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2005-08-09-19 Fraser syndrome © Cuillier www.thefetus.net/


Fraser syndrome   

Fabrice Cuillier, MD1, Alessandri J.L., MD2, Rivière J.P., MD3

1. Dept of Obstetrics and Gynecology, Hôpital Félix Guyon, rue des Topazes, 97400 Saint-Denis, Reunion Island, France. Ph : 0262 90 55 22.
2. Service de Néonatologie, Hôpital Félix Guyon, 97400 Saint-Denis, Ile de la Réunion, France.
3. Service d’anatomopathologie, Hôpital Guyon, 97400 Saint-Denis, Ile de la Réunion, France.

Definition: Fraser syndrome combines acro-facial and urogenital malformations with or without cryptophthalmos 1. Thomas et al (1986) established strict diagnosis criteria (major and minor) for the diagnosis of Fraser syndrome after birth. They outlined the following major criteria 2:

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

The following are the eight minor criteria:

  • 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 and
  • Mental retardation

Cases are diagnosed on the basis of at least two major criteria and one minor criterion or at least four minor criteria.
However, because of the difficulty of demonstrating the major criteria, the prenatal diagnosis of Fraser syndrome relies almost entirely on the detection of some easily detectable minor criteria like laryngeal atresia and renal agenesis3. 

We report a case of Fraser syndrome that was diagnosed at 16 weeks of gestation in a woman with a prior normal pregnancy. Abnormal sonographic findings included mega bladder, syndactyly and oligohydramnios. These findings together with the ocular anomalies led to the diagnosis of Fraser syndrome after the termination of pregnancy. Early prenatal diagnosis of Fraser syndrome is possible in the hands of expert, but due to the variety of possible malformation, the diagnosis will remain doubtful in most cases in which no previous child is affected.

The large bladder:

Picture of the postmortem fetal face showing bilateral cryptophthalmos and syndactyly.

Picture of the postmortem feet showing syndactyly between I, II and III digits.

Synonyms:
FS: Cryptophthalmos-syndactyly syndrome
Megabladder: Megalocystis, Megacystis.

History:
Zehender in 1872 first described a complex malformation syndrome that included bilateral cryptophthalmos, hypertelorism, syndactyly, abnormal genitalia, umbilical hernia, anal stenosis and hoarse voice 2. Similar cryptophthalmos syndromes were described in other cases 3.
In 1962, Fraser published a case of two siblings with cryptophthalmos, syndactyly, ear and noses defects, laryngeal stenosis and renal and genitalia malformations 4.
Lurie and Cherstvoy (1984) reported four families with cryptophthalmos- syndactyly syndrome. Nine affected fetuses died in the perinatal period 5. So the term Fraser syndrome has been used for similar malformation syndromes.
Thomas et al (1986) reviewed 124 cases of cryptophthalmos and associated syndromes and established diagnostic criteria clearly separating Fraser syndrome from isolated cryptophthalmos 2.
Feldman et al reported the first prenatal detection of Fraser syndrome in 1985. Their diagnosed was based on microphthalmia and hydrocephalus at 18 weeks of gestation, with a previously affected sibling 5.
Boyd (1988) also reported detailed postmortem findings in 11 cases of possible Fraser syndrome. These authors concluded that prenatal diagnosis was possible by ultrasound by a detailed examination of the eyes, digits and kidneys 5.
Schauer et al (1990) reported a case diagnosed prenatally at 18 weeks of gestation.
Berg (2001) performed a review of literature and found 16 cases of Fraser syndrome that underwent sonographic examination prior to delivery 2.

Incidence:
0.043 / 10,000 liveborn infants. 1.1 / 10,000 stillbirths 2.

Etiology:
Fraser syndrome is a multiple malformation syndrome with a probable autosomal recessive inheritance, since an unusual proportion of infants are born to consanguineous parents. The gene is unknown 2.

Recurrence risk:
Fraser syndrome has a recurrence risk of 25 % among siblings and therefore prenatal diagnosis and counseling the affected families is important 2. However, in the case of a previously affected sibling the diagnosis can be made even without the above Thomas’s criteria being fulfilled.

Diagnosis:
Prenatal diagnosis of Fraser syndrome has been reported rarely but the sonographic findings were very inconsistent rendering the definition of sonographic markers difficult as in our case. The diagnosis can be suggested prenatally by the combination of obstructive uropathy, microphthalmia, pulmonary obstruction from laryngeal atresia, ascites, fetal hydrops with nuchal edema and oligohydramnios.
Many reports of prenatal diagnosis of Fraser syndrome have been essentially in a family with a previous sibling having the Fraser syndrome. Prenatal diagnosis of Fraser syndrome with a negative family history is very rare and in fact, a definitive prenatal diagnosis of Fraser syndrome cannot be really made in such cases 6.
Maruotti et al (2004) described Fraser syndrome at 21 weeks of gestation based on oligohydramnios, laryngeal atresia, and microphthalmos. The diagnosis was confirmed after termination of pregnancy 2. Vijayaraghavan et al (2005) described Fraser syndrome at 26 weeks of gestation with microphthalmos and syndactyly 3.

In our case two anomalies were seen- mega bladder and abnormal hands, but this last anomaly was difficult to confirm because there was oligohydramnios at 15 weeks of gestation.

Pathogenesis:
A defect of apoptosis has been suggested since several of the anomalies result from the failure of programmed cell death (fusion of the eyelids, digits, larynx and the vagina). The responsible gene is not known.

Genetic anomaly:
Unknown

Associated anomalies:

  • Cryptophthalmos: the hidden eye is characterized by the continuous skin from the forehead to the cheek and the absence of the palpebral fissure. Cryptophthalmos is the leading feature of Fraser syndrome and has been described in 90 % of affected patients according to Vija and Berg 2.
  • Abnormalities of the ears and the nose: occur with a frequency of approximately 85 % and can be detected by ultrasound, in particular 3D ultrasound. In our case, there was no facial or ear defects. Hypertelorism has been described. Absent or malformed lacrimal duct, middle and outer ear malformations, a high palate, cleavage along the mid plane of nares and tongue have also been described.
  • Laryngeal stenosis: Different authors have suggested that the diagnosis of laryngeal abnormalities in the fetus is difficult even when prenatal ultrasound shows increased echogenicity of the lungs and fetal ascites. Hence the postmortem examination should be performed by a fetal pathologist.
  • Other anomalies: Primitive mesentery of small bowel, intestinal hypoplasia, or maldeveloped kidneys can exist.
    Labial fusion, enlargement of clitoris, bicornuate uterus and malformed fallopian tubes can be also be found.  Other anomalies are heart defects, major vascular anomalies, imperforate anus 7-8, thymic aplasia and cerebral malformations.
  • Syndactyly occurs in 79 % of fetuses with Fraser syndrome, but the prenatal diagnosis is really difficult due to the associated oligohydramnios.

Differential diagnosis:
Of echogenic lungs includes: congenital diaphragmatic hernia, cystic adenomatoid malformation type III, sequestered lung, tracheal and bronchial atresia (the last two diagnoses are very rare).
Differential diagnosis of the cryptophthalmos includes alobar holoprosencephaly or hydrocephalus.

Prognosis:
The prognosis is really poor.

Management:
Depends on the predominant associated anomalies, but termination of pregnancy may be recommended when renal agenesis or laryngeal atresia is present. Fraser syndrome needs to be confirmed by post-mortem examination.

References:

1. Thomas I.T., Frias J.L., Felix V., De Sanchez Leon L., Fernandez R.A., Jones M.C.- Isolated and syndromic cryptophtalmos. Am J Med Genet 1986 ; 25 : 85-98.
2. Berg C., Geipel A., Germer U., Pertersen-hansen A., Koch-Dörfler M., Gembruch U.- Prenatal detection of Fraser syndrome without cryptophthalmos : Case report and review of the literature. Ultrasound Obstet Gynecol 2001 ; 18 : 76-80.
3. Vijayaraghavan S.B., Suma N., Lata S., Kamakshi K.- Picture of the month. Prenatal sonographic appearance of crytophthalmos in Fraser syndrome. Ultrasound Obstet Gynecol 2005 ; 25 : 629-30.
4. Fraser G.R.- Our genetical load : a eview of some aspects of genetical variation. Ann Hum Genet 1962 : 25 : 387-415.
5. Balci S., Altinok G., Ozaltin F., Aktas D., Niron E.A., Onol B.- Laryngeal atresia presenting as fetal ascites, oligohydramnios and lung appearnance mimicking cystic ademnomatoid malformation in a 25-week-old fetus with Fraser syndrome. prenatal Diagn 1999 ; 19 : 856-8.
6. Fryns J.P., Van Schoubroeck D., Vandenberghe K., nagels H., Klerckx P.- Diagnostic echographic findings in cryptophtalmos syndrome (fraser syndrome). Prenatal Diagn 1997 ; 17 : 582-4.
7. Cuillier F., Cartault F., Rivière J.P., Tuaillon J.- Antenatal discovery of megacystis-microcolon-intestinal peristalsis syndrome (MMIHS) at 12 weeks gestation. J Gynecol Obstet Bio reprod 2004 ; 33 : 444-9. .
8. Mc Hugo J., Whittle M.- Enlarged fetal bladders : aetiology, management and outcome. Prenat Diagn 2001 ; 21 : 958-63.

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