aniridia

Aniridia 3

Clinical Characteristics
Ocular Features: 

One 4-generation Chinese family with 8 affected members has been reported. Complete bilateral iris defects were seen all patients who by 10 years of age also had cataracts.  No corneal opacities were seen.  Two patients were diagnosed with glaucoma.  No fundus abnormalities were reported.

Systemic Features: 

No systemic abnormalities have been reported. 

Genetics

Hereditary aniridia results from a dysfunction of the regulatory gene PAX6.  In aniridia 1 (106210) the PAX6 gene (a transcription regulator) gene itself contains mutations.  In anirdia 2 (617141) the mutation occurs in the ELP4 gene, whose product is a cis-regulatory enhancer of PAX6

Aniridia 3 results from heterozygous mutations in the TRIM44 gene (11p13).  The TRIM44 gene is a negative regulator which normally suppresses the expression of PAX6 and the reported missense mutation (p.G155R) enhances its activity.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical removal of cataracts and glaucoma treatment may be of benefit.

Aniridia 2

Clinical Characteristics
Ocular Features: 

A 17-year-old male with this condition was diagnosed at the age of two years with bilateral iris hypoplasia.  Cataracts were seen at the age of 17 years.  There was no foveal depression.

In a 5 generation Chinese family there were additional signs including optic atrophy, ectopia lentis, pigmentary retinopathy, and 'dysplasia' of the trabecular meshwork in 5 members.

Systemic Features: 

No systemic abnormalities have been reported.  A single extensively studied patient, who had no developmental problems, was normal by renal ultrasound, audiometric studies, and neurologic evaluations.

Genetics

Autosomal dominant aniridia is the result of PAX6 (a transcription regulator gene) dysfunction.  In the majority of cases there are mutations in the PAX6 gene itself as in AN1.  There are reports, however, of familial aniridia in which direct PAX6 mutations have been excluded.  Two additional forms of aniridia in which there are alterations in genes that modulate the expression of PAX6 have been reported.  AN2 described here with mutations in ELP4 (a nucleotide variant within an intron of the ELP4 gene (11p13) located distal to the 3-prime end of the PAX6 gene, plus AN3 (617142) with mutations in TRIM44.  Both ELP4 and TRIM44 are regulators of the PAX6 transcription gene.

Aniridia 2 has been reported in one patient with a nucleotide variant within an intron of the ELP4 gene (11p13) located distal to the 3-prime end of the PAX6 gene.  The gene product is a cis-regulatory enhancer.  

Other evidence for aniridia resulting from regulatory modification of PAX6 gene function comes from families in which there are structural alterations such as deletions in chromosome 11, downstream of the PAX6 gene location.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment has not been reported.

References
Article Title: 

Gracile Bone Dysplasia

Clinical Characteristics
Ocular Features: 

The eyes have been described as small.  Aniridia may be present.

Systemic Features: 

This is a usually fatal form of skeletal dysplasia with splenic and ocular features as well.  In utero death is not uncommon while newborns may not survive the neonatal period.  The face has been described as dysmorphic with a high forehead, flat nasal bridge, a cloverleaf-shaped skull, and hypoplastic cranial bones with premature suture closure.  The long bones are dysplastic as well with thinned diaphyses (sometimes fractured in utero), growth plate disorganization, excessive remodeling, and signs of arrested growth.  The ribs share in the dysplasia but pulmonary hypoplasia has also been described.  Most individuals have short limbs.

The spleen can be hypoplastic or aplastic and ascites has been noted in several infants.  Failure to thrive is common and seizures have been reported.  Males may have micropenis and hypospadias while females have been described with labial fusion.  

Low parathyroid hormone levels and hypocalcemia has been reported in most individuals.

Genetics

Heterozygous mutations in the FAM111A gene (11q12.1) have been associated with this disorder.  The functional role of FAM111A products is unknown but likely play a role in calcium metabolism, parathyroid hormone secretion, and osseous development.

Mutations in the same gene can be responsible for the allelic autosomal dominant Kenny-Caffey syndrome (127000) with some similar features.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

FAM111A mutations result in hypoparathyroidism and impaired skeletal development

Unger S, Gorna MW, Le Bechec A, Do Vale-Pereira S, Bedeschi MF, Geiberger S, Grigelioniene G, Horemuzova E, Lalatta F, Lausch E, Magnani C, Nampoothiri S, Nishimura G, Petrella D, Rojas-Ringeling F, Utsunomiya A, Zabel B, Pradervand S, Harshman K, Campos-Xavier B, Bonafe L, Superti-Furga G, Stevenson B, Superti-Furga A. FAM111A mutations result in hypoparathyroidism and impaired skeletal development. Am J Hum Genet. 2013 Jun 6;92(6):990-5.

PubMed ID: 
23684011

Gillespie Syndrome

Clinical Characteristics
Ocular Features: 

Bilateral aniridia, partial or complete, is the ocular characteristic of Gillespie syndrome.  The iris may be relatively intact but immobile leading to the description in some patients of "dilated and fixed pupils", or congenital mydriasis.  The pupillary margin may be scalloped with iris strands to the lens.  The pupillary sphincter is sometimes absent and the mesodermal surface missing.  The fovea sometimes appears hypoplastic and some patients have decreased visual acuity.  Strabismus and ptosis are often present.  There may also be retinal hypopigmentation.  Cataract, glaucoma, and corneal opacities are not present. 

Systemic Features: 

Most patients have some degree of developmental delay ranging from difficulties with fine motor tasks to frank mental retardation.  Many have a hand tremor, some degree of hypotonia, and learning difficulties.  MRI imaging often shows cerebellar and sometimes cerebral hypoplasia. 

Genetics

This is an autosomal dominant disorder usually due to a heterozygous mutation in the PAX6 gene (11p13).  However, some patients with typical features do not have a mutation in this gene suggesting that there is genetic heterogeneity.  Some patients without point mutations nevertheless have defects in adjacent DNA suggesting a positional effect.  The possibility of autosomal recessive inheritance in some families with parental consanguinity cannot be ruled out.  The PAX6 gene plays an important role in iris development as it is also mutant in simple aniridia (106210) and in Peters anomaly (604229).

Mutations in the ITPR1 gene have also been identified in Gillespie syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Identification of novel and hotspot mutations in the channel domain of ITPR1 in two patients with Gillespie syndrome

Dentici ML, Barresi S, Nardella M, Bellacchio E, Alfieri P, Bruselles A, Pantaleoni F, Danieli A, Iarossi G, Cappa M, Bertini E, Tartaglia M, Zanni G. Identification of novel and hotspot mutations in the channel domain of ITPR1 in two patients with Gillespie syndrome. Gene. 2017 Jul 8. pii: S0378-1119(17)30530-9. doi: 10.1016/j.gene.2017.07.017. [Epub ahead of print]

PubMed ID: 
28698159
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