Mædica - a Journal of Clinical Medicine
C ASE
MAEDICA – a Journal of Clinical Medicine
2016; 11(5): 80-83
REPORTS
Fraser Syndrome - a Case Report
and Review of Literature
Adrian DUMITRUa,b; Mariana COSTACHEa,b; Anca Mihaela LAZAROIUa,b;
George SIMIONa; Diana SECARAc; Monica CIRSTOIUb,c; Alina EMANOILc;
Tiberiu Augustin GEORGESCUa; Maria SAJINa,b
a
Department of Pathology, Emergency University Hospital, Bucharest, Romania
“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
c
Department of Obstetrics and Gynaecology, Emergency University Hospital,
Bucharest, Romania
b
ABSTRACT
Fraser syndrome is a rare autosomal recessive genetic disorder characterized by major features such
as cryptophthalmos, syndactyly, malformations of the larynx and genitourinary tract, craniofacial dysmorphism, orofacial clefting, mental retardation and musculoskeletal anomalies. In total, about 150
affected patients have been described in the literature. The diagnosis of this syndrome can be established
after clinical examination. We present the clinical findings of a rare case of Fraser syndrome with lethal
phenotype due to bilateral renal agenesis in a female stillborn.
Keywords: Fraser syndrome, cryptophthalmos, syndactyly, urogenital malformation
INTRODUCTION
F
raser syndrome (also known as cryptophthalmos-syndactyly syndrome,
Meyer-Schwickerath’s syndrome, Fraser-François syndrome or Ullrich-Feichtiger syndrome) (1) is a very rare
autosomal recessive disorder characterized by
major features such as cryptophthalmos, syndactyly, malformations of the larynx and genitourinary tract, craniofacial dysmorphism,
mental retardation and musculoskeletal anomalies (2). The syndrome is named after the Canadian genetician George R. Fraser, who first
described this disorder in 1962 (3). The incidence of Fraser syndrome is below 0.043 per
10.000 live born infants and 1.1 in 10.000 still-
births (4), making it a very rare syndrome. Another population-based epidemiological study
of 12.886.464 births using data provided by
the European Surveillance of Congenital
Anomalies (EUROCAT) network of birth defect
registries reported a prevalence of 0.2 per
10.000 births (5).
The genetic background of this disease has
been linked to FRAS1, a gene involved in skin
epithelial morphogenesis during early development (6). The FRAS1 gene is located on the
long arm of chromosome 4 (4q21). This disorder has also been associated with FREM2 gene
found in chromosome 13 (7) and with GRIP1
mutations of chromosome 12 (8).
The proper diagnosis of Fraser syndrome
can be made upon birth based on its distinctive
Address for correspondence:
Mariana Costache, Department of Pathology, Emergency University Hospital, 169 Independentei Avenue, 050098, Bucharest, Romania.
E-mail: [email protected]
Article received on the 18th of November 2015. Article accepted on the 25th of February 2016.
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A Journal of Clinical Medicine, Volume 11 No.1 2016
FRASER SYNDROME - A CASE REPORT AND REVIEW OF LITERATURE
association of malformations. Occasionally, it is
possible to diagnose this syndrome due to
atypical prenatal ultrasonographic features
such as polyhydramnios or oligohydramnios,
echogenic lungs and renal abnormalities or
agenesis (9).
The treatment and prognosis of Fraser syndrome usually has to deal with the severity of
cerebral, pulmonary, laryngeal and renal malformations. Some cases may benefit from proper genetic counseling. 
CASE REPORT
An autopsy was performed on a female stillborn with multiple congenital malformations to
determine the cause of death. The stillborn was
the product of the second pregnancy of nonconsanguineous healthy parents, delivered by
cesarean section. The stillborn weight was
1.480 g and the length was 38 cm.
Gross examination revealed a severe facial
dysmorphism with complete bilateral cryptophthalmos, low set ears, flat nasal bridge, micrognathia and incomplete ossification of the
skull bones. We noticed complete bilateral syndactyly on both hands and feet. Also, the newborn had an umbilical hernia, imperforate anus
and ambiguous genitalia. Major internal organ
anomalies were observed: hypoplastic lungs,
patent ductus arteriosus and foramen ovale, bilateral renal agenesia with agenesis of the ure-
ters, hypertrophic adrenal glands, hypoplasic
bladder. We also noticed two small paraovarian
nodules which proved to be ectopic adrenal
tissue on histopathological examination.
However, the causes of death were due to
an association of acute respiratory insufficiency
(caused by massive pulmonary hemorrhage)
and bilateral renal agenesis. 
DISCUSSION
The diagnosis of Fraser syndrome can be
made on clinical examination using the diagnostic criteria proposed by Thomas et al (10).
The major criteria include cryptophthalmos,
syndactyly, sibling with cryptophthalmos and
abnormal genitalia. The minor features are
congenital malformations of the nose, ear and
larynx, skeletal defects, umbilical hernia, renal
agenesis and mental retardation. The presence
of two major criteria or one major and four minor criteria are needed for diagnosis. In our
case all these requirements are satisfied. Before
the involvement of genetic mutation was clarified, Thomas et al. highlighted the teratogenetic effect of hypovitaminosis A in some animal
models such as pigs and rats. Malformations
similar to those found in Fraser syndrome are
produced when these animals are exposed to a
low retinoid diet (10).
The parents of affected children are sometimes, but not always consanguineous. Consan-
FIGURE 1. Phenotypic features of Fraser syndrome. Note the severe facial dysmorphism with
complete bilateral cryptophthalmos, multiple nasal anomalies and micrognathia, congenital
umbilical hernia, ambiguous genitalia, complete bilateral syndactyly (Type IV) of the hands and
feet, imperforate anus.
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A Journal of Clinical Medicine, Volume 11 No.1 2016
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FRASER SYNDROME - A CASE REPORT AND REVIEW OF LITERATURE
FIGURE 2. Microscopic appearance of the bilateral paraovarian
ectopic adrenal tissue (red arrows). Note the fallopian tube nearby
(green arrows), H.E. 40x.
guinity is reported in 15–24% of cases and the
recurrence rate among siblings is about 25%
suggesting an autosomal recessive pattern of inheritance (11,12).
Gattuso et al. estimated the frequency of
several clinical manifestations of Fraser syndrome based on 3 new cases and by reviewing
68 already published cases. Craniofacial abnormalities were found in all cases, cryptophthalmos in 93%, and syndactyly in 54% (13). They
also mentioned Warkany (1971) as citing the
description by Pliny the Elder in the first century A. D. of a family with 3 children born with
a membrane over the eye, thus suggesting that
the major feature of Fraser syndrome was well
known since ancient times.
Slavotinek and Tifft reviewed 117 cases of
Fraser syndrome or cryptophthalmos published
after the comprehensive review of Thomas et
al. in 1986. Their findings emphasized the clinical variability associated with this syndrome
and highlighted the heterogeneity of the disorder. They also noted syndromic associated
anomalies (for example, bicornuate uterus with
imperforate anus or anal stenosis and renal
malformations) that are found in other syndromes and associations without cryptophthalmos, suggesting that common mutant genes
may justify some of the phenotypic variation
found in some cases of Fraser syndrome. They
conclude by suggesting that categories of physical anomalies or phenotypic features can be
preserved across different syndromes and that
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they may prove to be useful tracks for the delineation of specific abnormalities within a syndrome and for the determination of relevant
molecular screening tests (11).
Van Haelst et al. studied the phenotype of
59 newly diagnosed cases with Fraser syndrome from 40 families, including 25 consanguineous families. Compared to previous reviews, they reported a higher frequency of
abnormalities of the skull, larynx, umbilicus,
urogenital tract and anus, and a lower frequency of mental retardation and cheiloschisis with
or without palatoschisis. According to the revised diagnostic criteria proposed by Van Haelst
et al. the airway tract and urogenital anomalies
should be included as major criteria while
mental retardation and clefting should be removed (2).
Prenatal diagnosis of Fraser syndrome is
possible as early as 18 weeks into the pregnancy and is accomplished due to the detection
via ultrasound and fetoscopy of a combination
of sindromic malformations or phenotypic features such as those above-mentioned. Diagnosis of the syndrome should be straightforward
when the four cardinal features of cryptophthalmos, abnormalities of the ear and nose,
syndactyly and urogenital malformations are
present. When cryptophthalmos is the only external abnormality it is important to investigate
the patient for underlying urinary or genital abnormalities. Cryptophthalmos without associated malformations is a completely different,
freestanding pathological entity and has been
reported as an autosomal dominant inheritance pattern.
Treatment options are limited. Therefore,
genetic counseling plays an important role.
When recommended, surgical treatment may
be an appropriate option to correct some of
the malformations associated with this disorder. 
CONCLUSION
The diagnosis of Fraser syndrome can be
made on clinical examination and perinatal autopsy and should be taken into consideration
in patients with a sindromic combination of acrofacial and urogenital malformations with or
without cryptophthalmos. As far as we know
this is the first case diagnosed and reported in
Romania.
FRASER SYNDROME - A CASE REPORT AND REVIEW OF LITERATURE
Conflict of interests: none declared.
Financial support: none declared.
Acknowledgement: We undersigned, certificate that the procedures and the experiments
we have done respect the ethical standards in
the Helsinki Declaration of 1975, as revised in
2000 (5), as well as the national law.
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