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