Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.
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Kaufman, R. L., Rimoin, D. L., Prensky, A. L. & Sly, W. S. An oculocerebrofacial syndrome. Birth Defects Orig. Artic. Ser. 7, 135–138 (1971).
Basel-Vanagaite, L., Dallapiccola, B., Ramirez-Solis, R., Segref, A., Thiele, H., Edwards, A. et al. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am. J. Hum. Genet. 91, 998–1010 (2012).
Basel-Vanagaite, L., Yilmaz, R., Tang, S., Reuter, M. S., Rahner, N., Grange, D. K. et al. Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations. Hum. Genet. 133, 939–949 (2014).
Flex, E., Ciolfi, A., Caputo, V., Fodale, V., Leoni, C., Melis, D. et al. Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome. J. Med. Genet. 50, 493–499 (2013).
Pedurupillay, C. R., Baroy, T., Holmgren, A., Blomhoff, A., Vigeland, M. D., Sheng, Y. et al. Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B. Am. J. Med. Genet. A 167A, 657–663 (2015).
Toriello, H. V., Carey, J. C., Addor, M.-C., Allen, W., Burke, L., Chun, N. et al. Toriello-Carey syndrome: delineation and review. Am. J. Med. Genet. 123A, 84–90 (2003).
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).
Campeau, P. M., Lu, J. T., Sule, G., Jiang, M. M., Bae, Y., Madan, S. et al. Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis. Hum. Mol. Genet. 21, 4904–4909 (2012).
Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic acids Res. 38, e164–e164 (2010).
Popovic, D., Vucic, D. & Dikic, I. Ubiquitination in disease pathogenesis and treatment. Nat. Med. 20, 1242–1253 (2014).
Scheffner, M. & Kumar, S. Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects. Biochim. Biophys. Acta 1843, 61–74 2014.
Gong, T.-W. L., Huang, L., Warner, S. J. & Lomax, M. I. Characterization of the human UBE3B gene: structure, expression, evolution, and alternative splicing. Genomics 82, 143–152 (2003).
Venhoranta, H., Pausch, H., Flisikowski, K., Wurmser, C., Taponen, J., Rautala, H. et al. In frame exon skipping in UBE3B is associated with developmental disorders and increased mortality in cattle. BMC Genomics 15, 1–9 (2014).
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).
Dentici, M. L., Mingarelli, R. & Dallapiccola, B. The difficult nosology of blepharophimosis-mental retardation syndromes: report on two siblings. Am. J. Med. Genet. A 155A, 459–465 (2011).
We thank the family for participating in this project, and The Réseau de Médecine Génétique Appliquée du Québec for help with bioinformatics analyses. NFA is funded by the CHU Sainte-Justine Foundation, the Fonds de recherche du Québec-Santé postdoctoral scholarship. PMC is funded by the Canadian Institutes of Health Research Grants CIHR RN315908 and RN324373, and the Fonds de recherche du Québec Santé grant FRQS 30647. This work was supported by the BCM Intellectual and Developmental Disabilities Research Center (HD024064) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, the BCM Advanced Technology Cores with funding from the NIH (AI036211, CA125123, and RR024574), the Rolanette and Berdon Lawrence Bone Disease Program of Texas, and the BCM Center for Skeletal Medicine and Biology and NIH grants U54 HG006542 (to RAG) and U54 HG003273-09 (to RAG).
The authors declare no conflict of interest.
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Kariminejad, A., Ajeawung, N., Bozorgmehr, B. et al. Kaufman oculo-cerebro-facial syndrome in a child with small and absent terminal phalanges and absent nails. J Hum Genet 62, 465–471 (2017). https://doi.org/10.1038/jhg.2016.151
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