Paula and Bobby
Parents of Lillie
What is Fraser syndrome?
Fraser syndrome is a rare disease. It is also known as Cryptophthalmos syndrome Cryptophthalmos With Other Malformations.
This is a variable syndrome, to the extent that cryptophthalmos might not be present in all cases. However, the main features are a "hidden eye", syndactyly and abnormal genitalia. The cryptophthalmos might be bilateral, unilateral or asymmetrical. Pankau et al., (1994) reported a probable case with anophthalmia. Usually the globe is present under the fused eyelids. Cryptophthalmos is frequently accompanied by an absence of eyebrows and eyelashes, and the covering skin might extend from the forehead to the cheeks. A tongue of hair can extend from the anterior hairline to the outer margin of the orbit. The nose is broad, with a flat bridge, and may have a groove at the tip or a coloboma of the nares. The external ear may be malformed or low-set. Stenosis of the external auditory meatus should be sought. Laryngeal stenosis, renal agenesis, and genital abnormalities (hypospadias, clitoromegaly) are common. Andiran et al., (1999) reported a male case with anterior urethral atresia. Stevens et al., (1994) reported sibs with pulmonary hyperplasia. The syndactyly involves only skin. Mental retardation occurs in 80% of survivors. Cryptophthalmos may also occur without other malformations - see Ghose et al., (1988) for a general review. Fryns et al., (1997) report prenatal diagnosis by ultrasound scans in the 2nd trimester of pregnancy. Berg et al., (2001) report a case of Fraser syndrome diagnosed at 16 weeks gestation by ultrasound and review other cases detected by ultrasound from the literature.
There is possible homology to mouse "bleb" mutants (Winter, 1990; Darling and Gossler, 1994). In these mice blebs occur early in development and appear to interfere mechanically with the development of eyelids and limb buds - renal agenesis is also seen. A patient with an orbito-palpebral cyst was reported by Amrith et al., (2003). Shrestha et al., (2012) reported a case with upper lid colobomata and partial symblepharon of the lower lid.
McGregor et al., (2003) mapped the gene to 4q21 in consanguineous pedigrees although the condition appeared to be genetically heterogeneous. Mutation analysis identified five frameshift mutations in a gene FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM.
Slavotinek and Tifft (2002) provide an excellent and exhaustive review of the clinical features.
A second gene, FREM2 has now been identified as being involved, and 2 patients homozygous for missense mutations in that gene, were reported by Jadeja et al., (2005). The gene was located at 13q13 and 1 of the families involved was of Spanish Gypsy origin, whereas the other although French, had a family name that might have come from the same Gypsy popuation. An Iranian family with a homozygous FREM2 mutation was reported by Shafeghati et al., (2008).
Note the sib-pair reported by Cavalcanti et al., (2007). One was phenotypically AMS whereas the other had Fraser syndrome. Both were homozygous for the FRAS1 mutation, and the authors suggest that AMS might be in the phenotypic spectrum of Fraser syndrome. Mutations in GRIP1 cause the same condition (Schanze et al., 2014)
Nayak et al. (2016) reported a severe brachydactyly of all the digits of upper and lower limbs in a consanguineous family with three fetuses affected with Fraser syndrome.
* This information is courtesy of the L M D.
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What gene changes cause Fraser syndrome?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 219000 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
FRAS1 - 4q21.21
GRIP1 - 12q14.3
FREM2 - 13q13.3
What are the main symptoms of Fraser syndrome?
The typical symptoms of the syndrome are:
Opacification of the corneal stroma, Visual impairment, Hypospadias, Hydrocephalus, Hypertelorism, Cognitive impairment, Depressed nasal bridge, Underdeveloped nasal alae, Bicornuate uterus, Hypoplastic superior helix, Hypoplasia of penis, Aplasia/Hypoplasia of the thumb, Aplasia/Hypoplasia of the sternum, Aplasia/Hypoplasia of the phalanges of the hand, Aplasia/Hypoplasia of the lungs, Aplasia/Hypoplasia affecting the eye, Wide nose, Wide nasal bridge, Malformed lacrimal duct, Absent eyebrow, Ambiguous genitalia, Cleft ala nasi, Cleft palate, Choanal stenosis, Abnormal vagina morphology, Abnormal umbilicus morphology, Abnormality of the thymus, Abnormality of the pinna, Abnormality of pelvic girdle bone morphology, Abnormality of the dentition, Abnormality of the small intestine, Abnormality of the palpebral fissures, Abnormal palate morphology, Abnormal nipple morphology, Bifid tongue, Bilateral microphthalmos, Blindness, Abnormality of the larynx, Abnormality of the anus, Lacrimation abnormality, Abnormal
How does someone get tested for Fraser syndrome?
The initial testing for Fraser syndrome can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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