Clinical characteristics: Encephalocraniocutaneous lipomatosis (ECCL) comprises a spectrum of predominantly congenital anomalies. In its typical form, ECCL is characterized by congenital anomalies of the skin (nevus psiloliparus, patchy or streaky non-scarring alopecia, subcutaneous lipomas in the frontotemporal region, focal skin aplasia or hypoplasia on the scalp, and/or small nodular skin tags on the eyelids or between the outer canthus and tragus), eye (choristoma), and brain (in particular intracranial and spinal lipomas). To a much lesser degree, the bones and the heart can be affected. About 40% of affected individuals have bilateral abnormalities of the skin or the eyes. About one third of affected individuals have normal cognitive development, another one third have mild developmental delay (DD) or intellectual disability (ID), and the final one third have severe or unspecified DD/ID. Half of individuals have seizures. Affected individuals are at an increased (i.e., above the general population) risk of developing brain tumors, particularly low-grade gliomas such as pilocytic astrocytomas. There is evidence that oculoectodermal syndrome (OES) may constitute a clinical spectrum with ECCL, with OES on the mild end and ECCL on the more severe end of the spectrum.

Diagnosis/testing: A clinical diagnosis of ECCL can be made in individuals with:

1. Involvement of at least three systems, with major criteria in at least two of the three systems; OR

2. Involvement of at least three systems, in which one major criterion is either a biopsy-proven nevus psiloliparus (NP) OR a possible NP with at least one other minor skin criterion; OR

3. At least one major criterion in each of two systems, where one major criterion is either a biopsy-proven NP or a possible NP with at least one other minor skin criterion.

A molecular diagnosis can be established in a proband with suggestive findings and a mosaic activating pathogenic variant identified in either FGFR1 or KRAS. Due to the mosaic nature of the condition, molecular genetic testing on DNA derived from affected tissue has the best detection rate and molecular methods that can detect low levels of mosaicism are recommended.

Management: Treatment of manifestations: Standard treatment for skin manifestations (when appropriate; most of the skin findings do not require active management), choristomas / eye anomalies (including community vision services, as needed), low-grade gliomas, DD/ID, and jaw/dental anomalies; standard treatment with anti-seizure medication for those with epilepsy; standard treatment of Wilms tumor per oncologist.

Surveillance: Assess for new neurologic manifestations (changes in tone, seizures), developmental progress, and educational needs at each visit; dental evaluation at least every six months; unless the individual has molecularly confirmed KRAS-related ECCL, consider performing brain MRI to screen for brain tumors annually or as clinically indicated; ophthalmologic evaluations annually in childhood and adolescence or as clinically indicated; consideration of renal ultrasound every three months until age eight years to screen for Wilms tumor in those who have a KRAS pathogenic variant that involves codon 12.

Genetic counseling: ECCL is not known to be inherited. No confirmed vertical transmission or sib recurrence has been reported. Given the postzygotic mutational mechanism of ECCL, the risk for an affected sib would be expected to be the same as in the general population.