Updated 2006-01-18 by Juliana Leite, MD

Original text 1999-05-13 Philippe Jeanty, MD, PhD & Sandra R Silva, MD

Synonym: Cryptophthalmos-syndactyly syndrome

Definition: Fraser syndrome is a rare genetic syndrome with abnormalities of the head, lungs, kidneys, and limbs. It combines acrofacial and urogenital malformations with or without cryptophthalmos.

Incidence: 0.043:10,000 live-born infants and 1.1:10,000 stillbirths.

Etiology: Probably autosomal-recessive because an unusual proportion of infants are born to consanguineous parents.

Recurrence risk: Fraser syndrome has a recurrence risk of 25 % among siblings and therefore prenatal diagnosis and counseling the affected families is important

Diagnosis: The diagnosis has been suggested prenatally by the combination of the major and minor characteristics. Cases are diagnosed on the basis of at least two major criteria and one minor criterion or at least four minor criteria.

The major characteristics are:

• Cryptophthalmos
• Syndactyly
• Genital anomalies
• Sibling with Fraser syndrome

The minor characteristics are:

• Alterations of the nose
• Alterations of the ears
• Alterations of the larynx
• Oral clefts (cleft lip and/or palate)
• Umbilical hernia
• Renal agenesis (unilateral or bilateral)
• Skeletal anomalies

The prenatal diagnosis of Fraser syndrome can be suspected, but because of the great variety of malformations the diagnosis will remain doubtful unless a previous child is affected (3).

Figure 1: Laryngeal atresia (not in a fetus with Fraser syndrome). Note the bulky echogenic lungs that invert the diaphragm, and compress the heart. (Reprinted with permission from Valcamonico et al[9])

Pathogenesis: A defect of apoptosis has been suggested because several of the anomalies result from failure of programmed cell death (fusion of eyelids, digits, larynx, and vagina).

Genetic anomalies: The Fraser syndrome gene is located to 4q21

Associated anomalies: Cryptophthalmos, absent or malformed lacrimal ducts, middle and outer ear malformations, high palate, cleavage along the midplane of nares and tongue, hypertelorism, laryngeal stenosis, syndactyly, wide separation of symphysis pubis, displacement of umbilicus and nipples, primitive mesentery of small bowel, maldeveloped kidneys, fusion of labia and enlargement of clitoris, and bicornuate uterus and malformed fallopian tubes.

Differential diagnosis: Of the echogenic lungs, includes congenital diaphragmatic hernia, cystic adenomatoid malformation (type III), sequestrated lung, and tracheal or bronchial atresia. The differential diagnosis of the cryptophthalmos includes alobar holoprosencephaly, which should be easy to recognize from the simple hydrocephalus of the Fraser fetuses.

Prognosis: Fatal if laryngeal atresia or renal agenesis is present. If cryptophthalmos is the main sign, even surgical repair will yield very poor vision (20/200 and 20/360) in the rare correctable cases.

Management: Depends on the predominant associated anomalies. Termination of the pregnancy can be recommended when renal agenesis or laryngeal atresia is present.

References:

[1] Martinez-Frias ML, Bermejo Sanchez E, Felix V, Calvo Celada R, Ayala Garces A, Hernandez Ramon F Fraser syndrome: frequency in our environment and clinical-epidemiological aspects of a consecutive series of cases. An Esp Pediatr 1998 Jun;48(6):634-8

[2] Ozgunen T, Evruke C, Kadayifci O, Demir C, Aridogan N, Vardar MA Fraser syndrome. Int J Gynaecol Obstet 1995 May;49(2):187-9

[3] Stevens, C. A.; McClanahan, C.; Steck, A.; Shiel, F. O"M.; Carey, J. C. : Pulmonary hyperplasia in the Fraser cryptophthalmos syndrome. Am. J. Med. Genet. 52: 427-431, 1994.

[4] Lesniewicz R, Midro AT: Ultrasound diagnosis of four fetuses with Fraser syndrome during pregnancy. Ginekol Pol 1998 Mar;69(3):152-7

[5] Fryns JP, van Schoubroeck D, Vandenberghe K, Nagels H, Klerckx P Diagnostic echographic findings in cryptophthalmos syndrome (Fraser syndrome). Prenat Diagn 1997 Jun;17(6):582-4

[6] Boyd, P. A.; Keeling, J. W.; Lindenbaum, R. H. : Fraser syndrome (cryptophthalmos-syndactyly syndrome): a review of eleven cases with postmortem findings. Am. J. Med. Genet. 31: 159-168, 1988.

[7] Serville, F.; Carles, D.; Broussin, B. : Fraser syndrome: prenatal ultrasonic detection. Am. J. Med. Genet. 32: 561-563, 1989.

[8] Schauer GM, Dunn LK, Godmilow L, Eagle RC Jr, Knisely AS Prenatal diagnosis of Fraser syndrome at 18.5 weeks gestation, with autopsy findings at 19 weeks. Am J Med Genet 1990 Dec;37(4):583-91

[9] Valcamonico A, Jeanty A: Laryngeal atresia. The Fetus 2:4 pp 7483-5, 1992

[10] Thomas, I. T.; Frias, J. L.; Felix, V.; Sanchez de Leon, L.; Hernandez, R. A.; Jones, M. C. : Isolated and syndromic cryptophthalmos. Am. J. Med. Genet. 25: 85-98, 1986.

[11] Fraser, G. R. : Our genetical "load:" a review of some aspects of genetical variation. Ann. Hum. Genet. 25: 387-415, 1962.

[12] Dibben K, Rabinowitz YS, Shorr N, Graham JM Jr Surgical correction of incomplete cryptophthalmos in Fraser syndrome. Am J Ophthalmol 1997 Jul;124(1):107-9