Kaufman Oculocerebrofacial Syndrome

A number sign (#) is used with this entry because of evidence that Kaufman oculocerebrofacial syndrome (KOS) is caused by homozygous or compound heterozygous mutation in the UBE3B gene (608047) on chromosome 12q24.

Clinical Features

Kaufman et al. (1971) described a distinctive syndrome in 4 of 7 sibs. Significant positive and negative features included intrauterine and postnatal growth retardation, microcephaly with mental retardation but no gross neurologic abnormalities or seizures, hypertelorism with epicanthi, ptosis of the eyelids, upslanted palpebral fissures, microcornea with pale optic discs, sparse and laterally broad eyebrows, flat philtrum, congenital hypotonia, micrognathia with neonatal respiratory distress, high and narrow palate, lordosis, constipation, and flat feet.

Jurenka and Evans (1979) reported a sporadic case, and Garcia-Cruz et al. (1988) described a case.

Buntinx and Majewski (1990) reported a child, born to nonconsanguineous parents, with what the authors considered to be a novel phenotype. The boy's neonatal period was complicated by poor suck and hypotonia. At age 6 months, he had severe developmental delay, bilateral conductive hearing loss, and an unusual facial appearance including prominent forehead, large anterior fontanel, blepharophimosis-epicanthus, upslanted palpebral fissures, iris coloboma, short nose, anteverted nostrils, low-set, posteriorly angulated, round ears with narrow external meati, microgenia, highly arched palate, and thick frenulum of the upper lip. He also had postaxial polydactyly of both hands. There were no abnormalities of hair, nails, skin, or genitals. Brain imaging showed aplasia of the corpus callosum.

Figuera et al. (1993) reported Kaufman oculocerebrofacial syndrome in 2 unrelated Mexican girls, aged 14 months and 6 years. Both showed psychomotor retardation, microcephaly, blepharophimosis, and delayed growth as the main features. The infant also showed preauricular tags and large clitoris.

Dentici et al. (2011) described 2 Italian sibs, a 6-year-old girl and an 18-month-old boy, who presented with overlapping clinical findings. Major characteristics included facial dysmorphism with upward slanting palpebral fissures, blepharophimosis, telecanthus, hypertelorism, posteriorly rotated and abnormal ears, and micrognathia. Ectodermal abnormalities consisted of fine hair, sparse eyebrows, and thin skin. Both sibs had feeding difficulties with gastroesophageal reflux and growth retardation with microcephaly. Psychomotor skills were severely delayed with no verbal capacity. The brother displayed low growth hormone levels, whereas the sister had low cholesterol and mildly elevated TSH levels. Additional features included renal anomalies, axial hypotonia, and abnormal neurologic findings.

Basel-Vanagaite et al. (2012) described 4 affected individuals from 3 unrelated families, including the family reported by Dentici et al. (2011), with blepharophimosis, ptosis, mild upslanting of the palpebral fissures, epicanthus, ectodermal anomalies, developmental delay, and severe intellectual disability with absent speech. Proportionate growth retardation with a small head circumference/microcephaly, congenital malformations, muscular hypotonia, and anomalies on brain imaging with hypoplasia of the corpus callosum were variably present. Three of the 4 affected individuals had low cholesterol levels. Basel-Vanagaite et al. (2012) referred to the disorder as blepharophimosis-ptosis-intellectual-disability syndrome (BPIDS).

Possible Heterogeneity

Briscioli et al. (1995) described a girl (previously reported in abstract by Briscioli et al., 1991) with severe mental retardation, microcephaly, long narrow face, ocular anomalies, and long, thin hands and feet. The diagnosis of Kaufman oculocerebrofacial syndrome was not made until she was 15 years old. The authors commented on the difficulties in making the diagnosis in childhood. Flex et al. (2013) did not find a causative mutation in the UBE3B gene in the patient reported by Briscioli et al. (1995). They further noted that the phenotype in this patient was distinctive for the lack of blepharophimosis, reduced corneal diameter, ear anomalies, micrognathia, and significant neonatal feeding problems.

Molecular Genetics

Basel-Vanagaite et al. (2012) performed exome sequencing of 2 unrelated individuals with Kaufman oculocerebrofacial syndrome and identified the UBE3B gene as the only gene with rare or unique biallelic damaging variants in both individuals. Individual 1 had a homozygous splice site mutation (c.1741+2T-C; 608047.0001), which was present in heterozygous state in her unaffected first-cousin parents. Individual 2 and her affected brother from the family reported by Dentici et al. (2011) had a maternally inherited deletion (c.2223_2224delAG; 608047.0002) and a paternally inherited splice site mutation (c.545-2AG; 608047.0003). All 3 of these mutations introduce premature termination codons and are thus expected to result in nonsense-mediated mRNA decay and/or protein truncation. By sequencing the coding exons of the UBE3B gene in a fourth affected individual, Basel-Vanagaite et al. (2012) detected another homozygous mutation (E727P; 608047.0004), which was present in heterozygous state in her unaffected first-cousin parents. None of the mutations were present in 100 ethnically matched control individuals or in the NHLBI Exome Sequencing Project database.