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:

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

Suggestive Findings

ECCL should be suspected in individuals with at least one major criterion in each of two different systems or in individuals with a biopsy-proven or possible nevus psiloliparus (NP), and one minor criterion in a second (non-skin) system (for clinical diagnostic criteria, see Clinical Diagnosis).

Major Criteria

Skin

• Biopsy-proven nevus psiloliparus (NP) (Figure 1)
• Possible NP in addition to one or more of the other minor skin criteria listed below
• Two or more minor skin criteria listed below

Figure 1:

Nevus psiloliparus: a smooth hairless fatty tissue nevus on the scalp Reproduced with permission from Moog [2009]

Eye. Choristoma (e.g., epibulbar dermoid) (Figure 2C)

Figure 2.

Linear alopecia (white arrows in A and B) and choristoma (C) in an affected individual age 2.5 years. Note overgrowth of the left lower face and epibulbar dermoid (white arrow in C), subcutaneous fatty masses (black arrows in B and C) and small nodular (more...)

Central nervous system (CNS)

• Intracranial lipoma (Figure 3)
• Intraspinal lipoma (Figure 4)
• Low-grade glioma (if associated with other suggestive findings)
• Two minor CNS criteria listed below

Figure 3.

Brain and spinal cord MRI in two individuals with ECCL Images from one affected individual (A–C) demonstrate hydrocephalus (A), moderate cerebellar vermis hypoplasia with large fluid collections or cysts behind and below the vermis (white (more...)

Figure 4.

Brain and spinal cord MRI in ECCL An image from one affected individual (A) shows several large lipomas ventral to the spinal cord (black asterisks) and a subcutaneous nuchal fatty mass.

Other

• Jaw tumor (osteoma, odontoma, or ossifying fibroma) (Figure 5)
• Multiple bone cysts (Figure 6)
• Aortic coarctation

Figure 5.

Panoramic radiographs of an affected individual showing hypoplasia of the left maxillary sinus (single white arrow), a bulky mass of dentine structures consistent with left maxillary odontomas (black arrow), and a solitary odontoma of the left lower jaw (more...)

Figure 6.

Multiple lytic bone lesions in the humerus Reproduced with permission from Moog [2009]

Minor Criteria

Skin

• Possible NP
• Patchy or streaky non-scarring alopecia (without fatty nevus) (Figure 2A, 2B)
• Subcutaneous lipoma(s) in the frontotemporal region (Figure 2B, 2C, and Figure 7)
• Focal skin aplasia/hypoplasia on the scalp
• Small nodular skin tags on the eyelids or between outer canthus and tragus

Figure 7.

An affected individual age 5 months. Note the bilateral subcutaneous fatty accumulations (white arrows). Adapted with permission from Moog et al [2007a]

Eye

• Corneal and other anterior chamber anomalies
• Ocular or eyelid coloboma
• Calcification of the globe

CNS

• Abnormal intracranial vessels (e.g., angioma, excessive vessels)
• Arachnoid cyst or other abnormality of meninges
• Complete or partial atrophy of a hemisphere
• Porencephalic cysts(s)
• Asymmetrically dilated ventricles or hydrocephalus
• Calcification not involving the basal ganglia

Establishing the Diagnosis

The clinical diagnosis of ECCL can be established in a proband based on clinical diagnostic criteria [Moog 2009], or the molecular diagnosis can be established in a proband with suggestive findings (i.e., findings consistent with ECCL as noted above but not sufficient to meet the clinical diagnostic criteria for ECCL) and a mosaic activating pathogenic variant in either FGFR1 or KRAS identified by molecular genetic testing (see Table 1).

Clinical Description

To date, at least 85 individuals with a clinical and/or molecular diagnosis of encephalocraniocutaneous lipomatosis (ECCL) have been reported [Moog 2009, Bennett et al 2016, McDonell et al 2018, Valera et al 2018]. Of these, 14 individuals have been identified with a pathogenic variant in FGFR1 [Bennett et al 2016, Bavle et al 2018, Valera et al 2018, Chacon-Camacho et al 2019, Córdoba et al 2019, Kordacka et al 2019] and a few with a pathogenic variant in KRAS [Boppudi et al 2016, McDonell et al 2018, Chacon-Camacho et al 2019, Nagatsuma et al 2019]. The following description of the phenotypic features in individuals with a clinical and/or molecular diagnosis associated with ECCL is based on these reports.

Note: 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. Individuals who do not fulfill the clinical diagnostic criteria for ECCL but display some features have sometimes been reported as having OES (see Nomenclature).

ECCL comprises a spectrum of predominantly congenital anomalies. In its typical form, ECCL is characterized by congenital skin, eye, and brain anomalies, 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. Although variable in its extent and severity, the pattern of skin and eye findings is often consistent and recognizable.

Since 2016, ECCL has also been recognized as a tumor predisposition syndrome [Bennett et al 2016].

Skin. Non-scarring alopecia (with or without underlying fatty tissue) and subcutaneous fatty masses are the most typical skin anomalies.

• A smooth, hairless fatty tissue nevus of the scalp, the so-called nevus psiloliparus (NP) (Figure 1), is the dermatologic hallmark and found in about 75% of affected individuals.
  • In about 40%, fatty subcutaneous masses are seen in the frontotemporal or zygomatic region (Figure 2B, 2C, and Figure 7).
  • Rarely, subcutaneous lipomas are seen outside the craniofacial region.
• Alopecia without a fatty nevus can be linear or patchy, and may follow the lines of Blaschko (Figure 2A, 2B). Some affected individuals have scarring alopecia resulting from focal skin aplasia.
• Areas of focal skin aplasia are usually not extensive (up to a few cm in size) and there have been no reports of affected individuals requiring surgical treatment, such as skin graft, for focal skin aplasia.
• Small nodular skin tags (which histologically are fibromas, lipomas, fibrolipomas, or choristomas) are found in about 70%-75% of affected individuals, most often on the eyelids or following a line from the outer canthus to the tragus.
• Some individuals have several café au lait spots. Linear hyperpigmentation following the lines of Blaschko and (rarely) asymmetric growth may be seen [Moog et al 2007b].

Eyes. Choristomas, with or without other eye anomalies, are seen in the majority of affected individuals (Figure 2C). Several affected individuals have had irregular or disrupted eyebrows.

• Choristomas are benign ocular tumors and include epibulbar or limbal dermoids (dermolipomas) derived from epidermis and dermis, and lipodermoids, which consist mainly of fat and rarely decrease vision [Hunter 2006].
  Dermolipomas can be associated with significant additional eye anomalies listed below.
• Most affected individuals without choristomas have one or more of the following associated eye anomalies:
  • Corneal and scleral anomalies
  • Other anterior chamber abnormalities
  • Ocular and palpebral colobomas
  • Aniridia
  • Microphthalmia
  • Calcification of the globe

Central nervous system (CNS) findings in 52 individuals who underwent imaging are summarized in Table 3. Note: The presence and extent of intracranial abnormalities does not correlate well with the severity of the developmental, skin, and eye findings.

• Lipomas. Intracranial lipomas (Figure 3) are the most common and specific CNS feature, found on neuroimaging in about 65% of affected individuals.
  • Almost 60% of these are located in the cerebello-pontine angle.
  • Spinal lipomas, which can extend over the whole length of the spinal cord (Figure 4), are also commonly seen on spinal cord imaging.
    Subcutaneous fatty masses may overlie the spinal lipomas or be found adjacent to the spinal cord (Figure 4).
• Vascular abnormalities. Abnormal intracranial blood vessels, such as leptomeningeal angiomatosis, thrombosed vascular malformations, and abnormal vessels, were found in nine individuals with ECCL in whom vascular imaging was performed.
  While this finding could represent ascertainment bias, it is suspected that these vascular abnormalities are common, as many of the other brain abnormalities observed could result from prenatal (or, less likely, postnatal) vascular perfusion defects or hemorrhage, including asymmetric brain atrophy, porencephaly, ventriculomegaly, and calcifications [Moog et al 2007a].

Neurology. The spectrum of neurologic dysfunction is broad, ranging from normal cognitive development and no seizures to a very disabling disorder with severe intellectual disability (ID), intractable seizures, and other physical disabilities.

• Among reported individuals with ECCL, about one third have normal cognitive development, one third have mild developmental delay (DD) or ID, and the final one third have severe or unspecified DD/ID.
• About half of affected individuals had a history of typically infant- or childhood-onset epileptic seizures of different types that may be refractory or difficult to treat.

Musculoskeletal

• Jaw tumors identified as osteomas, odontomas, or ossifying fibromas have been described in affected individuals [Zielińska-Kaźmierska et al 2005, Moog 2009] (see Tumors below). These tumors are typically not malignant but can grow into the surrounding tissues, thus displacing teeth and other facial tissues.
• In severely affected individuals, possibly progressive, multiple lytic bone lesions affecting the long bones have been described (Figure 6) [Moog et al 2007b].

Tumors (cancers). Apart from lipomas and jaw tumors, ECCL is associated with increased risk for:

• Brain tumors, specifically low-grade gliomas (although high-grade gliomas have also been observed) [Phi et al 2010, Bennett et al 2016, Valera et al 2018].
  Pilocytic astrocytomas have been reported in six of 14 (43%) individuals with FGFR1-related ECCL; they have not been reported in those with KRAS-related ECCL (see Phenotype Correlations by Gene).
• Possibly Wilms tumor
  • The first reported child with ECCL and Wilms tumor also had severe growth restriction, which is unusual in individuals with ECCL, such that Wilms tumor in this situation could represent a rare co-occurrence with ECCL [Damar et al 2017].
  • Currently, insufficient evidence has accumulated to support a general recommendation for Wilms tumor screening in individuals with ECCL. Such screening may, however, be considered in individuals with KRAS-related ECCL in whom a pathogenic variant involving codon 12 is identified.
  • Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic KRAS variants c.35G>A (p.Gly12Asp) and c.35G>T (p.Gly12Val), respectively, and phenotypes different from ECCL and oculoectodermal syndrome [Chang et al 2021] (see Genetically Related Disorders).

Other findings include:

• Macrocephaly (in ~20% of affected individuals);
• Congenital heart malformations, in particular aortic coarctation.

Oculoectodermal syndrome (OES; OMIM 600268) shares many features with ECCL, including focal alopecia or aplasia of the scalp, NP (possibly), periorbital skin tags, linear hyperpigmentation, ocular choristomas, macrocephaly, benign bone tumors, and coarctation of the aorta [Ardinger et al 2007]. Cranial MRI has been performed in about 60% of individuals with OES and may show arachnoid cysts, asymmetry of hemispheres, or mild dilatation of ventricles. Unlike ECCL, no lipomas or brain tumors (including pilocytic astrocytomas) have been reported in individuals with OES to date.

In at least seven individuals with a clinical diagnosis of OES, postzygotic activating variants in KRAS have been identified, many of which involve codon p.Ala146 [Boppudi et al 2016, McDonell et al 2018, Chacon-Camacho et al 2019]; pathogenic gain-of-function variants involving the p.Ala146 codon have also been identified in individuals who meet the clinical diagnostic criteria for ECCL. As noted above, recent data suggests that ECCL and OES are manifestations of a single spectrum (see Phenotype Correlations by Gene), as was first suggested in 2007 [Ardinger et al 2007, Moog et al 2007a]. Further research is needed to determine the phenotypes related to specific postzygotic activating pathogenic variants in KRAS.

Phenotype Correlations by Gene

Comparing FGFR1-related ECCL to KRAS-related ECCL, a gene-phenotype correlation emerges, especially when including individuals reported as having the OES phenotype who were found to have a KRAS pathogenic variant (see Nomenclature).

Compared to individuals with FGFR1-related ECCL, individuals with KRAS-related ECCL are:

• Less likely to have central nervous system lipomas
• Less likely to develop an astrocytoma (none reported to date)
• More likely to have:
  • Body asymmetry
  • Pigmentary mosaicism (hyperpigmented, hypopigmented, or both)
  • Epidermal nevi
  • Other malformations

Although these are preliminary considerations based on a small number of known affected individuals, the difference between FGFR1-related ECCL and KRAS-related ECCL (including those with an OES phenotype) needs to be reviewed in future, as different surveillance and management needs are likely ‒ underscoring the need for molecular confirmation of the diagnosis.

Genotype-Phenotype Correlations

To date, all individuals with molecularly confirmed ECCL have had mosaicism for one of a few known gain-of-function pathogenic variants in either FGFR1 or KRAS (see Molecular Genetics, Table 9, and Table 1).

Nomenclature

ECCL refers to the characteristic phenotypic findings involving the skin, eye, and central nervous system.

OES may be at one end of the ECCL spectrum [Ardinger et al 2007, Moog et al 2007a], and some individuals who do not fulfill the clinical diagnostic criteria for ECCL but display some features have been reported under this name. A subset of these individuals have indeed been found to have a mosaic KRAS pathogenic variant, providing further evidence that individuals with a clinical diagnosis of OES could fall within the spectrum of ECCL. However, pathogenic variants in other genes have also been found in individuals reported as having OES (see Differential Diagnosis).

Prevalence

The prevalence of ECCL is unknown. At least 85 individuals who meet the clinical diagnostic criteria or who have a molecular diagnosis of ECCL have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ECCL, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Encephalocraniocutaneous lipomatosis (ECCL) is not known to be inherited. No confirmed vertical transmission or sib recurrence has been reported.

Risk to Family Members

Parents of a proband. No parent of a child with ECCL has had any significant, distinctive manifestations of the disorder, nor would such a finding be expected, given the postzygotic mutational mechanism of this disorder.

Sibs of a proband. 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.

Offspring of a proband. Reproductive outcome data on adults with ECCL are limited. There are no instances of vertical transmission of ECCL.

Other family members. The risk to other family members is presumed to be the same as in the general population.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mosaic pathogenic variant. This is a relatively new area for clinical genetics, as only a small (albeit growing) number of disorders are known to be caused by this genetic mechanism. Counseling for recurrence risks in ECCL should emphasize that, while no pregnancy is at zero risk, all evidence suggests that the risk of recurrence for this disorder is not increased compared to the general population.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). Because ECCL is a mosaic disorder, DNA derived from affected tissue should be banked in addition to DNA derived from lymphocytes.

Prenatal Testing and Preimplantation Genetic Testing

As ECCL is not known to be inherited, prenatal diagnosis is usually not indicated. The authors recognize no potential role for preimplantation genetic testing in ECCL.

Molecular Pathogenesis

FGFR1 encodes a growth factor receptor, which, when activated, signals through the RAS/mitogen activated protein kinase (MAPK) pathway. KRAS is a component of the RAS/MAPK pathway, critical for regulating the pathway's activity level. Cell growth and cell differentiation are affected by this signaling pathway. Dysregulation of this signaling pathway during embryogenesis or later in life results in developmental malformations or malignant tumors, respectively. The pathogenic variants reported in ECCL are of postzygotic origin, but arise early during development. Dysregulation of the RAS/MAPK pathway ‒ typically, increased activation ‒ results in characteristic developmental malformations reflecting the mosaic distribution of the pathogenic variant. The spectrum of pathogenic missense variants causing developmental malformations but remaining compatible with survival is likely narrow ‒ accounting for the limited number of pathogenic variants identified in ECCL.

Mechanism of disease causation. Gain of function

Note: It is currently unknown why different gain-of-function pathogenic variants cause different, completely nonoverlapping phenotypes (e.g., FGFR1 p.Asn547Lys substitutions are associated with ECCL, but FGFR1 p.Pro252Arg substitutions cause Pfeiffer syndrome, a craniosynostosis syndrome).

Gene-specific laboratory technical considerations. In affected tissues, any sequencing method may detect ECCL-specific pathogenic variants. However, in unaffected tissues (blood, saliva, normal-appearing skin) and possibly also in affected tissues, low levels of mosaicism for the ECCL-specific pathogenic variants in FGFR1 and KRAS can only be detected using targeted approaches that yield deep sequencing data. The authors therefore recommend use of deep targeted approaches, particularly deep amplicon-based next-generation sequencing or digital droplet PCR (ddPCR) when ECCL is suspected.

Cancer and Benign Tumors

FGFR1 and KRAS are well known proto-oncogenes with somatic pathogenic KRAS variants comprising the most common genetic abnormalities in cancer, particularly pancreatic, colon, and lung cancers [Jancík et al 2010, Hunter et al 2015]. However, cancer has not been reported in KRAS-related ECCL.

Somatic FGFR1 pathogenic variants have also been observed in many different cancer types, including squamous cell (lung, head and neck, esophagus) carcinoma, ovarian cancers, and osteosarcoma [Dienstmann et al 2014]. More relevant for ECCL, somatic pathogenic variants in FGFR1 are common in pilocytic astrocytomas and related midline gliomas [Jones et al 2013, Picca et al 2018], the most frequent cancer reported in individuals with ECCL.

Finally, somatic pathogenic variants in both KRAS (the same as ECCL) and FGFR1 (different from ECCL) have been described in giant cell lesions of the jaw, which can occur in individuals with ECCL [Gomes et al 2018].

Revision History

• 27 January 2022 (ma) Review posted live
• 1 March 2021 (um) Original submission

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