Oculoectodermal syndrome ICD-10: Q82.4; ICD-11: LD27.0Y

Oculo-ectodermal syndrome (OES) is a rare syndrome of which only about 20 cases have been described. It is defined by ocular and skin symptoms, including epibulbar dermoids, focal aplastic skin defects (aplasia cutis) and non-scarring alopecia of the scalp (Moog U 2009; Hunter AG 2006).

Oculo-ectodermal syndrome (and ECL syndrome = Encephalocraniocutaneous Lipomatosis Associated with NRAS Mutation) is caused by mutations in various genes of the RAS-MAPK signaling pathway(HRAS, KRAS and FGFR1). This diversity of gene mutations leads to overlapping phenotypes (Ardinger HH et al. 2007; Moog U 2009). The circumscribed hamartomas of the skin indicate an underlying mosaicism (Bennett JT et al. 2016). In 2016, Bennett et al. discovered mutations in the FGFR1 gene (the FGFR1 gene encodes a fibroblast growth factor receptor) in ECL. Later, ECL was associated with mutations in the RAS-MAPK signaling pathway (Bennett JT et al. 2016). In oculo-ectodermal syndrome, mutations in the KRAS gene (affecting p.Leu19Phe and p.Gly13Asp) were detected in two cases (Peacock JD et al. 2015). These mutations were confirmed in four other cases (codon 146 of the KRAS gene - p.Ala146Val and p.Ala146Thr), confirming the role of the RAS-MAPK signaling pathway in this complex syndrome (Shoji MK et al. 2018).

Instead of a mutation in FGFR1 or KRAS, an NRAS variant was found in a mosaic pattern. NRAS variants are known to play a role in congenital melanocytic giant nevi, Schimmelpenning-Feuerstein-Mims syndrome and Noonan syndrome (Richters RJH et al. 2020). As NRAS is also a gene from the RAS-MAPK family, this phenotype is not surprising. In 2017, Altmuller et al. described phenotype and genotype spectra of NRAS variants and described a case with ectodermal dysplasia, intracerebral arachnoid cyst and subcutaneous edema. In addition to this new variant, this is the first case in which blistering skin lesions have been described in a patient with OES/ECL. However, blistering can also occur in aplasia cutis associated with syndromic or non-syndromic cases.

The diagnostic criteria for ECL were defined as follows:

• Eye: ocular choristoma
• Skin: psiloliparous nevus (a mesodermal nevus of the scalp characterized by absent or sparse hair and an excessive amount of adipose tissue); congenital craniofacial lipomas; multiple small craniofacial skin appendages, aplasia cutis or hypoplasia, possible combination of psiloliparous nevus with lipomas.
• CNS: intracranial lipomas, intracranial calcification and arachnoid cysts (Hunter et al. 2006).

OES and ECL overlap strongly in terms of phenotype and genotype. Ocular anomalies, such as dermoid cysts, and ipsilateral central nervous system malformations contribute to the triad that defines the syndromes.

1. Altmuller F et al. (2017) Genotype and phenotype spectrum of NRAS germline variants. Eur J Hum Genet 25: 823-831.
2. Ardinger HH et al. (2007) Expanding the phenotype of oculoectodermal syndrome: possible relationship to encephalocraniocutaneous lipomatosis. Am J Med Genet A 143A: 2959-2962.
3. Bennett JT et al. (2016) Mosaic activating mutations in FGFR1 cause encephalocraniocutaneous lipomatosis. Am J Hum Genet 98: 579-587.
4. Boppudi S et al. (2016) Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalo-craniocutaneous lipomatosis. Clin Genet 90: 334-342.
5. Hunter AG (2006) Oculocerebrocutaneous and encephalocraniocutaneous lipomatosis syndromes: blind men and an elephant or separate syndromes? Am J Med Genet A 140: 709-726.
6. Moog U (2009) Encephalocraniocutaneous lipomatosis. J Med Genet 46: 721-729.
7. Peacock JD et al. (2015) Oculoectodermal syndrome is a mosaic RASopathy associated with KRAS alterations. Am J Med Genet A 167: 1429-1435.
8. Richters RJH et al (2020) Oculoectodermal Syndrome - Encephalocraniocutaneous Lipomatosis Associated with NRAS Mutation. Acta Derm Venereol 100:adv00103.