When evaluated by us, the propositus was a 4-year-old Caucasian male with prenatally-diagnosed trisomy 21. He was initially diagnosed as having lobar holoprosencephaly. His complex medical history additionally included bilateral microophthalmia, choanal atresia, severe developmental delay, and renal dysplasia with recurrent urinary tract infections. Evidence for hypopituitarism included central hypothyroidism, secondary adrenal insufficiency, and a history of cryptorchidism and micropenis (now status-post testosterone treatment) making gonadotropin deficiency likely. He had neonatal-onset insulin-dependent diabetes mellitus which was very difficult to control, but abdominal MRI revealed no pancreatic anomalies.
Review of the propositus's brain MRI showed structural abnormalities not consistent with holoprosencephaly because of the lack of hemispheric fusion, but included multiple anomalies including agenesis of the corpus callosum, midline interhemispheric cyst, hypoplastic pons and vermis (absent inferiorly), possible Dandy-Walker malformation, dysplastic tectum, pituitary and hypothalamic hypoplasia, and a globular (though not fused) basal ganglia. The thalamic nuclei were well-separated by a large third ventricle. Microcephaly and asymmetric microophthalmia were also evident ().
Figure 1 Propositus with compound heterozygosity for mutations in PAX6. Facial features were consistent with trisomy 21, and were also notable for extreme microcephaly, microophthalmia, and a smooth philtrum. Axial, coronal, and sagittal (from top) brain MRI demonstrates (more ...)
On physical examination, the child displayed physical features consistent with his diagnosis of trisomy 21, as well as bilateral severe microophthalmia, extreme microcephaly (head circumference 50th centile for a 1-month-old with Down syndrome), and a smooth philtrum ().
The propositus's mother had a history of aniridia, but reported no other medical problems. She had an extensive family history of autosomal dominant aniridia, though no previous genetic study had been initiated (). On physical examination, no extraocular anomalies were appreciated. Ophthalmological examination showed bilateral aniridia, glaucoma, and corneal opacifications, as well as a dense cataract in the right eye (). While she had not been previously diagnosed with diabetes, she had an elevated fasting glucose on our evaluation.
Photos of parents' ocular findings (mother on left, father on right).
The propositus's father reported a history of cataracts in early childhood and eventual blindness, as well as hearing loss. He also had an extensive family history of similar visual problems and hearing loss (). On examination, he had a high palate and dental crowding in addition to ocular anomalies. Ophthalmological examination showed bilateral microcornea, a right eye cataract, and left aphakia (absent lens) (). He also had subtle iris hyoplasia and corectopia.
The propositus's brother, on whom DNA was not available for testing, was described as having very similar structural brain anomalies to the propositus. He additionally had neonatal diabetes mellitus and anophthalmia, and died in infancy.