Alternative titles; symbols
SNOMEDCT: 722056009; ORPHA: 2707; DO: 0111456;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Kaufman oculocerebrofacial syndrome | 244450 | Autosomal recessive | 3 | UBE3B | 608047 |
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.
Kaufman oculocerebrofacial syndrome (KOS) is a rare autosomal recessive disorder characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability (summary by Basel-Vanagaite et al., 2014).
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. Basel-Vanagaite et al. (2014) identified compound heterozygous mutations in the UBE3B gene in this patient; see MOLECULAR GENETICS.
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).
Basel-Vanagaite et al. (2014) reported 6 patients with KOS from 5 unrelated families and reviewed the 6 previously reported patients. They concluded that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. They noted phenotypic overlap with Toriello-Carey syndrome (217980), also known as agenesis of the corpus callosum with facial anomalies and Pierre-Robin sequence. The characteristic craniofacial features of KOS include arched, sparse, and laterally flared eyebrows, blepharophimosis with epicanthal folds with or without ptosis, flat zygomata, characteristic nasal shape with relatively narrow nasal bridge and broad nasal base, flat philtrum (long or short), thin lips, especially the upper lip, and small mouth. Ears are often apparently low-set, with over-folded helices or cupping, small earlobes, and in some instances underdeveloped ear crus. With advancing age the face becomes more elongated, the palpebral fissures become upslanting, and in some patients the lip vermilion becomes more everted. One adult had a long chin and very thick alae nasi with narrow nares. One patient with mild and atypical facial features was reported.
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.
The transmission pattern of KOS in the patients reported by Basel-Vanagaite et al. (2012) was consistent with autosomal recessive inheritance.
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.
Basel-Vanagaite et al. (2014) reported 6 patients from 5 unrelated families with KOS and homozygous or compound heterozygous mutation in the UBE3B gene. They identified homozygous missense mutations in cis outside the HECT domain (608047.0005) in a patient with mildly dysmorphic facial features, a homozygous missense mutation (G779R; 608047.0006) in sibs previously diagnosed with Toriello-Carey syndrome (217980) reported by Toriello et al. (2003), and compound heterozygosity (608047.0007; 608047.0008) in a patient previously reported as having a possibly novel disorder by Buntinx and Majewski (1990). Basel-Vanagaite et al. (2014) stated that their findings brought the number of reported KOS patients to 12 and expanded the clinical and mutational spectrum of the disorder.
Basel-Vanagaite, L., Dallapiccola, B., Ramirez-Solis, R., Segref, A., Thiele, H., Edwards, A., Arends, M. J., Miro, X., White, J. K., Desir, J., Abramowicz, M., Dentici, M. L., and 24 others. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am. J. Hum. Genet. 91: 998-1010, 2012. [PubMed: 23200864] [Full Text: https://doi.org/10.1016/j.ajhg.2012.10.011]
Basel-Vanagaite, L., Yilmaz, R., Tang, S., Reuter, M. S., Rahner, N., Grange, D. K., Mortenson, M., Koty, P., Feenstra, H., Farwell Gonzalez, K. D., Sticht, H., Boddaert, N., Desir, J., Anyane-Yeboa, K., Zweier, C., Reis, A., Kubisch, C., Jewett, T., Zeng, W., Borck, G. Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations. Hum. Genet. 133: 939-949, 2014. [PubMed: 24615390] [Full Text: https://doi.org/10.1007/s00439-014-1436-2]
Briscioli, V., Manoukian, S., Selicorni, A., Livini, E., Lalatta, F. Kaufman oculocerebrofacial syndrome in a girl of 15 years. Am. J. Med. Genet. 58: 21-23, 1995. [PubMed: 7573151] [Full Text: https://doi.org/10.1002/ajmg.1320580106]
Briscioli, V., Selicorni, A., Livini, E., Piguzzi, M. T., Lalatta, F. Kaufman oculocerebrofacial syndrome in a 15 year old girl. (Abstract) Am. J. Hum. Genet. 49 (suppl.): 146 only, 1991.
Buntinx, I., Majewski, F. Blepharophimosis, iris coloboma, microgenia, hearing loss, postaxial polydactyly, aplasia of corpus callosum, hydroureter, and developmental delay. Am. J. Med. Genet. 36: 273-274, 1990. [PubMed: 1694631] [Full Text: https://doi.org/10.1002/ajmg.1320360304]
Dentici, M. L., Mingarelli, R., Dallapiccola, B. The difficult nosology of blepharophimosis-mental retardation syndromes: report on two siblings. Am. J. Med. Genet. 155A: 459-465, 2011. [PubMed: 21567902] [Full Text: https://doi.org/10.1002/ajmg.a.33642]
Figuera, L. E., Garcia-Cruz, D., Ramirez-Duenas, M. L., Rivera-Robles, V., Cantu, J. M. Kaufman oculocerebrofacial syndrome: report of two new cases and further delineation. Clin. Genet. 44: 98-101, 1993. [PubMed: 8275567] [Full Text: https://doi.org/10.1111/j.1399-0004.1993.tb03855.x]
Flex, E., Ciolfi, A., Caputo, V., Fodale, V., Leoni, C., Melis, D., Bedeschi, M. F., Mazzanti, L., Pizzuti, A., Tartaglia, M., Zampino, G. Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome. J. Med. Genet. 50: 493-499, 2013. [PubMed: 23687348] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101405]
Garcia-Cruz, D., Arreola, R., Sanchez-Corona, J., Garcia-Cruz, O., Renteria, R., Villar, V., Gonzalez, M. E., Vargas-Moyeda, E., Cantu, J. M. Kaufman oculocerebrofacial syndrome: a corroborative report. Dysmorph. Clin. Genet. 1: 152-154, 1988.
Jurenka, S. B., Evans, J. Kaufman oculocerebrofacial syndrome: case report. Am. J. Med. Genet. 3: 15-19, 1979. [PubMed: 112864] [Full Text: https://doi.org/10.1002/ajmg.1320030106]
Kaufman, R., Rimoin, D. L., Prensky, A. L., Sly, W. S. An oculocerebrofacial syndrome. Birth Defects Orig. Art. Ser. 7(1): 135-138, 1971. [PubMed: 5006210]
Toriello, H. V., Carey, J. C., Addor, M.-C., Allen, W., Burke, L., Chun, N., Dobyns, W., Elias, E., Gallagher, R., Hordijk, R., Hoyme, G., Irons, M., and 13 others. Toriello-Carey syndrome: delineation and review. Am. J. Med. Genet. 123A: 84-90, 2003. [PubMed: 14556252] [Full Text: https://doi.org/10.1002/ajmg.a.20493]