Publications by authors named "Doris Taha"

24 Publications

  • Page 1 of 1

Familial neonatal nonautoimmune hyperthyroidism due to a gain-of-function (D619G) thyrotropin-receptor mutation.

J Pediatr Endocrinol Metab 2021 Feb 13;34(2):267-271. Epub 2020 Nov 13.

Division of Genetic, Metabolic and Genomic Disorders, Central Michigan University College of Medicine, Children's Hospital of Michigan, Detroit, MI, USA.

Objectives: Activating germline mutations of the thyroid-stimulating hormone receptor (TSHR) are responsible for a rare form of neonatal nonautoimmune hyperthyroidism (NAH). We report the first case of familial neonatal neonatal nonautoimmune associated with c.1856A>G (p.Asp619Gly) variant in the TSHR gene.

Case Presentation: We describe an eight-year-old African-American female presenting with neonatal NAH associated with an inherited heterozygous c.1856A>G (p.Asp619Gly) variant in the TSHR gene. This variant was previously described in one patient presenting with sporadic NAH in adolescence. Our patient was diagnosed with hyperthyroidism in the neonatal period. The mother had a history of hyperthyroidism and had thyroidectomy at the age of 4 years. The patient had goiter and elevated free thyroxine (FT4) and free triiodothyronine (FT3) levels that normalized with methimazole treatment; however, TSH level remained suppressed. Thyroid antibodies were negative. The patient also had bilateral exotropia, a trait shared by the mother and may represent a new association.

Conclusions: Familial neonatal NAH is associated with heterozygous c.1856A>G (p.Asp619Gly) variant of the TSHR gene.
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http://dx.doi.org/10.1515/jpem-2020-0291DOI Listing
February 2021

A Case of Congenital Hypopituitarism Associated With a 1p31 Microdeletion: A Possible Role for and .

J Endocr Soc 2017 Apr 28;1(4):278-282. Epub 2017 Feb 28.

Division of Genetic, Genomic, and Metabolic Disorders, Children's Hospital of Michigan.

Context: Genetic defects affecting the expression and function of factors involved in pituitary development have been found to be associated with congenital hypopituitarism (CH). However, for most cases of CH, the etiology remains unknown.

Case Description: We present an unusual case of an infant with CH, associated with septo-optic dysplasia with an absent anterior pituitary and an ectopic posterior pituitary gland, resulting from a 8.04-Mb interstitial deletion of chromosome 1p31.1-1p31.3. The deleted region includes several genes that might be involved in pituitary development, including and .

Conclusions: Haploinsufficiency of and/or might be associated with CH. This finding suggests a role for -mediated glycoprotein 130 signaling in human pituitary development.
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http://dx.doi.org/10.1210/js.2016-1072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686627PMC
April 2017

An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3).

Am J Med Genet A 2016 07 5;170(7):1918-23. Epub 2016 May 5.

Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, United Kingdom.

Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37680DOI Listing
July 2016

Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets.

Mol Genet Metab 2014 Jan 4;111(1):33-40. Epub 2013 Nov 4.

Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.

Context: Hereditary vitamin D resistant rickets (HVDRR), also known as vitamin D-dependent rickets type II, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia, secondary hyperparathyroidism and hypophosphatemia and is caused by mutations in the vitamin D receptor (VDR) gene. The human gene encoding the VDR is located on chromosome 12 and comprises eight coding exons and seven introns.

Objectives, Patients, And Methods: We analyzed the VDR gene of 5 previously unreported patients, two from Singapore and one each from Macedonia (former Yugoslav Republic), Saudi Arabia and Turkey. Each patient had clinical and radiographic features of rickets, hypocalcemia, and the 4 cases that had the measurement showed elevated serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). Mutations were re-created in the WT VDR cDNA and examined for 1,25(OH)(2)D(3)-mediated transactivation in COS-7 monkey kidney cells.

Results: Direct sequencing identified four novel mutations and two previously described mutations in the VDR gene. The novel mutations included a missense mutation in exon 3 causing the amino acid change C60W; a missense mutation in exon 4 causing the amino acid change D144N; a missense mutation in exon 7 causing the amino acid change N276Y; and a 2bp deletion in exon 3 5'-splice site (IVS3∆+4-5) leading to a premature stop.

Conclusions: These 4 unique mutations add to the previous 45 mutations identified in the VDR gene in patients with HVDRR.
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http://dx.doi.org/10.1016/j.ymgme.2013.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933290PMC
January 2014

Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

Orphanet J Rare Dis 2012 Sep 22;7:70. Epub 2012 Sep 22.

Provincial Medical Genetics Program, Department of Medical Genetics, Children's and Women's Health Centre of BC, 4500 Oak Street, Room C234, Vancouver, BC, V6H 3N1, Canada.

Background: Arteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown.

Methods: We reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients.

Results: Thirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression.

Conclusions: This first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.
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http://dx.doi.org/10.1186/1750-1172-7-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568709PMC
September 2012

Schimke immunoosseous dysplasia: defining skeletal features.

Eur J Pediatr 2010 Jul 15;169(7):801-11. Epub 2009 Dec 15.

Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.

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.
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http://dx.doi.org/10.1007/s00431-009-1115-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876264PMC
July 2010

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

Ann Saudi Med 2009 Sep-Oct;29(5):357-60

Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, PO Box 40047, Jeddah 21499, Saudi Arabia.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290052PMC
http://dx.doi.org/10.4103/0256-4947.55164DOI Listing
November 2009

Hyperglycemia and hypoinsulinemia in patients with Fanconi-Bickel syndrome.

J Pediatr Endocrinol Metab 2008 Jun;21(6):581-6

Division of Pediatric Endocrinology, Department of Pediatrics, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia.

Unlabelled: Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by the combination of hepatorenal glycogen accumulation and Fanconi-type nephropathy. Mutations in GLUT2, the gene for facilitative glucose transporter protein 2 (GLUT2), cause FBS.

Aim: To evaluate glucose and insulin responses to oral glucose load in patients with FBS.

Methods: Ten children (7.3 +/- 4.8 years) diagnosed with FBS in early infancy underwent a standard oral glucose tolerance test (OGTT); plasma glucose (PG) and serum insulin concentrations were measured at 30-min intervals for 2 hours. HbA1c, insulin-like growth factor-I, and fasting lipid profiles were also measured.

Results: Mean fasting and 2-h PG concentrations were 3.8 +/- 0.9 mmol/l and 8.6 +/- 3.0 mmol/1, respectively. 2-hour PG levels were above 11.1 mmol/l in two patients (20%) and between 7.75 and 11.1 mmol/ in four patients (40%). HbA1c was normal in all the patients with a mean of 5.4 +/- 0.3%. Mean fasting and peak serum insulin levels were 8.7 +/- 0.8 pmol/ and 98.6 +/- 43.0 pmol/l, respectively, and did not differ between the patients with normal and abnormal OGTT. Patients with abnormal OGTT were younger (4.8 +/- 3.2 vs 11.0 +/- 4.8 yr; p = 0.04). Fasting PG increased with age (r = 0.80, p < 0.01). Total and LDL cholesterol as well as triglyceride concentrations were elevated.

Conclusions: Most but not all patients with FBS have impaired glucose tolerance/diabetes range hyperglycemia after OGTT while maintaining normal HbA1c. Patients with FBS are relatively hypoinsulinemic. Both fasting hypoglycemia and post-OGTT hyperglycemia seem to improve with age.
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June 2008

Neonatal diabetes mellitus because of pancreatic agenesis with dysmorphic features and recurrent bacterial infections.

Pediatr Diabetes 2008 Jun;9(3 Pt 1):240-4

Division of Pediatric Endocrinology, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre - Jeddah, Jeddah, Saudi Arabia.

Pancreatic agenesis is a rare cause of neonatal diabetes mellitus (NDM). It can be associated with malformations of the heart, the biliary tract, and the cerebellum. We report an infant with NDM because of pancreatic agenesis, intra-uterine growth retardation, dysmorphic features, and recurrent bacterial infections. He was born to healthy consanguineous parents. With adequate replacement of insulin and pancreatic enzymes, his blood glucose levels were controlled and his weight slowly increased. However, he continued to develop recurrent serious bacterial infections and died at the age of 11 months with sepsis and respiratory failure. Analysis of the PTF1A and PDX1 genes, which have been associated with congenital agenesis of the pancreas, did not reveal any mutation. Genetic abnormalities of chromosome 6 associated with transient neonatal diabetes as well as mutations in the KCNJ11 and ABCC8 genes encoding the pancreatic potassium channel were also excluded as a cause of the NDM in this patient. The association of permanent neonatal diabetes because of pancreatic agenesis, dysmorphism, and non-specific immunodeficiency is previously undescribed and may represent a new possibly autosomal recessive syndrome.
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http://dx.doi.org/10.1111/j.1399-5448.2007.00365.xDOI Listing
June 2008

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

Am J Med Genet A 2007 Dec;143A(23):2835-7

Division of Pediatric Endocrinology, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre-Jeddah, Kingdom of Saudi Arabia.

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http://dx.doi.org/10.1002/ajmg.a.32051DOI Listing
December 2007

Schimke immunoosseous dysplasia: suggestions of genetic diversity.

Hum Mutat 2007 Mar;28(3):273-83

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Schimke immunoosseous dysplasia (SIOD), which is characterized by prominent spondyloepiphyseal dysplasia, T-cell deficiency, and focal segmental glomerulosclerosis, is a panethnic autosomal recessive multisystem disorder with variable expressivity. Biallelic mutations in switch/sucrose nonfermenting (swi/snf) related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1) are the only identified cause of SIOD. However, among 72 patients from different families, we identified only 38 patients with biallelic mutations in the coding exons and splice junctions of the SMARCAL1 gene. This observation, the variable expressivity, and poor genotype-phenotype correlation led us to test several hypotheses including modifying haplotypes, oligogenic inheritance, or locus heterogeneity in SIOD. Haplotypes associated with the two more common mutations, R820H and E848X, did not correlate with phenotype. Also, contrary to monoallelic SMARCAL1 coding mutations indicating oligogenic inheritance, we found that all these patients did not express RNA and/or protein from the other allele and thus have biallelic SMARCAL1 mutations. We hypothesize therefore that the variable expressivity among patients with biallelic SMARCAL1 mutations arises from environmental, genetic, or epigenetic modifiers. Among patients without detectable SMARCAL1 coding mutations, our analyses of cell lines from four of these patients showed that they expressed normal levels of SMARCAL1 mRNA and protein. This is the first evidence for nonallelic heterogeneity in SIOD. From analysis of the postmortem histopathology from two patients and the clinical data from most patients, we propose the existence of endophenotypes of SIOD.
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http://dx.doi.org/10.1002/humu.20432DOI Listing
March 2007

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

Nat Genet 2006 Jun 21;38(6):682-7. Epub 2006 May 21.

Institut Pasteur, Génétique des Maladies Infectieuses et Autoimmunes, 75015 Paris, France.

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 beta cells than in other pancreatic tissues. These results demonstrate a major role for GLIS3 in the development of pancreatic beta cells and the thyroid, eye, liver and kidney.
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http://dx.doi.org/10.1038/ng1802DOI Listing
June 2006

Type 2 diabetes mellitus in African-American adolescents: impaired beta-cell function in the face of severe insulin resistance.

J Pediatr Endocrinol Metab 2006 Feb;19(2):135-42

Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia,

We have previously demonstrated abnormalities in insulin secretion in adolescents with type 2 diabetes mellitus (DM2) in response to the mixed meal test and to glucagon. In order to further assess beta-cell function in DM2, we measured insulin and C-peptide responses to oral glucose in adolescents with DM2 in comparison to non-diabetic obese and lean adolescents. We studied 20 patients with DM2, 25 obese adolescents with matching body mass index (BMI) (33.8 +/- 1.4 vs 34.3 +/- 1.0 kg/m2), and 12 non-obese control adolescents (BMI 22.6 +/- 0.6 kg/m2). Mean age, sex and sexual maturation did not differ between the three groups. All adolescents with DM2 had negative islet cell antibodies (ICA); five patients were on diet and 15 on insulin treatment. Fasting lipid profiles were determined in all participants. Plasma glucose and serum C-peptide and insulin levels were measured at 0, 30, 60, 90, and 120 min after an oral glucose load. The C-peptide increment (deltaCP) was calculated as peak minus fasting C-peptide. Area under the curve (AUC) was estimated using the trapezoid method. Insulin resistance was estimated using the HOMA model (HOMA-IR). The first phase of insulin secretion (PH1) was computed using a previously published formula. Serum triglyceride levels were significantly higher in the patients with DM2 compared to the non-obese controls (1.4 +/- 0.1 vs 0.9 +/- 0.1 mmol/l; p = 0.02). Plasma glucose AUC was greater in the patients with DM2 compared to the obese and non-obese control groups (1,660 +/- 130 vs 717 +/- 17 vs 647 +/- 14 mmol/l x min; p < 0.0001). ACP was lower in adolescents with DM2 than in obese and non-obese adolescents (761 +/- 132 vs 1,721 +/- 165 vs 1,225 +/- 165 pmol/l; p < 0.001). Insulin AUC was lower in the patients with DM2 compared to obese controls (888 +/- 206 vs 1,606 +/- 166 pmol/l x h; p = 0.009), but comparable to that of the non-obese controls (888 +/- 206 vs 852 +/- 222 pmol/l x h; p = 0.9). Insulin AUC was also higher in the obese than in the non-obese group (p = 0.05). PH1 was significantly higher in the obese group compared to the patients with DM2 as well as to the non-obese controls (2,614 +/- 2,47.9 vs 929.6 +/- 403.5 vs 1,946 +/- 300.6 pmol/l, respectively; p = 0.001). PH1 was also higher in the non-obese controls than in the patients with DM2 (p = 0.05). HOMA-IR was three-fold higher in the patients with DM2 than in the BMI-matched obese group, and five-fold higher than in the lean controls (14.3 +/- 1.2 vs 5.4 +/- 0.8 vs 2.9 +/- 0.4; p = 0.0002). Adolescents with DM2 have dyslipidemia, a significant cardiovascular risk factor. Decreased beta-cell function is characteristic of adolescents with DM2 in the presence of severe insulin resistance.
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http://dx.doi.org/10.1515/jpem.2006.19.2.135DOI Listing
February 2006

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

Horm Res 2005 4;64(4):175-9. Epub 2005 Oct 4.

Department of Pediatrics, King Faisal Specialist Hospital and Research Centre-Jeddah, Jeddah, Saudi Arabia.

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.
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http://dx.doi.org/10.1159/000088793DOI Listing
December 2005

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

Clin Dysmorphol 2005 Oct;14(4):191-6

Division of General Pediatrics, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre-Jeddah, Kingdom of Saudi Arabia.

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.
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http://dx.doi.org/10.1097/00019605-200510000-00005DOI Listing
October 2005

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

Pediatr Nephrol 2005 Sep 12;20(9):1336-9. Epub 2005 Jul 12.

Department of Pediatrics, King Faisal Specialist Hospital and Research Centre-Jeddah, Jeddah, Kingdom of Saudi Arabia.

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.
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http://dx.doi.org/10.1007/s00467-005-1885-xDOI Listing
September 2005

Association of migraine-like headaches with Schimke immuno-osseous dysplasia.

Am J Med Genet A 2005 Jun;135(2):206-10

Department of Pediatrics, Division of Immunology, Uludag University Medical Faculty, Görükle-Bursa, Turkey.

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.
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http://dx.doi.org/10.1002/ajmg.a.30692DOI Listing
June 2005

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

Am J Med Genet A 2004 Dec;131(2):194-9

Department of Pediatrics, King Faisal Specialist Hospital and Research Centre-Jeddah, Jeddah, Saudi Arabia.

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).
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http://dx.doi.org/10.1002/ajmg.a.30356DOI Listing
December 2004

Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity.

Diabetes 2004 Jul;53(7):1876-83

Génétique des Maladies Infectieuses et Autoimmunes, INSERM E102, Institut Pasteur, Paris, France.

Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.
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http://dx.doi.org/10.2337/diabetes.53.7.1876DOI Listing
July 2004

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

Am J Med Genet A 2003 Oct;122A(3):269-73

Division of Pediatric Endocrinology, King Faisal Specialist Hospital and Research Center, PO Box 40047, Jeddah 21499, Kingdom of Saudi Arabia.

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.
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http://dx.doi.org/10.1002/ajmg.a.20267DOI Listing
October 2003

Monozygotic twins with congenital adrenal hyperplasia: long-term endocrine evaluation and gene analysis.

J Pediatr Endocrinol Metab 2003 Apr-May;16(4):565-70

Department of Pediatrics, Division of Pediatric Endocrinology and Metabolism, The Brookdale University Hospital and Medical Center, State University of New York at Brooklyn, NY 11212-3198, USA.

Monozygotic female twins with congenital adrenal hyperplasia due to 21-hydroxylase deficiency are described and evaluated over the first 6 years of life. Despite appropriate steroids, NaCl, and fludrocortisone therapies, there was significant fluctuation in the suppression of adrenal steroid secretion. Advanced bone maturation in both was noted. For the first time, molecular genetic analysis was performed and documented that the twins were compound heterozygotes for two different mutations: the maternal allele carried the 8-bp deletion mutation, whereas the paternal allele carried the 1172N missense mutation. Parental DNA samples confirmed that the mutations were on different alleles.
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http://dx.doi.org/10.1515/jpem.2003.16.4.565DOI Listing
July 2003

Hyperlipidemia in children with type 2 diabetes mellitus.

Authors:
Doris Taha

J Pediatr Endocrinol Metab 2002 Apr;15 Suppl 1:505-7

Department of Pediatrics, State University of New York Health Science Center at Brooklyn and Children Medical Center of Brooklyn, 11203, USA.

Atherosclerosis is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (DM). The increased risk of coronary artery disease in patients with type 2 DM is partly due to the lipoprotein abnormalities associated with DM. Dyslipidemia outweighs all other risk factors for cardiovascular disease in adults with type 2 DM. Hypertriglyceridemia and low levels of high-density lipoprotein (HDL)-cholesterol are the most common abnormalities in adults with type 2 DM. These abnormalities may improve, but commonly persist, after optimal glycemic control has been achieved. Children with type 2 DM also have hypertriglyceridemia, low levels of HDL-, as well as elevated levels of total and low-density lipoprotein (LDL)-cholesterol levels. Screening for dyslipidemia is recommended in children with type 2 DM. Several adult clinical trials that included patients with DM have demonstrated the efficacy of lowering LDL-cholesterol in preventing death from coronary artery disease. Weight loss, changing dietary habits, increasing physical activity, and improving glycemic control are initial approaches to the treatment of hyperlipidemia in children with type 2 DM. When goals are not met, drug therapy should be considered.
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April 2002

Beta-cell response to intravenous glucagon in African-American and Hispanic children with type 2 diabetes mellitus.

J Pediatr Endocrinol Metab 2002 Jan;15(1):59-67

Department of Pediatrics, State University of New York Health Science Center at Brooklyn and Children's Medical Center of Brooklyn, USA.

The incidence of type 2 diabetes mellitus (DM) in children and adolescents has substantially increased over the past decade. The present study was conducted to evaluate the beta-cell response to intravenous glucagon (a non-glucose secretagogue) in children with type 2 DM. Twenty pediatric patients with type 2 DM were compared to 15 control subjects matched for body mass index and sexual maturation. The patients' ages ranged between 10 and 19 years. The duration of DM ranged from 1 to 5 years. Nine patients were on insulin treatment and 11 were on diet alone (3 patients) or metformin (8 patients). The criteria for type 2 DM were absent islet cell (IA-2) and glutamic acid decarboxylase (GAD65) antibodies and a fasting serum C-peptide level of > or = 0.23 nmol/l. Plasma glucose and serum C-peptide levels were determined in the fasting state and six minutes after an intravenous injection of 1 mg of glucagon. The fasting and stimulated plasma glucose levels and the fasting serum C-peptide levels (1.02 +/- 0.43 vs 0.79 +/- 0.26 nmol/l, p < 0.05) were higher in the patients with DM compared to weight-matched control subjects. While the absolute C-peptide responses to glucagon were not different between the two groups, the stimulated C-peptide to glucose ratios were significantly lower in the patients with DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p < 0.05). Patients with DM treated with diet or oral therapy had significantly greater basal and stimulated C-peptide concentrations, incremental C-peptide, and C-peptide to glucose ratios than patients on insulin treatment. Both the fasting and the stimulated C-peptide levels were inversely correlated with the duration of DM (r = -0.53, p < 0.05). HbA1c at one year follow-up was inversely correlated with glucagon-stimulated C-peptide levels at the time of the study (r = -0.658, p < 0.01) and positively correlated with the duration of diabetes (r = 0.671, p = 0.002). The apparently normal serum C-peptide levels measured after glucagon challenge in these children with type 2 DM reflect their higher glucose levels. The lower stimulated C-peptide to glucose ratios in these children with type 2 DM compared to normal controls demonstrate their diminished beta-cell response to intravenous glucagon, a non-glucose secretagogue. Among the patients with DM, a higher glucagon-stimulated serum C-peptide response was associated with diet/metformin treatment, a shorter duration of DM and predicted improved glycemic control up to one year later. Thus, the fasting and glucagon-stimulated serum C-peptide levels provide an estimate of the potential insulin secretory capacity of the beta-cell and may predict glycemic control in pediatric type 2 DM.
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http://dx.doi.org/10.1515/jpem.2002.15.1.59DOI Listing
January 2002