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Nouhad Raissouni,
Andrey Kolesnikov,
Radhika Purushothaman,
Sunil Sinha,
Sonal Bhandari, Amrit Bhangoo,
Shahid Malik,
Revi Mathew,
Jean-Patrice Baillargeon,
Maria Isabel Hernandez,
Michael Rosenbaum,
Svetlana Ten,
David Geller
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ABSTRACT: First-degree relatives (FDRs) of women with PCOS are at increased risk for impaired insulin sensitivity and diabetes mellitus. Glucose tolerant FDR have evidence of insulin resistance and hyperinsulinemia prior to emergence of frank PCOS.
To study insulin dynamics parameters in the early adolescent FDR of women with PCOS.
This is a cross-sectional study involving 18 adolescents whose mothers or sisters had been diagnosed with PCOS and 21 healthy, age-matched control adolescents without FDR. Subjects underwent anthropometric measurements, steroid profiling and frequently sampled Intravenous Glucose Tolerance Test (IVGTT), Homeostasis Model Assessment (HOMA) index, Glucose Disposal Index (GDI), Acute Insulin Response (AIR) and Quantitative insulin sensitivity check index (QUICKI) were derived from IVGTT results.
FDRs showed significantly higher mean HOMA and lower GDI. There were no differences in mean age or BMI Z-score between the cohorts. No differences in sex steroids or AIR were identified between groups.
Female adolescent FDR of women with PCOS have higher HOMA index and lower QUICKI, reflecting altered insulin sensitivity and lower GDI reflecting poorer beta-cell function. The presence of multiple risk factors for type 2 diabetes suggests that aggressive screening of the early adolescent FDR of women with PCOS is indicated.
International Journal of Pediatric Endocrinology 05/2012; 2012(1):14.
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ABSTRACT: Sex steroids, such as estrogens, are known to influence endothelial function by their vasodilator action. The aim of this study was to study the relation of puberty and sex steroids with endothelial function using peripheral arterial tonometry (PAT).
In 89 healthy school boys and girls, we determined height, weight, waist circumference, percent body fat, BMI, BMI z-score, blood pressure (BP), BP percentiles, lipid profile, insulin, and glucose levels after overnight fast. Estrone (E(1)), estradiol (E(2)), DHEAS and E(1)-sulfate were measured using ultrasensitive assays. Participants were divided into 3 pubertal groups on the basis of their estrogen levels: group 1 (Tanner stage I), group 2 (Tanner stages II-III), and group 3 (Tanner stages IV-V). Endothelial function was measured by Endo-PAT 2000® and expressed as PAT index. A higher PAT index represents a higher reactive hyperemia response.
The PAT index was lowest at 1.42 ± 0.44 (mean ± SD) in group 1 and significantly increased in group 2 at 1.71 ± 0.35 (p = 0.02) and group 3 at 1.92 ± 0.38 (p < 0.001). The PAT index correlated positively with E(2), DHEAS and age.
Enhancement of the PAT index was associated with an increment in Tanner stages. The changes in E(2) and DHEAS levels may contribute to increasing endothelial response to shear stress or arterial blood flow.
Hormone Research in Paediatrics 07/2011; 76(4):226-33.
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Advances in experimental medicine and biology 01/2011; 707:147-8. · 1.09 Impact Factor
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ABSTRACT: The steroidogenic acute regulatory (StAR) protein is essential for all hormone-stimulated steroid biosynthesis. Accordingly, its absence gives rise to the most severe form of congenital adrenal hyperplasia (CAH), lipoid CAH. This life-threatening condition typically manifests itself in the perinatal period. Partial loss-of-function StAR mutations incompletely manifest the condition later in life and are a cause of familial glucocorticoid deficiency type 3. Here, we discuss StAR, its expression pattern and the clinical consequences of the loss of its activity.
Endocrine development 01/2011; 20:47-53.
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ABSTRACT: 17-β-Hydroxysteroid dehydrogenase type 3 (17βHSD-3) is expressed exclusively in the testes where it converts Δ4 androstenedione (Δ4) to testosterone (T). Here, we report a patient with a rare mutation at a critical site in HSD17B3 gene leading to deficiency of 17β HSD-3 enzyme.
We describe a 3-year old healthy female of consanguineous Lebanese descent, who presented to the endocrine service with isolated mild clitoromegaly. Adrenocorticotropic hormone (ACTH) and human chorionic gonadotrophin (hCG) stimulation tests were performed. Genes for sex-determining region Y (SRY), steroidogenic factor-1 (SF-1) and 17βHSD-3 (HSD17B3) were sequenced.
The post-hCG stimulation T levels and T/Δ4 ratio was low. Patient had a 46,XY karyotype. Sequence analysis of the HSD17B3 gene revealed a homozygous R80W missense mutation on exon 3. No mutation was found in SRY and SF1 genes. Mullerian structures were not detected on pelvic imaging.
A low T/Δ4 ratio is indicative of 17βHSD-3 deficiency and associated with isolated clitoromegaly. The R80 site is critical for NADPH binding, thus the mutation at this site leads to 17βHSD-3 deficiency presenting as 46,XY disorder of sex development.
Gynecological Endocrinology 01/2011; 27(11):890-4. · 1.58 Impact Factor
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ABSTRACT: In the context of present epidemic of childhood obesity, we aimed to find the prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in a cohort of obese children.
Retrospective chart analysis of 700 obese children was done for their anthropometric and biochemical investigations.
Some 15.4% (9.8% girls, 22% boys) subjects had NAFLD (ALT > 40 IU/L) after excluding other identifiable causes of liver dysfunction. Age, weight, TG, fasting serum insulin and HOMA-IR levels were higher in children with NAFLD. Twenty-eight percent children had MS. Children with NAFLD had an odds ratio of 2.65 for having MS (boys 4.6, girls 1.7). The prevalence of MS increased with age 5-9 years (21%), 10-16 years (30%), 17-20 years (35%).
Given high prevalence of NAFLD and MS in obese children, childhood obesity should be seriously considered as a disease and not just a cosmetic issue.
Journal of pediatric endocrinology & metabolism: JPEM 01/2011; 24(11-12):907-11. · 0.88 Impact Factor
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ABSTRACT: Partial androgen insensitivity syndrome (PAIS) is the milder variant of androgen receptor (AR) defects. The subtle effects of AR mutations present in a patient with micropenis, peno-scrotal hypospadias, infertility, clitoromegaly and posterior labial fusion. We studied the association of isolated micropenis with the genetic defects resulting in androgen resistance, that is, AR gene defects and 5-alpha reductase type 2 (SRD5A2) deficiency. We describe two cases of isolated micropenis: one in a 14-year-old boy and the other in a 3-year-old boy who was followed until he was 10 years old. There were no findings of hypospadias, cryptorchidism or gynecomastia in either of these patients. Serum gonadotrophin and androgen levels were obtained and karyotyping was done. Human chorionic gonadotropin (hCG) stimulation testing assessed the functional capacity of the testes. DNA was extracted from peripheral leukocytes, and all exons of the SRD5A2 and AR genes were amplified by polymerase chain reaction and sequenced. In both patients, baseline testosterone (T) level was low and the values were elevated after hCG testing. The sequence of the SRD5A2 gene was normal in patient 1, and a heterozygous polymorphism, V89L, was found in patient 2. Two known mutations, P390S and A870V, were identified in patients 1 and 2, respectively. Mutations in the AR gene can be associated with isolated micropenis without other features of PAIS, such as hypospadias or gynecomastia. This underlines the importance of including AR gene analysis in the evaluation of isolated micropenis with normal plasma T to ensure proper management of the patient and appropriate genetic counseling for the family.
Asian Journal of Andrology 03/2010; 12(4):561-6. · 1.52 Impact Factor
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ABSTRACT: 17-β-Hydroxysteroid dehydrogenase type 3 (17βHSD-3) deficiency is a rare, but frequently misdiagnosed autosomal recessive cause of 46,XY disorder of sex development (DSD). 17βHSD-3 enzyme is present almost exclusively in the testes and converts Δ4-androstenedione (Δ4) to testosterone (T). The diagnosis can be easily missed in early childhood as the clinical presentation may be subtle. Any young girl with an inguinal hernia, mild clitoromegaly, single urethral opening or urogenital sinus should raise suspicion. If not diagnosed early, patients present with severe virilization and primary amenorrhea in adolescence and may undergo a change from a female to male gender role. A low T/Δ4 ratio on baseline or hCG (human chorionic gonadotropin)-stimulated testing is suggestive of 17βHSD-3 deficiency. The diagnosis can be confirmed with molecular genetic studies. This review summarizes the clinical presentations, reported mutations, diagnosis, treatment and clinical course of this disorder. The Arg80 site in exon 3 is the most common location of repeated mutations and can be considered a hot spot in certain Arab populations.
Hormone Research in Paediatrics 01/2010; 74(4):229-40.
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ABSTRACT: Low resting energy expenditure (REE) and respiratory quotient (RQ) have been shown in adults to predispose to obesity and diabetes mellitus.
To correlate REE and RQ in 73 obese children and young adults (body mass index [BMI] 37 +/- 10 kg/m2) with measures of insulin secretion and resistance (IR) indices, percent carbohydrate and fat oxidation, and prolactin and leptin levels.
During a 3-day admission, REE and RQ were determined by indirect calorimetry. Blood chemistries and oral glucose tolerance test (OGTT) were obtained, and intravenous glucose tolerance test (IVGTT) modified by tolbutamide was conducted after an overnight fast, permitting calculation of acute insulin response (AIR), insulin resistance (SiIVGTT), and disposition index (DI).
Patients fell into two groups according to their SiIVGTT: those with normal insulin sensitivity (NIS) and those with insulin resistance (IR). IR patients were subdivided on the basis of DI (cut-off value 0.13 min(-1)) into compensated (CIR) or decompensated (DIR) groups. CIR patients had higher RQ, REE corrected by BMI, AIR, and carbohydrate oxidation and lower fat oxidation than NIS and DIR patients. REE correlated positively with BMI, leptin, and AIR, and negatively with SiIVGTT.
Findings in the CIR and DIR groups support the correlation of REE with metabolic changes consistent with an increased risk of diabetes mellitus.
Journal of pediatric endocrinology & metabolism: JPEM 05/2008; 21(4):359-67. · 0.88 Impact Factor
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ABSTRACT: Cytochrome P450c17 (CYP17) has two principal enzyme activities, 17alpha-hydroxylase and 17,20-lyase, which are required for cortisol and androgen biosynthesis, respectively. Mutations in the gene encoding for CYP17 result in 17alpha-hydroxylase deficiency (17OHD), a rare form of congenital adrenal hyperplasia, a disorder characterized by adrenal insufficiency, hypertension, primary amenorrhea and sexual infantilism. We describe a case of complete combined 17OHD caused by mutations in the CYP17 gene.
This study evaluates a 19 year-old Korean female born from a non-consanguineous relationship who presented with primary amenorrhea, hypertension, hyperpigmentation, absent axillary hair and pubic hair, and Tanner I breasts. Laboratory evaluation showed markedly elevated adrenocorticotropin and 11-deoxycorticosterone with suppressed plasma renin, aldosterone, and cortisol, consistent with 17OHD.
Genomic DNA was isolated from peripheral blood leukocytes. The eight exons of the human CYP17 gene were amplified in four segments by polymerase chain reaction. Amplicons were gel-purified and directly sequenced.
The patient was found to be compound heterozygous for mutations in exon 6: a novel mutation R358X (CGA--TGA) and Y329 del/ sub (TAC-->AA). Both alterations introduce premature stop codons prior to the hemebinding cysteine and are predicted to completely inactivate the encoded P450c17 proteins.
This patient is a compound heterozygote for nonsense mutations in the CYP17 gene, which confirms the diagnosis of 17OHD.
Journal of pediatric endocrinology & metabolism: JPEM 02/2008; 21(2):185-90. · 0.88 Impact Factor
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ABSTRACT: To understand the basis of the phenotypic variations of 46, XX girls with mutations in the gene for Steroidogenic Acute Regulatory (StAR) Protein. The patients with mutation in both the alleles of the StAR gene result in deficiency of all the steroidal hormones and severe adrenal insufficiency. The majority of the 46, XX females spontaneously undergo puberty but the underlying defect ultimately leads to the development of ovarian cysts and premature menopause. The mechanism of the lesion in the ovary remains to be understood completely.
We compiled the description of the clinical information and biochemical data of patients with StAR mutation from published manuscripts. These articles were collected from the NCBI website (www.pubmed.org) and from the subsequent reference searches of retrieved articles. The data of the 46,XX patients with proven StAR mutation were included for the review.
The majority of StAR 46,XX females developed irregular menses and ovarian cysts. The ovarian cyst enlargement progressively led to torsion and presented as a life-threatening emergency. The fertility of 46,XX StAR patients is severely compromised as ultimately premature menopause ensued.
Early hormonal replacement is warranted to prevent the progressive ovarian cyst formation. Newer techniques to preserve the fertility of these patients can be implied early in the pubertal developmental process if patients desire pregnancy.
Pediatric endocrinology reviews: PER 01/2008; 5(2):633-41.
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Maha Abdulhadi-Atwan,
Amy Jean,
Wendy K Chung,
Karen Meir,
Ziva Ben Neriah,
George Stratigopoulos,
Sharon E Oberfield,
Ilene Fennoy,
Harry J Hirsch, Amrit Bhangoo,
Svetlana Ten,
Israela Lerer,
David H Zangen
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ABSTRACT: Context: Congenital lipoid adrenal hyperplasia (CLAH), caused by mutations in steroidogenic acute regulatory protein (StAR), is most frequent in Japanese and Palestinians. We report eight Palestinians from four unrelated families with CLAH. Objective: The objective of the study was to identify the mutation(s) in StAR, correlate genotype with phenotype, and determine whether the common mutation represents a founder mutation. Patients and Setting: Clinical, histopathological, and molecular genetic characterization was performed in these eight patients. Results: All affected individuals (three XY, five XX) presented neonatally with undetectable adrenocortical hormones and are responding to replacement therapy. Only two sisters had neurodevelopmental deficits. Histopathological findings of excised XY gonads included accumulation of fat in Leydig cells. Significantly, already at 1 yr of age, positive placental alkaline phosphatase and octamer binding transcription factor staining indicated neoplastic potential. Sequence analysis of StAR revealed homozygosity for c.201_202delCT mutation in all eight cases, causing premature termination of the StAR protein. This mutation was confirmed to be a founder mutation using both an intragenic microsatellite and several single nucleotide polymorphism markers. Screening of 100 normal Jerusalem Palestinians detected no carriers of this mutation. Conclusion: CLAH is rare in the general Palestinian population. In most Palestinian cases, a founder c.201_202delCT mutation in StAR is the cause. The observed early neonatal presentation may reflect the major StAR protein truncation caused by this mutation. A crucial role for StAR in the central nervous system was not supported with normal neurological examinations in six of eight cases. Finally, we advocate early gonadectomy in XY CLAH cases, given the early onset of neoplastic changes observed histologically.
Journal of Clinical Endocrinology & Metabolism 11/2007; 92(10):4000-8. · 6.50 Impact Factor
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ABSTRACT: Alström syndrome (AS) is an autosomal recessive disorder characterized by progressive pigmentary retinopathy, sensorineural hearing loss, fatty liver infiltration, obesity, insulin resistance and early-onset type 2 diabetes mellitus (DM2). Early onset of insulin resistance and DM2 are key components of this syndrome.
To study the effect of early initiation of the insulin sensitizer metformin combined with rosiglitazone in a patient with AS with impaired glucose tolerance.
An 8 year-old boy with AS presented with acanthosis nigricans and insulin resistance at the age of 6 years. He had progressive excessive weight gain from 9 months of age. By the age of 1 year he developed photosensitivity, blindness and nystagmus. At the age of 5.5 years, his body mass index (BMI) was above the 95th percentile. He developed impaired glucose tolerance at 6 years of age and treatment with metformin was initiated. After 8 months of treatment with metformin he developed DM2. The dose of metformin was increased, and rosiglitazone added.
A 2-hour oral glucose tolerance test (OGTT) and a rapid intravenous glucose tolerance test (IVGTT) were performed before treatment was initiated, after treatment with metformin and at the end of 1 year of combination therapy with metformin and rosiglitazone to calculate quantitative insulin sensitivity check index (QUICKI) and acute insulin response (AIR). For mutation analysis, all exons and splice site sequences of the ALMS1 gene were amplified and sequenced.
Metformin treatment alone at the stage of impaired glucose tolerance did not prevent progression to DM2. However, metformin at a higher dose and in combination with rosiglitazone resulted in improvement of pancreatic beta-cell function, shown by markedly improved first-phase insulin response to glucose measured by AIR. The patient was found to have two heterozygous nonsense mutations in ALMS1, 8008 C-->T Ter, R2670X, and 11449 C-->T Ter, Q3817X. These alterations cause premature stops and result in a truncated ALMS1 protein.
We suggest that early initiation of combined therapy comprising a high dose of metformin plus rosiglitazone may be valuable in managing insulin resistance and DM2 in children with AS.
Journal of pediatric endocrinology & metabolism: JPEM 10/2007; 20(9):1045-52. · 0.88 Impact Factor
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ABSTRACT: Insulin resistance syndrome (IRS) is associated with the development of type 2 diabetes mellitus (DM2). However, it is unclear which individuals with insulin resistance will develop DM2.
To study the prevalence of IRS in childhood and to identify the group with the highest risk of further progression to DM2.
In a cross-sectional study, 86 obese individuals underwent an intravenous glucose tolerance test (IVGTT). Insulin resistance index (Si(IVGTT)), acute insulin response (AIR) and disposition index (DI) were calculated from IVGTT.
For analysis the participants were divided into insulin-sensitive (IS) (n = 25, 13.3 +/- 5.9 yr) and insulin-resistant (IR) groups on the basis of having an Si(IVGTT) greater or lesser than 4.5 x 10(-4) mU/ml/min, respectively. The IR group was then subdivided according to DI, with the standard cut-off value of 0.13 min(-1), into compensated IR (CIR) (n = 37, 13.0 +/- 3.5 yr) and decompensated IR (DIR) (n = 24, 21.9 +/- 12.6 yr) groups. The frequency of IRS was 43% in children, 78% in adolescents and 83.6% in adults. Decompensated insulin response first appeared during adolescence. The frequency of decompensation increased from 22% in adolescence to 67% in adulthood. The DIR group had increased triglycerides (TG) and urinary free cortisol levels.
The frequency and severity of IR increases with age. Decompensation first presents in adolescence with low AIR and elevated TG. Decompensated adolescents are the group at highest risk for further progression to DM2.
Journal of pediatric endocrinology & metabolism: JPEM 10/2007; 20(9):989-99. · 0.88 Impact Factor
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ABSTRACT: Mutations in the gene encoding 110-hydroxylase (CYPI]BJ) are the second most common cause of congenital adrenal hyperplasia (CAH), a disorder characterized by adrenal insufficiency and virilization of female external genitalia.
We describe a new case of 1113-hydroxylase CAH caused by donor splice site mutation in the CYPllB1 gene.
A 46,XX patient of Pakistani descent was identified with severe virilization soon after birth. The karyotype was negative for SRY. Pelvic ultrasound showed normal uterus and cervix. Periniogram revealed a 3-cm long urogenital sinus, ACTH stimulation test showed normal 17-hydroxyprogesterone, low cortisol, elevated 11-deoxycortisol and deoxycorticosterone (DOC) levels, consistent with 11beta-hydroxylase deficiency. Glucocorticoid treatment was started on the basis of a low baseline cortisol and severely virilized external genitalia. The patient did not develop salt wasting and/or hypertension.
Analysis of the CYPllBlgene revealed homozygosity for a codon 318+1G--C substitution at the 5'-splice donor site of intron 5 resulting in a missense mutation. The parents of the patients are consanguineous and are heterozygous for the same mutation.
In a previous reported case a donor splice mutation was identified for the first time at the same position codon 318 of the CYPIIB1 gene. We present this case in detail along with a literature review of 11beta-hydroxylase deficiency CAH.
Journal of pediatric endocrinology & metabolism: JPEM 11/2006; 19(10):1267-82. · 0.88 Impact Factor
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ABSTRACT: Congenital lipoid adrenal hyperplasia (lipoid CAH) is an autosomal recessive disorder characterized by severe adrenal insufficiency and male sex reversal. Lipoid CAH is caused by mutations in two proteins that are essential for all steroid biosynthesis, the steroidogenic acute regulatory (StAR) protein and cytochrome P450scc. In this review, we discuss the clinical presentation and mechanisms behind the pathology of this fatal disorder.
Pediatric endocrinology reviews: PER 04/2006; 3(3):258-71.
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ABSTRACT: Mutations in the gene encoding steroidogenic acute regulatory protein (StAR) are the most common cause of lipoid congenital adrenal hyperplasia (lipoid CAH), a disorder characterized by adrenal insufficiency and deficient gonadal steroid synthesis, resulting in female external genitalia in both genetic sexes.
We describe three new cases of lipoid CAH caused by novel mutations in the StAR gene.
An XY subject of Yemeni descent presented with adrenal insufficiency and severe undervirilization. Magnetic resonance imaging (MRI) of the brain showed enlarged subarachnoid spaces consistent with frontal and temporal atrophy. Two XX siblings of Palestinian descent presented with neonatal adrenal insufficiency. One had a borderline intelligence quotient and features of attention deficit hyperactivity disorder. MRI showed areas of supratentorial white matter lesions. In her sister, MRI revealed a Chiari-I malformation.
The XY subject was found to have a missense mutation (R182C). Both XX siblings had a dinucleotide deletion at nucleotides 327-328 that induces a frame shift that truncates the StAR protein after 68 amino acids.
These cases broaden the spectrum of known StAR mutations and suggest that disorders of central nervous system development may arise because of StAR deficiency and/or the metabolic consequences of neonatal adrenal deficiency.
Journal of Clinical Endocrinology & Metabolism 12/2005; 90(11):6303-9. · 6.50 Impact Factor
