Doris Taha

Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism

We recently described a new neonatal diabetes syndrome associated with congenital hypothyroidism, congenital glaucoma, hepatic fibrosis and polycystic kidneys. Here, we show that this syndrome results from mutations in GLIS3, encoding GLI similar 3, a recently identified transcription factor. In the original family, we identified a frameshift mutation predicted to result in a truncated protein. In two other families with an incomplete syndrome, we found that affected individuals harbor deletions affecting the 11 or 12 5′-most exons of the gene. The absence of a major transcript in the pancreas and thyroid (deletions from both families) and an eye-specific transcript (deletion from one family), together with residual expression of some GLIS3 transcripts, seems to explain the incomplete clinical manifestations in these individuals. GLIS3 is expressed in the pancreas from early developmental stages, with greater expression in β cells than in other pancreatic tissues. These results demonstrate a major role for GLIS3 in the development of pancreatic β cells and the thyroid, eye, liver and kidney.

Neonatal diabetes mellitus, congenital hypothyroidism, hepatic fibrosis, polycystic kidneys, and congenital glaucoma: A new autosomal recessive syndrome?

We report on two sibs (of 4) with a syndrome of minor facial anomalies, proportionate IUGR, neonatal non‐autoimmune diabetes mellitus (NDM), severe congenital hypothyroidism (CH), cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by large kidneys and multiple small cysts with deficient corticomedullary junction differentiation and normal kidney function. The phenotype observed in the two sibs was identical. Although a combination of liver, kidney, and pancreatic involvement has been described in Ivemark syndrome (hepato‐renal‐pancreatic syndrome), the coexistence of NDM, CH, and glaucoma in both sibs suggests the possibility that this combination of manifestations describes a new autosomal recessive syndrome. Mutation analysis for several candidate genes is warranted.

Association of migraine‐like headaches with Schimke immuno‐osseous dysplasia

Schimke immuno‐osseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia, nephropathy, and T‐cell deficiency. SIOD is caused by mutations in the putative chromatin remodeling protein SMARCAL1. We report an 8‐year‐old boy with SIOD and recurrent, severe, refractory migraine‐like headaches. Through a retrospective questionnaire‐based study, we found that refractory and severely disabling migraine‐like headaches occur in nearly half of SIOD patients. We have also found that the vasodilator minoxidil provided symptomatic relief for one patient. We hypothesize that these headaches may arise from an intrinsic vascular, neuroimmune, or neurovascular defect resulting from loss of SMARCAL1 function.

Absent or delayed adrenarche in Pit-1/POU1F1 deficiency.

Mutations of the PIT1/POU1F1 gene are responsible for a rare variant of anterior hypopituitarism, including deficiency of growth hormone, prolactin and thyrotropin. In 8 ethnically diverse POU1F1-deficient patients (4 different mutations) with normal circulating levels of cortisol and adrenocorticotropic hormone, and with spontaneous onset and progression of puberty, we observed an absence or delay of adrenarche (median circulating dehydroepiandrosterone-sulfate –6.2 SD); in each of the 4 postmenarcheal females, pubarche (i.e. appearance of pubic hair) was also absent or delayed. The absence/delay of adrenarche in POU1F1-deficient patients and the absence/delay of pubarche in POU1F1-deficient females suggest that a POU1F1-dependent factor contributes to the normal development of adrenarche and female pubarche.

Arthrogryposis, renal tubular acidosis and cholestasis (ARC) syndrome: two new cases and review.

ARC syndrome, the association of arthrogryposis, renal tubular dysfunction and cholestasis, is a rare genetic disorder. We report two Saudi infants from two different families with ARC syndrome. Magnetic resonance imaging of the brain of one of the infants showed lissencephaly, a previously unreported finding in this syndrome. We also review 39 ARC cases reported in the literature using the Medline database from January 1966 to September 2004.

The prevalence of metabolic syndrome and cardiovascular risk factors in a group of obese Saudi children and adolescents: a hospital-based study.

Background and Objectives: We assessed the distribution of risk factors associated with the metabolic syndrome in a group of obese Saudi children and adolescents. No previous studies had addressed this issue in the Saudi pediatric population. Subjects and Methods: We retrospectively reviewed the medical records of patients evaluated for obesity between 2004 and 2008 and collected data on age, weight, height, body mass index (BMI), BP, fasting lipid profile, fasting glucose, insulin concentrations, and insulin resistance based on the homeostasis assessment model-insulin resistance (HOMA-IR) score. Obesity was defined as a BMI above the 95th percentile for age and gender and metabolic syndrome was diagnosed according to standard criteria. Results: We studied 57 obese Saudi children and adolescents with a mean (standard deviation) age of 9.8 (3.5) years. Mean weight and body mass index (BMI) were 63.7 (28.3) kg and 31.6 (8.0) kg/m 2 , respectively. Systolic BP was elevated in 24 (42%) of the 57 subjects. Of the 39 children who had a lipid profile in their records, 10 had hypertriglyceridemia, 8 had hypercholesterolemia, 6 had elevated LDL cholesterol levels, and 6 had low HDL cholesterol levels. Impaired fasting glucose was found in 10 of 38 patients in which it was measured, and 9 of 25 patients had fasting hyperinsulinemia. Eleven of 37 patients (29.7%) met the diagnosis of the metabolic syndrome. Diastolic BP correlated positively with BMI (r=0.440, P =.001), and HDL cholesterol correlated negatively with weight and BMI (r=-0.487, P =.002 and r=-0.317, P =.05). HOMA-IR correlated positively with BMI and triglyceride levels and negatively with HDL cholesterol levels. Conclusions: Obese Saudi children and adolescents have multiple risk factors associated with metabolic syndrome.

Schimke immunoosseous dysplasia: defining skeletal features

Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by prominent spondyloepiphyseal dysplasia, T cell deficiency, and focal segmental glomerulosclerosis. Biallelic mutations in swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD, but approximately half of patients referred for molecular studies do not have detectable mutations in SMARCAL1. We hypothesized that skeletal features distinguish between those with or without SMARCAL1 mutations. Therefore, we analyzed the skeletal radiographs of 22 patients with and 11 without detectable SMARCAL1 mutations. We found that patients with SMARCAL1 mutations have a spondyloepiphyseal dysplasia (SED) essentially limited to the spine, pelvis, capital femoral epiphyses, and possibly the sella turcica, whereas the hands and other long bones are basically normal. Additionally, we found that several of the adolescent and young adult patients developed osteoporosis and coxarthrosis. Of the 11 patients without detectable SMARCAL1 mutations, seven had a SED indistinguishable from patients with SMARCAL1 mutations. We conclude therefore that SED is a feature of patients with SMARCAL1 mutations and that skeletal features do not distinguish who of those with SED have SMARCAL1 mutations.

Nephrocalcinosis in glucose-galactose malabsorption, association with renal tubular acidosis

We report an association of renal tubular acidosis (RTA) in two children with glucose-galactose malabsorption (GGM), who were found to have nephrocalcinosis. Although GGM has been reported previously with nephrocalcinosis, this report is the first to show that renal tubular acidosis could explain the coexistence of nephrocalcinosis in patients with glucose galactose malabsorption.

A novel VPS33B mutation in an ARC syndrome patient presenting with osteopenia and fractures at birth.

Doris Taha,* Amina Khider, Andrew R. Cullinane, and Paul Gissen Division of Pediatric Endocrinology, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre-Jeddah, Kingdom of Saudi Arabia Department of Pediatrics, King Faisal Specialist Hospital and Research Centre-Jeddah, Kingdom of Saudi Arabia Section of Medical and Molecular Genetics, University of Birmingham, Edgbaston, Birmingham, UK

Fatal lymphoproliferative disorder in a child with Schimke immuno-osseous dysplasia

Schimke immuno‐osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, nephrotic syndrome, and cell‐mediated immunodeficiency. Mutations in the SMARCAL1 gene (SW1/SNF2‐related, matrix‐associated, actin‐dependent regulator of chromatin, subfamily a‐like1) cause SIOD. We report a patient with SIOD and SMARCAL1 mutations, who presented with fever of unknown origin secondary to B‐cell lymphoma. To our knowledge, this is the first report of an SIOD patient with a primary lymphoproliferative disorder (LPD).