Case report
A 5-year-old boy was referred to our clinic by the ophthalmology department because of the presence of ocular abnormalities, Blashkoïd hyperpigmentation and focal alopecia. He was the only child of healthy, non-consanguineous parents of Romanian descent. He presented with segmental areas of hyperpigmentation following a Blashkoïd distribution on the right upper half of the body and extending to right arm. In the neck, lesions were slightly palpable. Similar abnormalities in the posterior part of the neck displayed a more yellowish-orange colour. On the scalp, he had three areas with yellow skin colour, diminished hair density and fair, almost white hairs. Despite the lack of palpable lesions, skin abnormalities were suggestive for linear epidermal and sebaceous nevus, respectively.
Ocular abnormalities included congenital coloboma of the right eyelid and epibulbar dermoid involving both eyes, for which surgical correction was performed at young age. Additional inspection revealed subconjunctival multinodular tissue extending to the corneal limbus and covering parts of the pupils. Strabismus with amblyopia of the left eye was present because of high astigmatism. Vision was decreased bilaterally, but improved due to correction of the astigmatism with glasses and occlusion.
Additional investigations consisted of normal cardiac echocardiography, electrocardiogram, audiometry and skeletal survey of hips and lumbar spine. A brain MRI identified no structural intracranial abnormalities, but increased fat accumulation in the right upper eyelid. His neurocognitive development was normal and he had no other health problems.
Molecular genetic testing comprised conventional and molecular karyotyping on DNA isolated from peripheral leukocytes, which showed a 620 kb duplication on the Y chromosome, which was paternally inherited and identified as a benign variant. Subsequent next-generation sequencing analysis on DNA directly extracted from a lesional skin biopsy was able to identify a mosaic missense mutation (c.436G>A, (p.Ala146Thr)) in the KRAS gene, illustrated by variant allele frequencies of 60% in the epidermis and 22% in the dermis. This confirms the diagnosis of oculoectodermal syndrome.
Discussion
Oculoectodermal syndrome (OES) is a rare disorder characterized by the consistent combination of congenital scalp lesions and epibulbar dermoids. Aplasia congenita cutis (ACC) is the most common skin finding, representing hairless, atrophic and non-scarring regions with asymmetrical distribution (1). In some cases, hamartomas may be associated to the areas of ACC. Other ectodermal findings include linear hyperpigmentation often following the lines of Blaschko, and more rarely, epidermal nevus-like lesions. Ocular abnormalities consist of uni- or bilateral epibulbar dermoids, skin tags, or rarely optic nerve or retinal changes. The phenotype of OES is highly variable and additional features may include growth retardation, cardiovascular features (aortic coarcatation, ASD/VSD, hypertrophic cardiomyopathy) and neurodevelopmental problems (developmental delay, learning difficulties and behavioural problems) (2,3,4). Patients are predisposed to develop age-dependent benign tumor-like lesions such as non-ossifying fibromas of the long bones and giant cell granulomas of the jaws (5).
OES shows considerable phenotypic overlap with encephalocraniocutaneous lipomatosis (ECCL), sharing focal alopecia, epibulbar dermoids, linear hyperpigmentation, and the aforementioned predisposition to develop benign skeletal tumors (4,5,6). The nevus psiloliparus, a smooth, hairless fatty tissue nevus on the scalp, was considered as a pathognomonic hallmark of ECCL, but also has been reported in OES (7). Central nervous system involvement is the distinguishing feature of ECCL and comprises structural brain abnormalities, seizures and developmental retardation (8).
As such, both diseases belong to a similar phenotypic spectrum, with OES representing the milder form. Whole-exome sequencing identified somatic mosaicism for KRAS mutations as a common genetic etiology for OES and ECCL and confirmed that both disorders belong to the group of RASopathies (4,5). The group of RASopathies constitutes a group of developmental disorders caused by pathogenic variants in genes encoding the Ras/mitogen-activated protein kinase (MAPK) pathway (HRAS, NRAS, KRAS), including Noonan, cardiofaciocutaneous (CFC) and Costello syndrome. Mosaic RASopathies comprise an expanding group of (neuro)cutaneous disorders with high variability in phenotypic expression, illustrated by for example nevus sebaceous, Schimmelpenning syndrome, OES and ECCL. Mutations leading to over-activation of RAS-MAPK signalling are similar to the somatic driver mutations observed in these proto-oncogenes during tumorigenesis. As these oncogenic mutations are not tolerated in the germline and result in embryonal lethality, most RASopathy disorders are caused by hypomorphic mutations associated with less over-activation of the pathway. However, oncogenic KRAS mutations, as established in OES/ECC, should warrant for associations with increased tumor risks and justify regular clinical follow-up (4).
References
- Toriello HV, Lacassie Y, Droste P, Higgins JV. Provisionally unique syndrome of ocular and ectodermal defects in two unrelated boys. AM J Med Genet. 1993;45:764-766.
- Fajish Habib, Mahmoud F. Elsaid, Khalid Yacout Salem, Khalid Omer Ibrahim, Khalid Mohamed. Oculo-ectodermal syndrome: A case report and further delineation of the syndrome. Qatar Medical Journal, Volume 2014, Issue 2, January 2015.
- Deniz Aslan 1, Rustu Fikret Akata, Julia Schröder, Rudolf Happle, Ute Moog, Oliver Bartsc. Oculoectodermal syndrome: report of a new case with a broad clinical spectrum. Am J Med Genet A. 2014 Nov;164A(11):2947-51.
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- Peacock, J. D., Dykema, K. J., Toriello, H. V., Mooney, M. R., Scholten, D. J. 2nd, Winn, M. E., Steensma, M. (2015). Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. American Journal of Medical Genetics. Part A, 167A, 1429–1435.
- Chacon-Camacho O, Lopez-Moreno D , Morales-Sanchez M, Hofmann E, Pacheco-Quito M, Wieland I, Cortes-Gonzalez V, Villanueva-Mendoza C, Zenker M, Zenteno JC. Expansion of the phenotypic spectrum and description of molecular findings in a cohort of patients with oculocutaneous mosaic RASopathies. Mol Genet Genomic Med. 2019 May;7(5):e625.
- Happle R, Küster W. Nevus psiloliparus: a distinct fatty tissue nevus. Dermatology. 1998;197(1):6-10. doi: 10.1159/000017968. PMID: 9693178.
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Aude Beyens (AZ Sint-Jan Brugge), Laure Dequeker Laure (UZ Gent), Hilde Brems (UZ Leuven), Sandra Janssens (UZ Gent), Patricia Delbeke (AZ Sint-Jan Brugge), Anne D’Hooghe (AZ Sint-Jan Brugge), Marleen Goeteyn (AZ Sint-Jan Brugge)