ear malformations

Fraser Syndrome 1

Clinical Characteristics
Ocular Features: 

Cryptophthalmos is the major ocular malformation in Fraser syndrome but is a feature in only 93% of patients.  The globe is often small and sometimes completely absent or in some cases consisting of only rudimentary ocular tissue.  The cornea is often adherent to the eyelid tissue.  The lacrimal ducts may be deformed or absent and the lids are often fused.

Systemic Features: 

The most common malformations seen in this disorder are syndactyly (61.5%), cryptophthalmos (88%), and genitourinary malformations but others of a great variety have also been reported, such as laryngeal stenosis, deafness, and deformities of the nares and external auditory meati.  Ambiguous genitalia occur in 17%.   Some infants are stillborn and many do not survive the neonatal period.  Cognitive deficits and congenital heart disease are common.

Genetics

Fraser syndrome 1 is caused by homozygous or heterozygous mutations in the FRAS1 gene (4q21.21).

Fraser syndrome 2 (617666) results from homozygous mutations in the FREM2 gene (13q13.3).  Parental consanguinity is common (25%) and familial patterns are consistent with autosomal recessive inheritance.

Fraser syndrome 3 (617667) results from homozygous mutations in the GRIP1 gene (12q14.3).  Three consanguineous families have been reported.  

Mutations in GRIP1 (PAD14) (12q14.3) have also been found in 3 families in which the parents were consanguineous.

Isolated cryptophthalmos  (123570) also occurs in autosomal dominant pedigrees as well as sporadically.  It is rarely found as an incidental feature of other syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

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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