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2000-07-22-11 Cryptophthalmos with other malformations © Navarro www.thefetus.net/


Cryptophthalmos with other malformations

Julio Navarro MD*, Philippe Jeanty, MD, PhD

*San Salvador, El Salvador C.A. 

Definition:  Fraser syndrome[1] consist of the association of four major characteristics (cryptophthalmos, syndactyly, genital anomalies and affected siblings) and eight minor characteristics (alterations of the nose, ears, larynx, oral clefts, umbilical hernia, renal agenesis, skeletal anomalies and mental retardation)[2]. The diagnosis requires either the presence of 2 major and one minor characteristic, or one major and four minor characteristics[3]. Cryptophthalmos is a rare congenital anomaly of the eye, characterized by continuity of the skin from the forehead to the cheek over a malformed eye. Cryptophthalmos is classified into three types: complete, incomplete and abortive[4].

Synonyms:   Fraser syndrome, cryptophthalmos-syndactyly syndrome 

Etymology:  Greek: kruptoV = cryptos = hidden and ofqalmos = ophtalmos = eye

Case report: This patient with no remarkable personal of familial anamnesis had no prenatal ultrasound. At delivery the newborn was found to have cryptophthalmos, hypertelorism, outer ear malformations with dysplastic pinna, cleavage along the midplane of the nose, hypoplastic notched upturned nostrils, oligodactyly with webbing of the fingers, widely spaced nipples, enlargement of the clitoris

 

Prevalence:  0.05:10,000 deliveries and 1.1:10,000 stillbirth1.

Etiology and recurrence risk:  Autosomal recessive, the recurrence risk is thus 25%. About 15% of the parents are consanguineous[5]. The clinical expression inside families is very constant with respect to cryptophthalmos, syndactyly and internal malformations[6]. Further the families with fetuses with fatal outcome consistently have recurrent fatal outcome in affected siblings. This is important for genetic counseling: the discovery of a lethal form of the disease would recur, making identification at sonography particularly important.

Genetic anomaly: unknown

Pathogenesis: A defect of apoptosis has been suggested since several of the anomalies results from failure of programmed cell death (fusion of the eyelids, digits, larynx and the vagina)2.

Sonographic findings[7],[8],[9],[10],[11],[12],[13],[14],[15],[16]  ,:

CNS

·         hydrocephalus

Face and neck

·        laryngeal substenosis or atresia resulting in increased echogenicity of lungs mimicking CAM (cystic adenomatoid malformation) type III

·        nuchal oedema

·        cryptophthalmia or anophthalmia

·        hypertelorism

·        microphthalmia

·        malformed ears

Lungs

·        increased echogenicity of lungs

·        enlarged lungs

Skeletal

·         syndactyly of the hands and or feet

Amniotic fluid

·        oligohydramnios

·        polyhydramnios

Urinary

·        renal agenesis (unilateral or bilateral)

·        multicystic renal dysplasia

Genital

·        abnormal genitalias

Others

·        ascites

·        hydrops

·        intrauterine growth retardation

A case has been reported with monozygotic twins[17]. 

Differential diagnosis: The 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 and other crypto- anophtalmos without the associates malformations2.

Associated anomalies[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34] ,:  

CNS

  • hydrocephalus

Face and neck
(100%)

  • Eyes:
    • cryptophthalmos (93%) (but there may be functional visual pathway at retinal and post-retinal levels)
    • absent or malformed lacrimal ducts
    • rarely normal eyelids may be present
    • hypertelorism
  • Ears (44%):
    • middle and outer ear malformations
    • dysplastic pinna
    • atresia or stenosis of external auricular meatus
    • absence of the Eustachian tube with connective tissue occupying the tympanic cavity and bone occluding the external acoustic meatus
  • Nose (37%):
    • cleavage along the midplane of nares
    • hypoplastic notched nares
    • choanal stenosis or atresia
  • Mouth:
    • cleavage of the tongue
    • high palate
  • Larynx:
    • laryngeal stenosis, substenosis or atresia
    • glottic web, subglottic stenosis

Skeletal

  • syndactyly (54%) of the hands (often 3rd and 4th digit) and or feet
  • postaxial polydactyly
  • soft-tissue webbing between the digits
  • wide separation of symphysis pubis

Chest & abdomen

  • displacement of umbilicus and nipples

Gastrointestinal

  • primitive mesentery of small bowel
  • whom malrotation of the small bowel
  • aberrant pancreas in duodenum
  • diaphragmatic defects

Urinary tract
(37%)

  • maldeveloped kidneys
  • anterior urethral atresia

Genitalia
(49%)

  • Girls:
    • fusion of labia and
    • enlargement of clitoris
    • bicornuate uterus
    • malformed fallopian tubes
    • primary amenorrhea with normal pituitary gonadotropins
  • Boys:
    • anterior urethral atresia
    • undescended testes
    • small penis
    • hypospadias

Respiratory

  • hypoplastic lung
  • hyperplasia of the lungs from retention of lung secretion by laryngeal or tracheal obstruction

Cardiovascular

  • cardiac defect

Outcome

  • stillbirth (26%)
  • death during the first year of life (19%)

(numbers between parenthesis express reported frequencies)

Prognosis:   The prognosis depends on the severity of the renal and laryngeal malformations[35],16. Overall 26% die as stillbirth and death occurs during the first year of life in another 19%33.

Management: Prenatal: Termination of the pregnancy can be recommended when renal agenesis or laryngeal atresia is present. Postnatal: In selected cases of incomplete cryptophthalmos, oculoplastic and corneal surgery may result in some vision and in some eyelid movement[36],[37] 

References:

See also Fraser syndrome


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

[2] Thomas IT, Frias JL, Felix V, Sanchez de Leon L, Hernandez RA, Jones MC Isolated and syndromic cryptophthalmos. Am J Med Genet 1986 Sep;25(1):85-98

[3] 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

[4] Kanhere S, Phadke V, Mathew A, Irani SF Cryptophthalmos. Indian J Pediatr 1999 Sep-Oct;66(5):805-8

[5] Francois, J.Syndrome malformatif avec cryptophtalmie. Acta Genet. Med. Gemellol. 18: 18-50, 1969.

[6] Lambert JC, Touitou I, Paquis V, Saunieres AM Expressivity of familial forms of Fraser syndrome. J Genet Hum 1989 Jun;37(2):119-26

[7] Balci S, Altinok G, Ozaltin F, Aktas D, Niron EA, Onol B Laryngeal atresia presenting as fetal ascites, olygohydramnios and lung appearance mimicking cystic adenomatoid malformation in a 25-week-old fetus with Fraser syndrome. Prenat Diagn 1999 Sep;19(9):856-58

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

[9] 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

[10] Perez Aytes A, Fabregat Ferrer E, Ramos Fernandez V, Uixera Marzal L, Froufe Sanchez A Fraser syndrome, renal agenesis and fetal ascites. An Esp Pediatr 1993 Aug;39(2):163-6

[11] Comas C, Martinez Crespo JM, Puerto B, Borrell A, Fortuny A Bilateral renal agenesis and cytomegalovirus infection in a case of Fraser syndrome. Fetal Diagn Ther 1993 Jul-Aug;8(4):285-90

[12] 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

[13] Ramsing M, Rehder H, Holzgreve W, Meinecke P, Lenz W Fraser syndrome (cryptophthalmos with syndactyly) in the fetus and newborn. Clin Genet 1990 Feb;37(2):84-96

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