Autosomal recessive malformative syndrome. Commonest anomalies in humans are cryptophthalmos, cutaneous syndactyly of digits, abnormal ears and genitalia, renal agenesis, and congenital heart defects. Almost half of affected infants are stillborn or die in infancy, and mental retardation is common.

Cryptophthalmos may be partial or complete, unilateral or bilateral, apparently nonsyndromal or syndromal. Cryptophthalmos is a developmental field defect on the basis of heterogeneity (autosomal dominant and recessive forms) and phylogeneity (occurrence also in the pheasant, rabbit, pigeon, dog, and mouse).

In humans this autosomal recessive disorder maps to 4q21, is homologous to the bleb (bl/bl) mouse, and is due to mutations in the FRAS1 gene that codes for a 4007 amino acid protein 85% identical to the Fras1 gene of the bleb mouse.

Synopsis

 systemic anomalies

 craniofacial anomalies

• unusual hairline (hair growth on temples extending to lateral eyebrow)
• middle ear malformations
• external ear malformations
• cryptophthalmos
• absent or malformed lacrimal ducts
• hypertelorism
• blindness
• hypoplastic, notched nares
• broad, low nasal bridge
• midline nasal cleavage
• cleft lip / cleft palate
• teeth crowding

 laryngeal anomalies

• laryngeal stenosis
• laryngeal atresia

 widely spaced nipples
 umbilical anomaly

 genital anomalies

• small penis
• hypospadias
• cryptorchidism
• clitoral enlargement
• vaginal atresia
• bicornuate uterus

 renal agenesis/renal hypoplasia
 diastasis of symphysis pubis
 syndactyly
 unusual hairline

 cerebrospinal anomalies

• mental retardation
• microcephaly
• meningomyelocele
• encephalocele

Etiology

 germline mutations in

• FRAS1 gene (MIM.607830)
• FREM2 gene (MIM.608945)

References

 Comstock JM, Putnam AR, Opitz JM, Pysher TJ, Szakacs J. Prenatal death in fraser syndrome. Fetal Pediatr Pathol. 2005 Jul-Aug;24(4):223-38. PMID: #16396829#