation between thyroid morphology (55% normal, 35% hemiagenesis or hypoplasia, and 10% athyreosis in 46 published cases) and the commonly mild elevation of thyroid-stimulating hormone (TSH). The lung form presents most commonly as IRDS at term, suggestive for congenital surfactant protein deficiency. In a subgroup of patients, the disease progresses to chronic interstitial lung disease. In other patients, recurrent mild to severe pulmonary infections may be the initial sign of lung disease. The neurological form presents during the first year of life with hypotonia and psychomotor delay, which progresses to BHC between 1 and 5 years of age. Non-progressive BHC after the age of 5 years is the most common and specific sign of the syndrome. Additional non-classical symptoms including hypo- or oligodontia, microcephaly, intellectual deficit, failure to thrive, growth retardation, dysmorphism, hypoparathyroidism and malabsorption have been reported only in patients with large deletions on chromosome 14 including the NKX2-1 gene. Mild intellectual deficit may be present in some patients.
Etiology
Brain-lung-thyroid syndrome is caused by mutations in the thyroid transcription factor 1 gene (NKX2-1/TITF1; 14q13.3).
Diagnostic methods
Diagnosis is based on neonatal screening rather than clinical presentation of overt hypothyroidism such as feeding difficulty, prolonged jaundice, or large fontanels. Congenital hypothyroidism is screened systematically in many countries and raises suspicion of NKX2-1 defects when found in combination with neurological or respiratory problems. Diagnosis of BHC is based on clinical observation. Cerebral MRI may reveal malformations in about 20% of patients (e.g. dysgenetic basal ganglia, or cerebral atrophy). Diagnosis of brain-lung-thyroid syndrome is confirmed by genetic testing showing mutations in the NKX2-1 gene.
Differential diagnosis
Differential diagnoses include other forms of congenital hypothyroidism, other causes of infant respiratory distress syndrome, genetic forms of surfactant protein deficiency, and other causes of chorea.
Genetic counseling
Genetic counseling of families is essential in the context of autosomal dominant transmission due to life-long morbidity.
Management and treatment
Treatment of congenital hypothyroidism is based on life-long levothyroxin substitution according to international guidelines (starting dose 10-15 mcg/kg/day). Treatment of compensated hypothyroidism / hyperthyrotropinemia should be considered as early as possible. Patients with IRDS at term may require mechanical ventilation for up to several weeks. Treatment options for BHC are not well established.
Prognosis
Prognosis varies considerably depending on the severity of symptoms. BHC causes life-long morbidity of varying degrees. Lung disease, if present, can cause mortality in a subgroup of patients.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Pr Gabor SZINNAI


A rare, dominantly inherited multiple congenital anomalies syndrome characterized by highly variable clinical phenotype involving the three main affected systems: branchial (cutaneous) defects, ophthalmic malformations and facial anomalies. Additional features can be present.

Summary:
Epidemiology
The prevalence of branchio-oculo-facial syndrome (BOFS) is unknown but fewer than 150 individuals with a well-described clinical and/or molecular diagnosis have been reported in the literature so far.
Clinical description
The branchial defects include cervical or infra- and/or supra-auricular skin defects that vary in size and shape but are typically characterized as thinned erythematous cutaneous defects. Ocular features are highly variably expressed including microphthalmia, anophthalmia, coloboma, cataract, ptosis, nasolacrimal duct obstruction, strabismus and significant visual impairment. The characteristic craniofacial features include dolichocephaly, hypertelorism, telecanthus, upslanted palpebral fissures, broad nose with full nasal tip, pre-auricular and upper lip pits, external ear anomalies (malformed and prominent pinnae), inner ear and petrous bone anomalies (such as cochlear dysplasia, Mondini dysplasia and enlarged vestibular aqueduct), cleft lip (including lesser forms, such as microform, ''pseudocleft'' or abnormal philtrum) with or without cleft palate, and lower facial nerve and/or muscle hypoplasia (partial 7th cranial nerve weakness). Patients have conductive/sensorineural/mixed hearing loss. Additional findings include ectopic dermal thymus, renal anomalies (dysplastic, multisystem or absent kidneys, vesicoureteral reflux) and ectodermal anomalies (premature hair graying, hypoplastic teeth, dysplastic nails and subcutaneous dermoid-like cysts, often on the scalp). Psychomotor development is typically normal. Autism spectrum disorder, intellectual disability, growth restriction, congenital heart defects and polydactyly are rare.
Etiology
BOFS is caused by mutations involving the gene TFAP2A (6p24.3) that encodes the transcription factor AP-2 alpha that regulate gene expression during embryogenesis (of the eye, ear, face, body wall, limbs and neural tube).
Diagnostic methods
The clinical diagnosis of BOFS is established if all three of the main features (branchial, ocular and craniofacial) are present or if two of the three main features are present in addition to either ectopic thymus or a positive family history in a first-degree relative. Diagnosis may be confirmed with molecular testing.
Differential diagnosis
The most important differential diagnosis of BOFS is the branchio-oto-renal syndrome (BOR syndrome).
Antenatal diagnosis
Prenatal diagnosis and preimplantation genetic testing are possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
BOFS has shown almost complete penetrance and a significant inter- and intrafamilial variability. No clear genotype-phenotype correlation exists. Transmission is autosomal dominant and an affected individual has a 50% chance of having an affected child at each pregnancy. About 50-60% of the diagnosed individuals have a de novo pathogenic variant.
Management and treatment
Multidisciplinary care is required, including craniofacial specialists, plastic surgeons, ophthalmologists, otolaryngologists, dentists and genetic counseling for affected families. Renal and cardiac abnormalities should be excluded and when necessary supportive therapies should be considered.
Prognosis
Prognosis is generally good but depends on the severity of associated manifestations.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Dr Patricia DIAS | ITHACA* - Dr Mariana NEVES | ITHACA*

                                * European Reference Network


Branchiogenic deafness syndrome is a multiple congenital anomalies syndrome, described in one family to date, characterized by branchial cysts or fistulae; ear malformations; congenital hearing loss (conductive, sensorineural, and mixed); internal auditory canal hypoplasia; strabismus; trismus; abnormal fifth fingers; vitiliginous lesions, short stature; and mild learning disability. Renal and uretral abnormalities are absent.


Branchiootic syndrome is a rare, genetic multiple congenital anomalies syndrome characterized by second branchial arch anomalies (branchial cysts and fistulae), malformations of the outer, middle and inner ear associated with sensorineural, mixed or conductive hearing loss, and the absence of renal abnormalities. Typical ear findings consist of malformed auricles (e.g. lop or cupped ears), preauricular pits and/or tags, and middle and/or inner ear dysplasias (inculding cochlear, vestibular and semicircular channel hypoplasia, malformation of the ossicles and of middle ear space).


Branchioskeletogenital syndrome is a rare multiple congenital anomalies/dysmorphic syndrome characterized by moderate intellectual disability, distinctive craniofacial features (including brachycephaly, facial asymmetry, marked hypertelorism, blepharochalasis, proptosis, a broad nose with concave nasal ridge and bulbous nasal tip, midface hypoplasia, bifid uvula or partial cleft palate, and prognathism), progressive dental anomalies (dentigerous cysts, radicular dentin dysplasia and early tooth loss), vertebral fusions (particularly of C2-C3), and hypospadias. Hearing loss is an additional observed feature.


Brazilian hemorrhagic fever, caused by the Sabia virus (a newly discovered arenavirus), is a viral hemorrhagic fever, believed to originate from Sao Paulo, Brazil, with only 3 reported cases (2 of which were due to laboratory accidents) to date, characterized by fever, nausea vomiting myalgia tremors, and hemorragic manifestations such as conjunctival petechia and haematemesis, leading potentially to shock, coma and death.


A rare genetic, multiple congenital malformation syndrome characterized by brain anomalies (thinning of the corpus callosum with dilatation of ventricles), intellectual disability, ectodermal dysplasia, skeletal deformities (vertebral anomalies, scoliosis, polydactyly), ear/eye anomalies (maldevelopment, small optic nerves, low set and large ears with hearing loss) and kidney dysplasia/hypoplasia. In the case that clinical manifestation is also associated to Hirschsprung disease and cleft palate or cryptorchidism, it is named as BRESHECK syndrome.


A rare, hereditary connective tissue disease characterized by severe ocular manifestations due to extreme corneal thinning and fragility with rupture in the absence of significant trauma, often leading to irreversible blindness. Extraocular manifestations comprise deafness, developmental hip dysplasia, and joint hypermobility.


A rare genetic skeletal muscle disease characterized by childhood onset of exercise-induced progressive impairment of muscle relaxation, stiffness, cramps, and myalgia, predominantly in the arms, legs, and face (eyelids), and, biochemically, by a reduced sarcoplasmic reticulum Ca(2+)-ATPase activity. Symptoms improve after a few minutes of rest and may be exacerbated by cold. The term Brody syndrome refers to a clinically distinguishable subset of patients without ATP2A1 mutations, with adolescence or adult onset and selective muscular involvement, in which myalgia is more common.


A rare neuroendocrine neoplasm characterized by origin from pulmonary neuroendocrine cells and ranging from low-grade typical carcinoid and intermediate-grade atypical carcinoid to high-grade large-cell neuroendocrine carcinoma and small-cell carcinoma. Two thirds of the tumors are located in the major bronchi, with a predilection for the right lung, in particular the middle lobe. Most patients with central bronchial tumors present with hemoptysis, cough, recurrent pulmonary infections, fever, chest discomfort, and unilateral wheezing, while peripheral carcinoids are usually discovered only incidentally. Carcinoid syndrome or Cushing syndrome are very rare. The tumors may be part of multiple endocrine neoplasia type 1.


A rare lung disorder that is mainly associated with chronic allograft dysfunction after lung transplantation and that is characterized by inflammation and fibrosis of bronchiolar walls that reduce the diameter of the bronchioles and result in progressive and irreversible airflow obstruction.


Congenital malformations resulting from abnormal budding of the foregut and are most commonly found in the mediastinum.


Bronchopulmonary dysplasia is a chronic respiratory disease that results from complications related to lung injury during the treatment of infant acute respiratory distress syndrome (see these terms) in low-birth-weight premature infants or from abnormal lung development in older infants. Clinical signs are tachypnea, tachycardia and signs of respiratory distress such as intercostal recession, grunting and nasal flaring.


A rare genetic disease characterized as an inherited skin tumour predisposition syndrome presenting with skin appendage tumours, namely cylindromas, spiradenomas and trichoepitheliomas

Summary:
Epidemiology
To date, more than 200 cases of Brooke-Spiegler syndrome (or CYLD Cutaneous Syndrome, CCS) have been reported in the literature. Increased severity in females is recognized.
Clinical description
CCS typically manifests in adolescence and early adulthood with the appearance of multiple skin tumours including cylindromas, spiradenomas and trichoepitheliomas. Tumour development is progressive and can affect the head and neck as well as torso. Cylindromas present as different sized pink nodules on the scalp which can become confluent (historically called ''turban tumour''). Spiradenomas are painful blue nodules that can measure several centimeters across. Trichoepitheliomas manifest as skin colored papules or firm nodules, bilateral and symmetrically distributed, preferring the central face region, particularly the nose and the surrounding skin. Patients may also develop small milia on the skin of the face. Mosaic presentations are recognised, with risk of genetic transmission to children. A minority of patients can also get major and minor salivary glands neoplasms, usually membranous basal cell adenoma. Malignancies arising in preexisting spiradenoma, cylindroma and spiradenocylindroma have been reported. Malignant tumours may be aggressive carcinomas with local infiltrative growth or metastases. Rarely, skin cylindromas may metastasise to the lung without involvement of lymph nodes (pulmonary cylindromas). Malignant metastases to bone, lung and the liver have been reported.
Etiology
CCS is due to germline mutations in the CYLD gene (16q12-q13), a tumour suppressor gene which encodes a protein that plays a key role in negatively regulating several signaling pathways, such as NF-KB, JNK, Wnt, TGFB and TRK.
Diagnostic methods
Diagnosis of CCS is based mainly on clinical examination, family history and skin biopsy. Histopathologic findings of cylindromas, spiradenomas and trichoepitheliomas are consistent with CCS. CYLD gene testing is now performed in affected individuals that fit clinical diagnostic criteria.
Differential diagnosis
Differential clinical diagnosis for multiple skin and/or scalp tumours include Birt-Hogg-Dubé syndrome, neurofibromatosis type 1, Cowden syndrome, tuberous sclerosis complex, Marie-Unna hypotrichosis, basal cell naevus syndrome, pilar cysts, multiple syringomas. These can be usually excluded following clinical examination and skin biopsy of a tumour, followed by dermatopathological assessment.
Genetic counseling
CCS is inherited as an autosomal dominant trait with high penetrance and variable expressivity. Prognostication regarding severity, tumour type, or clinical presentation is currently not possible in confirmed CYLD mutation carriers.
Management and treatment
Removal of cylindroma, spiradenoma, and trichoepithelioma is by conventional surgery. For an optimal outcome, as much normal scalp and skin as possible must remain in place. '' Scalp-sparing'' strategies include early primary excision with direct skin closure, tumour enucleation followed by direct skin closure, and excision followed by secondary intention healing techniques. Hyfrecation for selected small tumours and laser ablation of smaller lesions may be considered. Mohs micrographic surgery for recurrent benign tumours after primary surgical excision may have limited benefit, and lead to unnecessarily large surgical defects. Multidisciplinary skin cancer team management of tumours that have undergone malignant transformation is advised, and such a team may include a dermatologist, plastic surgeon, oncologist, radiologist and pathologist. Radiotherapy should be avoided as this may cause additional new tumours, and may increase risk of maligant transformation. Although malignant transformation is uncommon, patients are advised to report tumours that grow rapidly, or ulcerate and bleed. These features should prompt excision and histological assessment.
Prognosis
Tumours observed in CCS are usually benign and most patients have a normal life span. The development of malignant tumours may shorten lifespan.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Neil RAJAN


Brucellosis is an anthropozoonotic infection, endemic in the Mediterranean region, the Middle East, Latin America and parts of Asia and Africa, that is caused by gram-negative coccobacilli of the genus Brucella transmitted through consumption of unpasteurized dairy products or through direct contact with infected animals, placentas or aborted fetuses. Brucellosis is characterized by fever, fatigue, malaise, headache, anorexia, weight loss, sweating, osteomuscular pain (joint and lumbar pain), and arthritis.


Bruck syndrome is characterised by the association of osteogenesis imperfecta and congenital joint contractures.

Summary:
Epidemiology
Prevalence is unknown but less than 40 cases have been reported in the literature so far.
Clinical description
Features include osteoporosis and bone fragility, progressive joint contractures sometimes associated with pterygia, wormian bones, scoliosis due to vertebral deformities and short stature. Mental development is normal.
Etiology
The syndrome is genetically heterogeneous: the locus was mapped to chromosome 17p12 in one family (Bruck syndrome 1) but mutations in the  PLOD2 gene (3q24) encoding telopeptide lysyl hydroxylase (Bruck syndrome 2) have been identified in other affected individuals.
Genetic counseling
Transmission is autosomal recessive.

                            Last update:
                            July 2008


A cardiac disorder characterized on electrocardiogram (ECG) by ST segment elevation with a coved aspect on the right precordial leads, and a clinical susceptibility to ventricular tachyarrhythmias and sudden death occurring in the absence of overt myocardial abnormalities.

Summary:
Epidemiology
Given that the ECG pattern diagnostic for Brugada Syndrome is fluctuant, unlike other inherited arrhythmogenic syndromes, the data regarding the prevalence of the disease are controversial. According to a recent metanalysis, the worldwide prevalence of Brugada syndrome is estimated at 1/2,000, but it varies according to region and ethnicity. Brugada syndrome is rare in Hispanic and Caucasian populations and non-rare in Asian populations. By region, the prevalence is estimated at 1/20,000 in North America and 1/10,000 in Europe. Prevalence is higher in Asia and Middle East where estimates range between 1/270-625. The disease is observed more frequently in men than in women (8:1) and it is extremely rare in children.
Clinical description
Symptoms usually manifest in the third-fourth decade of life. Syncope, typically occurring at rest, is a common presentation. In some cases, tachycardia does not terminate spontaneously and leads to sudden death. Most frequently, the disease occurs in a normal heart, but subtle structural abnormalities of the right ventricle have been described in a subset of patients. Triggers for the onset of arrhythmias may include fever, abundant meals, some drugs (including antiarrhythmics and antidepressants). On ECG, three different patterns may be observed. Type 1, which is the only diagnostic pattern, is defined as a coved-type ST-segment elevation (0.2 mV) followed by a negative T wave. In type 2, ST-segment elevation has a saddleback appearance with a high-takeoff ST-segment elevation (0.2 mV), a trough (0.1mV) displaying ST elevation, and then either a positive or biphasic T wave. Type 3 has either a saddleback appearance or a coved-type ST-segment elevation (maximum 0.1mV). It is important to underline that only Type 1 ECG is diagnostic for the syndrome.
Etiology
The gene SCN5A (3p22.2) is responsible for 30% of cases with a gene variant implicated. Other identified genes include CACNA1C (12p13.33), SCNN1A (12p13), SLMAP (3p14.3), SEMA3A (7q21.11), SCN2B (11q23.3). However, in nearly 70% of affected families the genetic cause is unknown.
Diagnostic methods
The diagnosis is based on clinical examination and detection of type 1 ECG pattern using a 12-lead Holter ECG. In some cases, the ECG manifestations are not obvious or non-diagnostic (type 2, 3 and S ECG patterns). In such instances, a provocative test with the administration of class IC antiarrhythmic drugs (ajmaline, flecainide or procainamide) may be used to confirm/exclude diagnosis. Genetic testing is available after a clinical diagnosis has been established.
Differential diagnosis
Disorders that could present the typical Brugada ECG pattern include isolated right bundle branch block, pectus excavatum, arrhythmogenic right ventricular cardiomyopathy, acute pericarditis, acute myocardial ischemia or infarction, and early repolarization.
Genetic counseling
Both sporadic and familial cases have been reported and pedigree analysis suggests an autosomal dominant pattern of inheritance.
Management and treatment
Implantable cardioverter defibrillator (ICD) is the only therapeutic option of proven efficacy for primary and secondary prophylaxis of cardiac arrest. Thus, correct risk stratification is a major goal for management. Quinidine may be regarded as an adjunctive therapy for patients at higher risk and may reduce the number of cases of ICD shock in patients at risk of recurrence. Recently, epicardial ablation of the right ventricular outflow tract has emerged as a therapeutic option in patients at higher risk.
Prognosis
The majority of patients remain asymptomatic, 20-30% experience syncope and 8-12% experience at least one cardiac arrest (potentially leading to sudden death). Risk factors for cardiac arrest and sudden death are a spontaneously diagnostic ECG pattern and a history of syncope.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Andrea MAZZANTI  - Pr Silvia PRIORI


A rare vascular liver disease characterized by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava.

Summary:
Epidemiology
Prevalence of Budd-Chiari syndrome (BCS) remains largely unknown but estimates range between 1/50,000 and 1/100,000.
Clinical description
The obstruction leads to hepatic congestion and ischemic necrosis. Severity depends on the speed of onset and extent of the obstruction. Obstructions are generally caused by thrombosis (primary BCS). With time, thrombi reorganize to form a fibrous tissue that leads either to localized stenosis of the thrombotic vein or to diffuse obliteration resulting in its transformation into fibrous cords. Localized stenoses may present as the appearance of a membrane-like structure. Secondary BCS results from tumor invasion into the lumen or compression of the vein by an expansive lesion. BCS presentation and manifestations are extremely diverse, so that the diagnosis must be considered in any patient with acute, acute-on-chronic or chronic liver disease. The principal manifestations of BCS are ascites (which is often massive and intractable) leading to undernutrition and renal insufficiency, gastrointestinal hemorrhage due to portal hypertension, and hepatic insufficiency resulting in encephalopathy and severe infections. However, asymptomatic forms have also been reported.
Etiology
Primary BCS is associated with a combination of factors that lead to a susceptibility for venous thrombosis: primary myeloproliferative neoplasms (present in 50% of cases and manifesting as a 'forme fruste' or atypical forms of the disease, but identified through detection of the JAK2 V617F mutation, CALR mutations or others), Factor V Leiden thrombophilia, protein C deficiency, antiphospholipid syndrome, Behcet disease, paroxysmal nocturnal hemoglobinuria, use of estrogen-progesterone oral contraceptives and systemic inflammatory diseases.
Diagnostic methods
Diagnosis can usually be established by non-invasive means through imaging of the hepatic veins and the inferior vena cava (Doppler ultrasound, tomodensitometry and MRI) but requires a radiologist with sufficient experience and with an awareness of the potential diagnosis. Liver biopsy should not be performed to diagnose BCS when vascular imaging demonstrates obstruction of the hepatic venous outflow tract. Hepatic venography or cavography, and liver puncture biopsy are necessary only when BCS of the small hepatic veins is not seen on imaging.
Differential diagnosis
Differential diagnoses include hepatic veno-occlusive disease / sinusoidal obstruction syndrome (VOD/SOS), cardiac failure, decompensated chronic liver disease, and tumoral invasion of the liver.
Management and treatment
Treatment approaches include correction of the factors leading to an increased risk of thrombosis, long-term anticoagulant therapy, recanalization of the obstructed veins by interventional radiology, TIPS (transjugular intrahepatic portosystemic shunt) and liver transplantation in case of failure of other treatment methods.
Prognosis
The natural course of the disease is very severe (less than 10% of patients survive for more than 3 years without treatment). At present, when the diagnosis is made quickly and treatment is initiated rapidly, the survival rate is 90% at 5 years. The long-term prognosis depends on the associated risk factors for thrombosis.

                            Last update:
                            November 2021

                            - Expert reviewer(s):
                            Dr Aurélie PLESSIER | RARE-LIVER*

                                * European Reference Network


A rare systemic disease characterized by inflammatory, non-necrotizing, non-atherosclerotic, occlusive vascular disease with thrombosis and recanalization affecting small and medium sized arteries and veins of upper and lower extremities.

Summary:
Epidemiology
The prevalence is estimated at 1/10,000 in Europe but the disease is found worldwide.
Clinical description
Patients present with clinical manifestations of an occlusive vascular disease characterized by distal arteriopathy of upper limbs: Raynaud's phenomenon at the beginning, rapidly followed by digital ischemia and/or gangrene. In lower limbs vascular disease is characterized at the beginning by plantar claudication then rapidly followed by ischemic distal lesions.
Etiology
The etiology of Buerger disease is unknown, but use or exposure to tobacco is central to the initiation and progression of the disease.
Diagnostic methods
The clinical criteria edited by Olin in 2000 include: age under 45 years; current or recent history of tobacco use; presence of distal-extremity ischemia, indicated by claudication, pain at rest, ischemic ulcers or gangrenes, and documented by non-invasive vascular testing; exclusion of autoimmune diseases, hypercoagulable states and diabetes mellitus; exclusion of a proximal source of emboli by echocardiography or arteriography; consistent arteriographic findings in the clinically involved and non-involved limbs. Vascular Doppler ultrasound is a useful tool which confirms distal arterial lesions (under elbow and knee). Computed tomography (CT-scan) is less useful as vascular lesions are distal. In case of superficial venous thrombosis, Doppler ultrasound will exclude venous insufficiency which is the major risk factor of superficial venous thrombosis. Dynamic oximetry of lower limbs reveals tissue hypoxia contrasting with apparent good clinical condition. Vascular biopsy is never performed because it's an invasive method but it will show specific histological findings: panvasculitis with hypercellular fresh thrombus including many macrophages and polynuclear/multinucleated cells.
Differential diagnosis
The differential diagnosis includes systemic vasculitis, thrombophilia, diabetes with macrovascular complications, dyslipidemia.
Management and treatment
If the patient smokes, stopping completely is an essential first step of treatment. The role of other treatments (including vasodilating or anti-clotting drugs, surgical revascularization or sympathectomy) in preventing amputation or treating pain remains unclear.
Prognosis
Buerger disease may be associated with functional consequences. Tobacco consumption is associated with a higher risk of limb amputation, either fingers in upper limbs or sub-gonal amputation, in which case, patients may require lower limb prosthesis.

                            Last update:
                            September 2023

                            - Expert reviewer(s):
                            Pr Marc LAMBERT


Bullous diffuse cutaneous mastocytosis (BDCM) is a form of diffuse cutaneous mastocytosis (DCM; see this term) characterized by generalized erythroderma and severe blistering associated with the accumulation of mast cells in the skin.

Summary:
Epidemiology
BDCM accounts for the majority of cases of DCM, with round 40 cases described in the literature to date.
Clinical description
Onset usually occurs during early infancy or during the neonatal period.
Etiology
Mutations in the KIT gene (4q11-q12) have been detected in patients with BDCM.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Pr A.P. [Arnold] ORANJE


A rare, acquired, typically benign, bacterial infectious disease caused by Staphylococcus aureus characterized by large, fragile vesicles and flaccid bullae on an erythematous base, which evolve into moistened erosions with a thin, varnish-like crust, usually localized in intertriginous areas of the trunk and extremities (armpits, groins, between the fingers or toes, beneath the breasts). Although uncommon, systemic symptoms, such as fever, diarrhea, and weakness, may be associated.


Bullous lichen planus is a variant of rare lichen planus (see this term) characterized by the development of vesico-bullous lesions.

Summary:
Epidemiology
Prevalence is unknown and only a few cases, both sporadic and familial, have been described in the literature.
Clinical description
The disease manifests during childhood or adolescence. Bullous lesions develop on top of preexisting lichen planus papules or on normal skin and generally affect the lower limbs or the lower mucosal lip, and in some rare cases the torso. In this condition, the epithelium separates from the dermis. In the case of oral bullous lichen planus, the vesicles and bullae burst soon after they appear which results in erosions.
Etiology
Etiology is unknown.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Dr Susan COOPER