Expanded Phenotype of Axenfeld Spectrum: Congenital Hypothyroidism and Glaucoma

Abstract

 

Purpose

 

To report a new familial variant of Axenfeld-Rieger syndrome with anterior chamber abnormalities, congenital glaucoma, congenital hypothyroidism, hearing loss, microcephaly, developmental delay and limb abnormalities.

 

Methods

 

Eight individuals in 3 generations from the same family with specific ocular and systemic characteristics were identified. The subjects underwent clinical examination, blood and genetic testing.

 

Results

 

Eight subjects from this family, belonging to three different generations, presented anterior segment anomalies characteristic of Axenfeld-Rieger’s syndrome: thick anterior displaced Schwalbe’s line, variable degrees of iris atrophy and congenital glaucoma. Five of the family members presented congenital hypothyroidysm, all had microcephaly, four had developmental delay and all eight had minor limb abnormalities (hypoplastic toes and one with severe metatarsus adductus). Four patients had hearing loss. There were also some minor facial abnormalities like flat midface and thin upper lip. All the children in the family had bilateral congenital glaucoma and required multiple glaucoma angle surgeries and glaucoma shunt implants. They presented congenital hypothyroidism, microcephaly and developmental delay. One of the patients underwent genetic testing and had normal karyotype (46, XY) and was negative for mutations in PITX2 and FOXC1. CGH microarray and extensive biomechanical testing including lactate, pyruvate, very long chain fatty acids, amino acids, organic acids, carnitine, acylcarnitine profile and carbohydrate deficient transferring had all negative results. None of the patients had hypodontia or periumbilical abnormalities which are usually seen in individuals with Axenfeld-Rieger type 1 and have PITX2 mutation. None had hydrocephalus, dental or cardiac abnormalities seen in Axenfeld -Rieger type 2, or in Axenfeld-Rieger type 3 with mutations of FOXC1. They were also different than other syndromes with anterior chamber anomalies such as SHORT syndrome or Peter Plus. Table1 shows differences between ARS and this new variant.

 

Conclusions

 

This is a new autosomal dominant variant of Axenfeld-Rieger syndrome, with congenital hypothyroidism, microcephaly, developmental delay, hearing loss and minor limb abnormalities.

 

 

Differences between Axenfekd-Rieger syndrome and the new variant.

 

 

Genetic pedigree of the family and clinical findings.

 

Keywords: 539 genetics • 568 intraocular pressure • 604 mutations