Birk-Barel Syndrome

A number sign (#) is used with this entry because of evidence that Birk-Barel syndrome is caused by heterozygous mutation in the KCNK9 gene (605874) on chromosome 8q24.

Clinical Features

Barel et al. (2008) reported an Israeli-Arab kindred with an apparently maternally transmitted (imprinted with paternal silencing) syndrome of mental retardation, hypotonia, and characteristic dysmorphism. All affected individuals had moderate to severe mental retardation and were hyperactive. Severe feeding difficulties at infancy, requiring tube feeding in most, were followed in all patients by dysphagia of solid foods until near puberty. Generalized hypotonia at an early age was followed by weakness of proximal muscles and of the supra- and infrascapular and trapezius muscles. Coordination, tendon reflexes, deep and superficial sensation, and vibration were all normal. Babinski sign was negative. Hearing, vision, and ophthalmologic examination were normal. All affected individuals had similar dysmorphic features with most elements being more prominent at younger ages. The face was elongated with narrow bitemporal diameter, mild atrophy of temporalis and masseter muscles, and reduced facial movements. The eyebrows were flared, bushy, and arched upward, and downturned eyelids and congested conjunctivae were present in most patients. Ears were mildly protruding with a very prominent fold of the crux of the helix and a prominent antihelical fold. The nasal bridge was high and narrow with a broad nasal tip. The columella was normal, but the philtrum was extremely short, broad, and thick in all patients. The maxillary and premaxillary regions were prominent with hypotonia of the mandible and micrognathia, leading, in combination with the short philtrum, to an open-mouthed appearance. The lips were thick, with downturned upper lip and lower lip that was shorter than the upper lip. Most patients had a narrow, high-arched palate with full or submucous cleft and dysphonic speech. Large and protruding incisors were seen in younger patients. All patients had narrow, elongated necks, trunks, and feet. In some infants, mild joint contractures of the hips, elbows, phalanx, and feet were present and became prominent with age. Most patients had a pilonidal dimple or sinus. X-ray evaluation was normal. Muscle biopsies in 2 patients were compatible with spinal muscular atrophy, with normal molecular SMA tests. Mitochondria appeared normal on electron microscopy examination, and there was normal activity of the mitochondrial respiratory chain enzymes in muscle.

Graham et al. (2016) described 4 unrelated patients, aged 18 months to 3 years, with Birk-Barel syndrome. All had congenital hypotonia, developmental delay, feeding difficulties, restricted facial movements, and variable dysmorphic features, including dolichocephaly with bitemporal narrowing, short philtrum, tented upper lip, palatal abnormalities, and small mandible. Three of the patients tested had normal brain imaging. Two of the children were being treated with the nonsteroidal antiinflammatory drug mefenamic acid (MFA), one child for 6 months and the other for 1 year, with some improvement in development and responsiveness.

Mapping

Barel et al. (2008) performed linkage analysis of 7 affected individuals, 1 healthy individual, and 4 obligatory-transmitting mothers with 400 polymorphic markers. Assuming the disease was caused by mutation in a maternally imprinted gene, Barel et al. (2008) looked for a genomic locus with a haplotype shared by the obligatory transmitting healthy mothers and their affected children, but not their healthy children. They identified a single locus spanning 37.9 cm on chromosome 8q24, between marker D8S514 and the telomeric end of 8q. Further linkage analysis narrowed the interval.

Molecular Genetics

Within the interval on 8q24 linked to a mental retardation dysmorphism syndrome, Barel et al. (2008) identified only one imprinted gene: KCNK9 (605874), which undergoes paternal silencing in humans and mice and is exclusively expressed from the maternal allele in the brain. Barel et al. (2008) identified a missense mutation in exon 2 of the maternal copy of KCNK9, a gly236-to-arg substitution (G236R; 605874.0001). Identification of this mutation in all affected family members and their obligatory carrier mothers implied dominant inheritance with paternal imprinting. The mutation was not found in any of 548 chromosomes from ethnically matched controls.

By exome sequencing in 4 unrelated children with developmental delay and central hypotonia, Graham et al. (2016) identified de novo heterozygosity for the KCNK9 G236R mutation previously identified by Barel et al. (2008).