Encephalocraniocutaneous lipomatosis ICD-10: Q82.4; ICD-11: LD27.0Y

Encephalo-cranio-cutaneous lipomatosis is a rare genetic syndrome of which only about 50 cases have been described. It is defined by eye and skin symptoms and CNS disorders (intracranial lipomas), including epibulbar dermoids, focal aplastic skin defects(aplasia cutis) and non-scarring alopecia of the scalp (Moog U 2009; Hunter AG 2006).

Encephalo-cranio-cutaneous lipomatosis (and oculo-ectodermal syndrome) is caused by mutations in different 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 OES, 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). Since NRAS is also a RAS-MAPK gene, it is not surprising that mutations in NRAS can also lead to this phenotype. In 2017, Altmuller et al. described phenotype and genotype spectra of NRAS variants and described a case with ectodermal dysplasia and 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.

Prenatal, neonatal period

The diagnostic criteria for encephalo-craniocutaneous lipomatosis (ECL) were defined as follows:

• Eye: ocular choristoma; coloboma,
• Skin: psiloliparous nevus (a mesodermal nevus of the scalp characterized by absent or sparse hair and atopic localized adipose tissue-DD aplasia cutis); congenital craniofacial lipomas; multiple small craniofacial skin appendages, skin aplasia or hypoplasia, possible combination of a psiloliparous nevus with lipomas.
• CNS: intracranial lipomas, intracranial calcification and arachnoid cysts (Hunter et al. 2006);
• Furthermore, abnormal intracranial vessels, hemispheric atrophy, porencephalic cyst and hydrocephalus have been associated with this syndrome.

Both encephalo-cranio-cutaneous lipomatosis and oculo-ectodermal syndrome may have other skin abnormalities, including nevus sebaceus. They also include a predisposition to jaw tumors, non-ossifying fibromas and, in the case of ECCL, low-grade gliomas. As it is not always possible to clearly assign previously used clinical diagnoses, the term (KRAS-associated) mosaic RASopathy is often more appropriate.

Oculo-ectodermal syndrome (OES, mutations in KRAS) with the main features epibulbar dermoids and congenital defects of the scalp.

RASopathies" refers to a group of diseases surrounding Noonan syndrome, which are based on a dysregulation of the RAS/RAF signaling pathway through mostly activating, constitutional mutations of genes involved. Common clinical features are:

• cardiovascular abnormalities
• reduced growth
• dysmorphia
• Abnormalities of the skin
• developmental disorders of variable severity.

In some cases there is also a tumor predisposition. Like the PI3K/AKT signaling pathway, to which it is linked, the RAS/RAF signaling pathway stimulates cell growth and is mediated by RAS proteins after growth factors bind to receptors on the cell surface. The classical RAS proteins are encoded by the HRAS, KRAS and NRAS genes. Somatic mutations in these genes, which occur spontaneously in individual cells and lead to clonal expansion due to a growth advantage, play a widespread role in oncogenesis.

ECL and OES strongly overlap in terms of phenotype and genotype. Ocular abnormalities, 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. 2020 Apr 6;100(8):adv00103.
9. Shoji MK et al. (2018) Epibulbar mass with upper eyelid cleft and focal scalp alopecia in a neonate: a new case of oculoectodermal syndrome. Ophthalmic Plast Reconstr Surg 34: e133-e136.