cryptophthalmos

Fraser Syndrome 2

Clinical Characteristics
Ocular Features: 

Cryptophthalmos, both unilateral and bilateral, is the ocular hallmark.  The lid margins may be fused.

Systemic Features: 

Multiple systemic malformations are usually present.  A small mouth, nasal dysplasia with hypoplastic alae nasi, and syndactyly may be seen.  Urogenital malformations such as renal dysgenesis or dysplasia, ambiguous genitalia, streak ovaries may be present.  Pulmonary hypoplasia and imperforate anus have been reported.

Genetics

Homozygous mutations in the FREM2 gene (13q13.3) have been identified in Fraser syndrome 2.  

See Fraser syndrome 1 (219000) for additional features that may be present in Fraser syndrome.

Fraser syndrome 3 (617667) results from homozygous mutations in GRIP1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Fraser Syndrome 3

Clinical Characteristics
Ocular Features: 

Cryptophthalmos is always present.  The anterior chamber was described as 'abnormal' in several stillborn male fetuses.

Systemic Features: 

Low-set simple ears were noted in two stillborn fetuses.  Micrognathia and a broad and beaked nose with notched alae nasi were described together with a malformed and atretic larynx.  The fingers and toes may be short and cutaneous syndactyly may be present.  The position of the anus may be abnormal.  The lungs may have abnormal lobulation and appear hyperplastic and hyperechogenic.  The bladder and kidneys may be absent.

Genetics

Homozygous mutations in the GRIP1 gene (12q14.3) have been identified in this autosomal recessive condition.

Fraser syndrome 1 (219000) results from homozygous mutations in the FRAS1 gene.

Fraser syndrome 2 (617666) is caused by homozygous mutations in the FREM2 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mutations in GRIP1 cause Fraser syndrome

Vogel MJ, van Zon P, Brueton L, Gijzen M, van Tuil MC, Cox P, Schanze D, Kariminejad A, Ghaderi-Sohi S, Blair E, Zenker M, Scambler PJ, Ploos van Amstel HK, van Haelst MM. Mutations in GRIP1 cause Fraser syndrome. J Med Genet. 2012 Apr 17. [Epub ahead of print].

PubMed ID: 
22510445

Manitoba Oculotrichoanal Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been completely defined because of the limited number of families reported.    Colobomas, unilateral and bilateral, of the upper eyelids seems to be the most consistent finding. Clinical hypertelorism is also a common finding. Nasolacrimal duct obstruction, unilateral clinical anophthalmia, cryptophthalmos, and a cloudy cornea have also been reported.

Systemic Features: 

The anterior scalp hairline is abnormally low, sometimes extending to the eyebrows.  The anus is anomalous and may be stenotic in some cases.  The nasal tip is often broad and has a notch.  Several patients had omphaloceles.

Genetics

Autosomal recessive inheritance has been assumed as no direct transmission from parent to child has been reported, and most affected individuals (including sibs) have been found in an isolated population of Manitoba Indians with a high rate of consanguinity.  Homozygous deletions of exons 8-23 in FREM1 as well as simple 4bp deletions (9p22.3) have been found in several families confirming the presumed autosomal recessive mode of inheritance.

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Lid colobomas and anal stenosis should be repaired.

References
Article Title: 

Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1

Slavotinek AM, Baranzini SE, Schanze D, Labelle-Dumais C, Short KM, Chao R, Yahyavi M, Bijlsma EK, Chu C, Musone S, Wheatley A, Kwok PY, Marles S, Fryns JP, Maga AM, Hassan MG, Gould DB, Madireddy L, Li C, Cox TC, Smyth I, Chudley AE, Zenker M. Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. J Med Genet. 2011 Jun;48(6):375-82.

PubMed ID: 
21507892

Cryptophthalmos

Clinical Characteristics
Ocular Features: 

It may be that ankyloblepharon occurs in the absence of other abnormalities but in most cases the globes are small and malformed as well.  The combination of upper and lower lid fusion associated with microophthalmia effectively precludes visualization of the globes in many cases, hence the term cryptophthalmos. Lid colobomas may be present in patients with incomplete fusion of the lid margins.  There are often adhesions between the lids and cornea while the anterior chamber may have features of Peters anomaly.  Posterior chamber abnormalities such as optic nerve hypoplasia and retinal dysplasia with other tissues such as bone may also be present.  Rarely patients may respond to bright lights.  The condition may be unilateral or bilateral. The lacrimal drainage system may be malformed or absent while the eyebrows are often missing as well.  In severe cases, the forehead skin appears to be continuous with that of the cheeks.

Cryptophthalmos is also feature of other malformation syndromes most notably that described by Fraser (219000).

Systemic Features: 

The type of cryptophthalmos described here is sometimes called simple or isolated since no systemic malformations are associated.  It should be noted, however, that other ocular abnormalities are almost always associated and the clinical features of the hidden eye are anything but isolated or simple.

Genetics

A small number of families with a vertical pattern of inheritance suggest that at least some cases are inherited in an autosomal dominant pattern but no locus has been identified.  This pattern distinguishes such cases from those with the Fraser cryptophthalmos syndrome (219000) which has an autosomal recessive pattern of inheritance.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Attempts have been made to surgically create a lid fissure but the lack of conjunctival cul de sacs and fusion of the lids to the cornea in many cases can lead to irreparable complications.

References
Article Title: 

Isolated and syndromic cryptophthalmos

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. Review.

PubMed ID: 
3099574

Fraser Syndrome 1

Clinical Characteristics
Ocular Features: 

Cryptophthalmos is the major ocular malformation in Fraser syndrome but is a feature in only 93% of patients.  The globe is often small and sometimes completely absent or in some cases consisting of only rudimentary ocular tissue.  The cornea is often adherent to the eyelid tissue.  The lacrimal ducts may be deformed or absent and the lids are often fused.

Systemic Features: 

The most common malformations seen in this disorder are syndactyly (61.5%), cryptophthalmos (88%), and genitourinary malformations but others of a great variety have also been reported, such as laryngeal stenosis, deafness, and deformities of the nares and external auditory meati.  Ambiguous genitalia occur in 17%.   Some infants are stillborn and many do not survive the neonatal period.  Cognitive deficits and congenital heart disease are common.

Genetics

Fraser syndrome 1 is caused by homozygous or heterozygous mutations in the FRAS1 gene (4q21.21).

Fraser syndrome 2 (617666) results from homozygous mutations in the FREM2 gene (13q13.3).  Parental consanguinity is common (25%) and familial patterns are consistent with autosomal recessive inheritance.

Fraser syndrome 3 (617667) results from homozygous mutations in the GRIP1 gene (12q14.3).  Three consanguineous families have been reported.  

Mutations in GRIP1 (PAD14) (12q14.3) have also been found in 3 families in which the parents were consanguineous.

Isolated cryptophthalmos  (123570) also occurs in autosomal dominant pedigrees as well as sporadically.  It is rarely found as an incidental feature of other syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 
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