Heterogeneity in phenotype of usher-congenital hyperinsulinism syndrome: hearing loss, retinitis pigmentosa, and hyperinsulinemic hypoglycemia ranging from severe to mild with conversion to diabetes.

OBJECTIVE: To evaluate the phenotype of 15 children with congenital hyperinsulinism (CHI) and profound hearing loss, known as Homozygous 11p15-p14 Deletion syndrome (MIM #606528). RESEARCH DESIGN AND METHODS: Prospective clinical follow-up and genetic analysis by direct sequencing, multiplex ligation-dependent probe amplification, and microsatellite markers. RESULTS: Genetic testing identified the previous described homozygous deletion in 11p15, USH1C:c.(90+592)_ABCC8:c.(2694-528)del. Fourteen patients had severe CHI demanding near-total pancreatectomy. In one patient with mild, transient neonatal hypoglycemia and nonautoimmune diabetes at age 11 years, no additional mutations were found in HNF1A, HNF4A, GCK, INS, and INSR. Retinitis pigmentosa was found in two patients aged 9 and 13 years. No patients had enteropathy or renal tubular defects. Neuromotor development ranged from normal to severe delay with epilepsy. CONCLUSIONS: The phenotype of Homozygous 11p15-p14 Deletion syndrome, or Usher-CHI syndrome, includes any severity of neonatal-onset CHI and severe, sensorineural hearing loss. Retinitis pigmentosa and nonautoimmune diabetes may occur in adolescence.

Mutation of the CYP2R1 vitamin D 25-hydroxylase in a Saudi Arabian family with severe vitamin D deficiency.

CONTEXT: Inherited forms of vitamin D deficiency are rare causes of rickets and to date have been traced to mutations in three genes, VDR, encoding the 1α,25-dihydroxyvitamin D receptor, CYP27B1, encoding the vitamin D 1α-hydroxylase, and CYP2R1, encoding a microsomal vitamin D 25-hydroxylase. RESULTS: Multiple mutations have been identified in VDR and CYP27B1 in patients with rickets, and thus, the roles of these two genes in vitamin D metabolism are unassailable. The case is less clear for CYP2R1, in which only a single mutation, L99P in exon 2 of the gene, has been identified in Nigerian families, and because multiple enzymes with vitamin D 25-hydroxylase activity have been identified. Here we report molecular genetic studies on two siblings from a Saudi family who presented with classic symptoms of vitamin D deficiency. The affected offspring inherited two different CYP2R1 mutations (367+1, G→A; 768, iT), which are predicted to specify null alleles. CONCLUSION: We conclude that CYP2R1 is a major vitamin D 25-hydroxylase that plays a fundamental role in activation of this essential vitamin.

The syndrome of septo-optic dysplasia in Saudi children.

OBJECTIVE: To describe the clinical, ophthalmological, endocrinological and radiological features of 10 Saudi children with the syndrome of septo-optic dysplasia and hypothalamic hypopituitarism. METHODS: All patients underwent complete ophthalmological and endocrinological evaluation at the Pediatric Endocrine Clinics, King Faisal Specialist Hospital and Research Center and King Fahad National Guard Hospital, Riyadh, Kingdom of Saudi Arabia, from October 1999 through to May 2004. The hormonal evaluation included growth hormone, adrenocorticotrophic hormone, thyroid stimulating hormone, gonadotropin and anti diuretic hormone testing, and the neuroradiological assessment included brain magnetic resonance imaging or computed tomogram scanning, or both. RESULTS: The current age of patients ranged from 18- months to 5-years. The mean age of initial presentation for endocrine evaluation was 14-months. Hormonal studies indicated that all children had multiple pituitary hormone deficiencies (2 or more of the pituitary hormones were deficient). Ten children had growth hormone deficiency, 8 had thyroid stimulating hormone deficiency, 8 had adrenocorticotrophic hormone deficiency, 2 children were suspected to have gonadotropin deficiency and central diabetes insipidus was present in one patient. Pendular nystagmus and impaired vision were common initial signs. All children had bilateral optic nerve hypoplasia. Neuroradiologic findings were variable. Eight children had absent septum pellucidum, 3 had pituitary gland hypoplasia, 2 had pituitary stalk dysplasia (pituitary stalk was either attenuated or not visualized), 2 had absent corpus callosum and one had absent posterior pituitary high intensity signal. All patients were replaced with appropriate hormonal replacement therapy. Two male children had micropenis which responded to testosterone therapy. CONCLUSION: The syndrome of septo-optic dysplasia is commonly associated with hypothalamic hypopituitarism including anterior and posterior pituitary hormonal deficiencies. Early diagnosis of this syndrome is critical as the hormonal deficiencies can be life threatening.