FGFR1

Encephalocraniocutaneous Lipomatosis

Clinical Characteristics
Ocular Features: 

Ocular choristomas of the periocular tissue such as epibulbar dermoids or lipodermoids are seen in 80% of individuals.  Some degree of microphthalmia, a 'hypertrophic' conjunctiva, and sclerocornea have been reported.  The pupils are small and iris hypoplasia with anterior chamber anomalies has been described.  The macular reflex can be absent and colobomas of the eyelids (and rarely uveal tract) have been seen.

Systemic Features: 

Preauricular skin tags may be present.   Fatty tissue nevi associated with alopecia as well as frontotemporal or zygomatic subcutaneous fatty lipomas, and focal dermal hypoplasia are seen externally in many patients.   Coarctation and/or hypoplasia of the thoracic aorta along with aortic valve anomalies are sometimes present.

Intracranial and intraspinal lipomas are present in over 60% of individuals.  Arachnoid cysts with ventricular enlargement, and leptomeningeal angiomatosis are frequently present.  Jawbone cysts and tumors are common. The skull and heart may also have lipomas.  Seizures and some intellectual disability have been diagnosed in many affected individuals but a third or more have normal intellect.  The affected cortex may calcify later in life.

Genetics

ECCL is considered to result from postzygotic activating mutations in the FGFR1 gene (8p11.23) resulting in a mosaic distribution.  This may help explain the highly variable and widespread distribution of skin and CNS lesions.  A 5-year-old female with an affected father and paternal grandmother have been reported suggesting autosomal dominant inheritance.

Mutations in the same gene have been found in Pfeiffer syndrome (101600).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the overall condition but selective removal of tumors with cosmetic and pressure consequences should be considered.

References
Article Title: 

Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis

Bennett JT, Tan TY, Alcantara D, Tetrault M, Timms AE, Jensen D, Collins S, Nowaczyk MJ, Lindhurst MJ, Christensen KM, Braddock SR, Brandling-Bennett H, Hennekam RC, Chung B, Lehman A, Su J, Ng S, Amor DJ; University of Washington Center for Mendelian Genomics; Care4Rare Canada Consortium, Majewski J, Biesecker LG, Boycott KM, Dobyns WB, O'Driscoll M, Moog U, McDonell LM. Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. Am J Hum Genet. 2016 Mar 3;98(3):579-87.

PubMed ID: 
26942290

Pfeiffer Syndrome

Clinical Characteristics
Ocular Features: 

Patients may have extreme proptosis (95%) secondary to shallow orbits and exposure keratitis (41%) is a risk.  Hypertelorism, strabismus, and antimongoloid lid slants are common.  More rare signs include anterior chamber anomalies and optic nerve hypoplasia.

Systemic Features: 

Pfeiffer syndrome has been divided into 3 types, of which cases with types 2 and 3 often die young.  Type 1 has the more typical features with midface hypoplasia, broad thumbs and toes, craniosynostosis, and often some degree of syndactyly.  Adult patients with type 1 may be only mildly affected with some degree of midface hypoplasia and minor broadening of the first digits.  Hearing loss secondary to bony defects is relatively common.  Cleft palate is uncommon.  Airway malformations especially in the trachea can cause respiratory problems.

Genetics

This is a genetically heterogeneous disorder resulting from mutations in at least 2 genes, FGFR1 (8p11.2-p11.1) and FGFR2 (10q26).  The less common cases with the latter mutation are allelic to Apert (101200), Crouzon (123500), and Jackson-Weiss (123150) syndromes.  Inheritance is autosomal dominant but some cases are only mildly affected.  New mutations exhibit a paternal age effect.

Other forms of craniosynostosis in which mutations in FGFR2 have been found are: Beare-Stevenson Syndrome (123790), and Saethre-Chotzen Syndrome (101400).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Exposure keratitis requires the usual treatment.  Fronto-orbital advancement surgery for the midface underdevelopment is generally helpful for the complications of proptosis.  Airway obstruction may require tracheostomy or surgical correction of the air passages.

References
Article Title: 

FGFR2 mutations in Pfeiffer syndrome

Lajeunie E, Ma HW, Bonaventure J, Munnich A, Le Merrer M, Renier D. FGFR2 mutations in Pfeiffer syndrome. Nat Genet. 1995 Feb;9(2):108.

PubMed ID: 
7719333
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