anophthalmia

Branchiooculofacial Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmos, or anophthalmia, and an imperforate nasolacrimal duct are the primary ocular features in this syndrome.  The nasolacrimal ducts may open onto the skin adjacent to the lacrimal sac.  Uveal tract and optic nerve colobomas are present in nearly half of patients. Strabismus is sometimes seen.  Cataracts are present in about 25% of patients as well.  The lid fissures are often slanted upwards.

Systemic Features: 

A cleft lip and/or palate are common features.  There may be preauricular pits, lip pits, a highly arched palate, and hypodontia.  Some individuals have subcutaneous cysts in the scalp.  Postauricular cervical branchial and supraauricular defects are often present as well.  It is not unusual to see some skin discoloration behind the ears.  The nasal bridge is broad, the top of the nose is flattened, and the philtrum is often short.  The ears are often enlarged or malformed and in 70% of patients there is some hearing loss which is usually conductive in origin but neurosensory deafness has also been documented.  Premature graying of hair is common.  Kidney malformations and dysfunction have been documented.  Mental function is usually normal.  Preaxial polydactyly is an uncommon feature.

Genetics

This is an autosomal dominant disorder resulting from mutations in the TFAP2A gene (6p34.3).  Both deletions and insertions have been identified.  However, 50-60% of patients have de novo mutations.  As in many autosomal dominant disorders there is considerable clinical heterogeneity and few patients have all of the signs.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment requires a multidisciplinary approach with oculoplastic, ophthalmic, and ENT surgeons.  Physical, speech, hearing, and learning specialists can be helpful.

References
Article Title: 

Further delineation of the branchio-oculo-facial syndrome

Lin AE, Gorlin RJ, Lurie IW, Brunner HG, van der Burgt I, Naumchik IV, Rumyantseva NV, Stengel-Rutkowski S, Rosenbaum K, Meinecke P, et al. Further delineation of the branchio-oculo-facial syndrome. Am J Med Genet. 1995 Mar 13;56(1):42-59. Review.

PubMed ID: 
7747785

Microphthalmia with Limb Anomalies

Clinical Characteristics
Ocular Features: 

Patients have either microphthalmia or anophthalmia which may be present unilaterally or bilaterally.  The MRI in several patients has revealed complete absence of the globes, optic nerves, chiasm, and optic tracts.  The eyelashes are often sparse with shortened palpebral fissures and broad lateral eyebrows.

Systemic Features: 

Global developmental delays, failure to thrive, and mild to moderate mental retardation are common.   Syndactyly, polydactyly, and oligodactyly with hypoplasia of the long bones are present to a variable degree.  Synostosis in the digits, ankles, and wrist is often seen.  A split hand (lobster-claw deformity) is variably present.  Other anomalies such as the kidneys (horseshoe kidney), undescended testes, anomalous venous circulation and deformed vertebrae have been reported.  The midface is often flattened.  A high palate, cleft lip, and mild scoliosis may be seen.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the SMOC1 gene (14q24.2) but there is some evidence of genetic heterogeneity as the disorder has been mapped to 10p11.23 in several families.  However, no causative mutations were found in this region.  Consanguinity among parents is common.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment in most cases for the ocular malformations.  Some of the limb anomalies may be surgically correctable.

References
Article Title: 

SMOC1 is essential for ocular and limb development in humans and mice

Okada I, Hamanoue H, Terada K, Tohma T, Megarbane A, Chouery E, Abou-Ghoch J, Jalkh N, Cogulu O, Ozkinay F, Horie K, Takeda J, Furuichi T, Ikegawa S, Nishiyama K, Miyatake S, Nishimura A, Mizuguchi T, Niikawa N, Hirahara F, Kaname T, Yoshiura K, Tsurusaki Y, Doi H, Miyake N, Furukawa T, Matsumoto N, Saitsu H. SMOC1 is essential for ocular and limb development in humans and mice. Am J Hum Genet. 2011 Jan 7;88(1):30-41.

PubMed ID: 
21194678

A locus for ophthalmo-acromelic syndrome mapped to 10p11.23

Hamanoue H, Megarbane A, Tohma T, Nishimura A, Mizuguchi T, Saitsu H, Sakai H, Miura S, Toda T, Miyake N, Niikawa N, Yoshiura K, Hirahara F, Matsumoto N. A locus for ophthalmo-acromelic syndrome mapped to 10p11.23. Am J Med Genet A. 2009 Mar;149A(3):336-42.

PubMed ID: 
19208380

Microphthalmia, Syndromic 9

Clinical Characteristics
Ocular Features: 

Both microphthalmia and clinical anophthalmia have been described in this syndrome.  However, autopsy has shown true anophthalmia in a few cases who were stillborn or died in the neonatal period.  At least one eye can be cystic. The optic nerves are often hypoplastic and may be absent.  High, upward-arching eyebrows may be seen.

Systemic Features: 

An early manifestation of this disorder is neonatal pulmonary distress.  The lungs are usually hypoplastic or malformed. Cardiac malformations such as patent ductus arteriosus, septal and valvular defects, tetralogy of Fallot, and single ventricles are often present.  Diaphragmatic hernias or defects are common but hiatal hernias and frank eventration of abdominal contents have also been reported.  Renal anomalies and intrauterine growth retardation have been noted.         

Some infants have micrognathia, low-set ears, a broad nasal bridge, brachycephaly, and midline clefts of the palate.  Cerebral malformations are seldom present.

Genetics

Homozygous mutations in the STRA6 gene (15q24.1) have been found in a few cases which suggests autosomal recessive inheritance.  Parental consanguinity has been reported in some families.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at the repair of the organ defects in selected cases that have survival potential.   Survival rates are poor but those less severely affected may live for a decade.

References
Article Title: 

The PDAC syndrome (pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect) (Spear syndrome, Matthew-Wood syndrome): report of eight cases including a living child and further evidence for autosomal

Chitayat D, Sroka H, Keating S, Colby RS, Ryan G, Toi A, Blaser S, Viero S, Devisme L, Boute-B?(c)n?(c)jean O, Manouvrier-Hanu S, Mortier G, Loeys B, Rauch A, Bitoun P. The PDAC syndrome (pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect) (Spear syndrome, Matthew-Wood syndrome): report of eight cases including a living child and further evidence for autosomal recessive inheritance. Am J Med Genet A. 2007 Jun 15;143A(12):1268-81.

PubMed ID: 
17506106

Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation

Pasutto F, Sticht H, Hammersen G, Gillessen-Kaesbach G, Fitzpatrick DR, N?ornberg G, Brasch F, Schirmer-Zimmermann H, Tolmie JL, Chitayat D, Houge G, Fern?degndez-Mart??nez L, Keating S, Mortier G, Hennekam RC, von der Wense A, Slavotinek A, Meinecke P, Bitoun P, Becker C, N?ornberg P, Reis A, Rauch A. Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. Am J Hum Genet. 2007 Mar;80(3):550-60.

PubMed ID: 
17273977

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
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