We present a mildly affected girl with de novo dup(17)(p11.2p11.2). The patient was evaluated because of minor anomalies noted during a hospitalization for nonrecurrent tonic-clonic seizures associated with transient hypoglycemia. She also had unilateral renal hypoplasia and relative short stature, but at 2 years of age, she scored within the low normal range on neurodevelopmental examinations. Compared with other similar duplications, this patient represents the milder range of the spectrum for this karyotypic abnormality. Am. J. Med. Genet. 94:296-299, 2000.

We describe the phenotype of a 5 year old girl with features resembling Temtamy syndrome, including agenesis of the corpus callosum, ventriculomegaly, frontal bossing, peaked eyebrows, ptosis, malformed and low set ears, a depressed nasal bridge, a long philtrum, and iris and chorioretinal colobomas. Features unique to this child include profound mental retardation, bilateral sensorineural hearing loss, agenesis of the corpus callosum, patent ductus arteriosus, ventricular septal defect, unilateral renal agenesis, neurogenic bladder and hydronephrosis. High resolution chromosome analysis demonstrated a de novo, balanced translocation [46,XX,t(2;9)(p24;q32)]; and her case has some overlapping phenotypic features with cases of monosomy for 2p. This is the first documented case of Temtamy syndrome with a specific chromosomal anomaly, and will assist with the elucidation of the syndrome's underlying genetic defect.

Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta (RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period (n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans.