Clinical Characteristics
Ocular Features
This rare malformation syndrome affects primarily the eyes and ears. The globes are small and usually have colobomas of both anterior and posterior segments. The corneas likewise are small and often have opacities. The anterior segment is dysplastic with anterior and/or posterior synechiae. Glaucoma may be present. The lenses may be small and often become cataractous. There is a progressive rod-cone dystrophy associated with a pigmentary retinopathy. Chorioretinal lacunae have been seen in the equatorial region. The retinal degeneration is progressive, beginning with rod dysfunction but followed by deterioration of all receptors. The onset in early childhood results in poor vision and nystagmus.
Systemic Features
The external ears are abnormal. The earlobes may have colobomas or may be aplastic. The intertragic notch is often underdeveloped. Audiograms and vestibular function tests, however, show normal function and MRI of the middle and inner ears likewise reveals no anatomic abnormalities.
Among the few patients reported, dental anomalies, spina bifida oculta, and mild dyscrania have been noted in individual patients.
Genetics
Inheritance
This rare disorder has been reported in only a few families. Based on parental consanguinity and homozygosity of mutations in the HMX1 gene (4p16.1) in affected sibs, this is an autosomal recessive disorder. In one family there was a homozygous 26 bp deletion and in another a homozygous missense mutation. The parents are heterozygous for the deletion.
HMX1 is a homeobox gene and the deletion abolishes its function by establishing a stop codon at position 112.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.