Alternative titles; symbols
SNOMEDCT: 723554006; ORPHA: 3339; DO: 0111705;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p12.1 | Oculoectodermal syndrome, somatic | 600268 | 3 | KRAS | 190070 |
A number sign (#) is used with this entry because of evidence that oculoectodermal syndrome (OES) is caused by somatic mosaicism for mutations in the KRAS gene (190070) on chromosome 12p12.
Oculoectodermal syndrome (OES) is characterized by the association of epibulbar dermoids and aplasia cutis congenita. Affected individuals exhibit congenital scalp lesions which are atrophic, nonscarring, hairless regions that are often multiple and asymmetric in distribution, and may have associated hamartomas. Ectodermal changes include linear hyperpigmentation that may follow the lines of Blaschko and, rarely, epidermal nevus-like lesions. Epibulbar dermoids may be uni- or bilateral. Additional ocular anomalies such as skin tags of the upper eyelid and rarely optic nerve or retinal changes or microphthalmia can be present. Phenotypic expression is highly variable, and various other abnormalities have occasionally been reported, including growth failure, lymphedema, and cardiovascular defects, as well as neurodevelopmental symptoms such as developmental delay, epilepsy, learning difficulties, and behavioral abnormalities. Benign tumor-like lesions such as nonossifying fibromas of the long bones and giant cell granulomas of the jaws have repeatedly been observed and appear to be age-dependent, becoming a common manifestation in individuals aged 5 years or older (summary by Boppudi et al., 2016).
Toriello et al. (1993) reported 2 unrelated boys with aplasia cutis congenita, epibulbar dermoids, and cutaneous hyperpigmentation. Additional features of 1 of these patients (patient 2) included giant cell granulomas and nonossifying fibromas (Toriello et al., 1999). Peacock et al. (2015) reported that patient 2's nonossifying fibromas spontaneously resolved following skeletal maturity. At age 25, he was healthy and had normal cognitive function.
Gardner and Viljoen (1994) described 2 unrelated South African girls with aplasia cutis congenita, epibulbar dermoids, and strabismus. Evers et al. (1994) described a similar case in a female child who also had macrocephaly.
Lees et al. (2000) reported 2 unrelated patients with the combination of aplasia cutis congenita and epibulbar dermoids. In addition, 1 patient had bladder exstrophy with epispadias.
Martin et al. (2007) reported the eleventh published case of oculoectodermal syndrome in a 6-year-old Chinese girl who had aplasia cutis, left epibulbar dermoid and left eyelid coloboma, macrocephaly, minor dysmorphism, and mild facial asymmetry. CT scan of the head revealed an arachnoid cyst, which the authors stated was the third to be described in the 6 patients with oculoectodermal syndrome who had undergone cranial imaging. Martin et al. (2007) suggested that arachnoid cyst may be a phenotypic feature of the syndrome.
Federici et al. (2004) reported a patient with oculoectodermal syndrome who developed giant cell granulomas of the jaw. They reviewed the findings in 10 reported patients and suggested that the development of giant cell granulomas in childhood is part of what they referred to as a new tumor predisposition syndrome.
Ardinger et al. (2007) reported 2 new cases and reviewed 13 previously reported cases of oculoectodermal syndrome. Their patient 1 had a scalp lesion histologically interpreted as a smooth muscle hamartoma (with some features suggestive of nevus psiloliparus). When they evaluated the 15 cases by the diagnostic criteria of Hunter (2006), 8 had a definite and 7 had a probable diagnosis of encephalocraniocutaneous lipomatosis (ECCL; see 176920). Ardinger et al. (2007) proposed that OES may be a mild variant of ECCL, differing primarily by lack of intracranial anomalies on brain imaging.
Horev et al. (2011) described 2 patients with alopecia of the scalp and epibulbar dermoids, including 1 of the patients reported by Lees et al. (2000), both of whom also had coarctation of the descending aorta, cerebral arterioocclusive vasculopathy, and moyamoya-type collaterals presenting as seizures, recurrent transient ischemic attacks, and cerebrovascular accidents during early childhood. Horev et al. (2011) suggested that vascular findings are an integral part of the unifying diagnosis of OES and that disturbance in vasculogenesis contributes to the pathogenesis.
Epibulbar dermoids occur with Goldenhar syndrome (164210) and with Proteus syndrome (176920). Aplasia cutis congenita occurs as an isolated defect (107600) or in association with gastrointestinal atresia in Carmi syndrome (226730), with limb defects in Adams-Oliver syndrome (100300), and with other associated abnormalities (see 302803, 100300, and 207731).
Chacon-Camacho et al. (2019) reported 2 Mexican children with OES and somatic mosaicism for mutations in the KRAS gene (see MOLECULAR GENETICS). Additional clinical findings in these patients included facial asymmetry, left body hemihypertrophy, atrial septal defect, patent ductus arteriosus, and supernumerary nipple in the 4-year-old girl (patient 1), and microcornea, nystagmus, short neck, and hypertrophic cardiomyopathy in the 12-year-old boy (patient 2).
Toriello et al. (1993) concluded that a new dominant mutation is possible in this disorder, but autosomal recessive inheritance could not be excluded.
In an 8-year-old girl (patient 1) and an unrelated 25-year-old man (patient 2) with oculoectodermal syndrome, Peacock et al. (2015) identified somatic missense mutations in the KRAS gene (190070.0003 and 190070.0024, respectively). The man was one of the original boys with OES (patient 2) described by Toriello et al. (1993). Allele frequencies fell below 40% in all tissues examined in both patients, suggesting that OES is a mosaic RAS-related disorder ('RASopathy').
In 3 unrelated children with OES, including a 6-year-old boy who was originally described by Aslan et al. (2014), Boppudi et al. (2016) identified somatic missense mutations in the KRAS gene, A146T (190070.0027) and A146V (190070.0028), that were mosaic in lesional tissue and absent from leukocyte DNA. Proportions of mutant alleles ranged from less than 10% to 40% in lesional tissue samples.
In a 4-year-old Mexican girl (patient 1) and an unrelated 12-year-old Mexican boy (patient 2) with OES, Chacon-Camacho et al. (2019) identified somatic mosaicism for the previously reported KRAS variants, A146T and A146V, respectively. The mutant allele frequency was approximately 30% in lesional tissues, and the variants were not detected in DNA isolated from blood leukocytes or buccal cells.
Ardinger, H. H., Horii, K. A., Begleiter, M. L. Expanding the phenotype of oculoectodermal syndrome: possible relationship to encephalocraniocutaneous lipomatosis. Am. J. Med. Genet. 143A: 2959-2962, 2007. [PubMed: 17963257] [Full Text: https://doi.org/10.1002/ajmg.a.31969]
Aslan, D., Akata, R. F., Schroder, J., Happle, R., Moog, U., Bartsch, O. Oculoectodermal syndrome: report of a new case with a broad clinical spectrum. Am. J. Med. Genet. 164A: 2947-2951, 2014. [PubMed: 25251940] [Full Text: https://doi.org/10.1002/ajmg.a.36727]
Boppudi, S., Bogershausen, N., Hove, H. B., Percin, E. F., Aslan, D., Dvorsky, R., Kayhan, G., Li, Y., Cursiefen, C., Tantcheva-Poor, I., Toft, P. B., Bartsch, O., Lissewski, C., Wieland, I., Jakubiczka, S., Wollnik, B., Ahmadian, M. R., Heindl, L. M., Zenker, M. Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis. Clin. Genet. 90: 334-342, 2016. [PubMed: 26970110] [Full Text: https://doi.org/10.1111/cge.12775]
Chacon-Camacho, O. F., Lopez-Moreno, D., Morales-Sanchez, M. A., Hofmann, E., Pacheco-Quito, M., Wieland, I., Cortes-Gonzalez, V., Villanueva-Mendoza, C., Zenker, M., Zenteno, J. C. Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies. Molec. Genet. Genomic Med. 7: e625, 2019. Note: Electronic Article. [PubMed: 30891959] [Full Text: https://doi.org/10.1002/mgg3.625]
Evers, M. E. J. W., Dijkman-Neerincx, R. H. M., Hamel, B. C. J. Oculo-ectodermal syndrome: a new case. Am. J. Med. Genet. 53: 378-379, 1994. [PubMed: 7864049] [Full Text: https://doi.org/10.1002/ajmg.1320530415]
Federici, S., Griffiths, D., Siberchicot, F., Chateil, J.-F., Gilbert, B., Lacombe, D. Oculo-ectodermal syndrome: a new tumour predisposition syndrome. Clin. Dysmorph. 13: 81-83, 2004. [PubMed: 15057122]
Gardner, J., Viljoen, D. Aplasia cutis congenita with epibulbar dermoids: further evidence for syndromic identity of the ocular ectodermal syndrome. Am. J. Med. Genet. 53: 317-320, 1994. [PubMed: 7864039] [Full Text: https://doi.org/10.1002/ajmg.1320530403]
Horev, L., Lees, M. M., Anteby, I., Gomori, J. M., Gunny, R., Ben-Neriah, Z. Oculoectodermal syndrome with coarctation of the aorta and moyamoya disease: expanding the phenotype to include vascular anomalies. Am. J. Med. Genet. 155A: 577-581, 2011. [PubMed: 21337683] [Full Text: https://doi.org/10.1002/ajmg.a.33104]
Hunter, A. G. W. Oculocerebrocutaneous and encephalocraniocutaneous lipomatosis syndromes: blind men and an elephant or separate syndromes? Am. J. Med. Genet. 140A: 709-726, 2006. [PubMed: 16523517] [Full Text: https://doi.org/10.1002/ajmg.a.31149]
Lees, M., Taylor, D., Atherton, D., Reardon, W. Oculo-ectodermal syndrome: report of two further cases. Am. J. Med. Genet. 91: 391-395, 2000. [PubMed: 10767005] [Full Text: https://doi.org/10.1002/(sici)1096-8628(20000424)91:5<391::aid-ajmg14>3.0.co;2-f]
Martin, M. M., Lockspieler, T., Slavotinek, A. M. Oculo-ectodermal syndrome: is arachnoid cyst a common finding? Clin. Dysmorph. 16: 35-38, 2007. [PubMed: 17159512] [Full Text: https://doi.org/10.1097/MCD.0b013e328010b7f9]
Peacock, J. D., Dykema, K. J., Toriello, H. V., Mooney, M. R., Scholten, D. J., II, Winn, M. E., Borgman, A., Duesbery, N. S., Hiemenga, J. A., Liu, C., Campbell, S., Nickoloff, B. P., Williams, B. O., Steensma, M. Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. Am. J. Med. Genet. 167A: 1429-1435, 2015. [PubMed: 25808193] [Full Text: https://doi.org/10.1002/ajmg.a.37048]
Toriello, H. V., Bultman, R., Panek, R. W., Hammers, Y., Kohut, G., Droste, P., Freyer, D. R. Non-ossifying fibromas and giant cell reparative granulomas in child with ocular-ectodermal syndrome. Clin. Dysmorph. 8: 265-268, 1999. [PubMed: 10532175]
Toriello, H. V., Lacassie, Y., Droste, P., Higgins, J. V. Provisionally unique syndrome of ocular and ectodermal defects in two unrelated boys. Am. J. Med. Genet. 45: 764-766, 1993. [PubMed: 8456858] [Full Text: https://doi.org/10.1002/ajmg.1320450620]