RESUMEN
Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.
Asunto(s)
Ano Imperforado/genética , Displasia Ectodérmica/genética , Trastornos del Crecimiento/genética , Pérdida Auditiva Sensorineural/genética , Hipotiroidismo/genética , Discapacidad Intelectual/genética , Mutación/genética , Nariz/anomalías , Enfermedades Pancreáticas/genética , Ubiquitina-Proteína Ligasas/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Ano Imperforado/patología , Bases de Datos Genéticas , Enanismo/genética , Enanismo/patología , Displasia Ectodérmica/patología , Trastornos del Crecimiento/patología , Pérdida Auditiva Sensorineural/patología , Humanos , Hipotiroidismo/patología , Discapacidad Intelectual/patología , Nariz/patología , Enfermedades Pancreáticas/patología , FenotipoRESUMEN
Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency, hypoplastic or aplastic nasal alae, cutis aplasia on the scalp, and other features including developmental delay, failure to thrive, hearing loss, mental retardation, hypothyroidism, dental abnormalities, and anomalies in cardiac and genitourinary systems. More than 60 cases of this syndrome have been reported to date. We describe the case of a male infant with typical symptoms of JBS. In addition, a new clinical feature which has not previously been documented, that is anemia requiring frequent blood transfusions and mild to moderate thrombocytopenia was observed. A molecular study was performed which revealed a novel homozygous UBR1 mutation. Possible explanations for this new association are discussed.