An ancient founder mutation in PROKR2 impairs human reproduction.

Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutation's age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same ~123 kb haplotype whose population frequency is ≤10%. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.

Insulin resistance, lipodystrophy and cardiometabolic syndrome in HIV/AIDS.

HIV associated insulin resistance, lipodistrophy and cardiometabolic syndrome have been extensively studied and continue to be the scope of much research. There is compelling evidence that both the HIV itself and the therapeutical regimes are major contributors to all of these associated comorbidities. HIV has increasingly been recognized as a disease of accelerated aging, manifested by increased progression of vascular disease and cellular markers of aging. The antiretroviral medication can increase insulin resistance and cause lipotoxocity and HIV-associated lipodystrophy leading to cardiovascular pathology. In this article we review the pathogenesis, management, and prevention of the long-term complications of HIV and its therapies, including cardiovascular disease, lipodystrophy, and insulin resistance along with the growing focus on biomarkers to predict development of end-organ disease. Through a focused literature search we review the established evidence, the developing research about the treatment strategies in treated HIV infection as well as identify potential areas for future research.

Fasting Serum IGFBP-1 as a Marker of Insulin Resistance in Diverse School Age Groups.

Introduction: The known markers of insulin resistance in obese children are well studied. However, they require serial measurements and complicated calculations. The objective is to study IGFBP-1 and its relation with other known risk measures. Materials and Methods: The study included 98 New York City school students of diverse ethnic/racial backgrounds (57 males and 41 females), 11-15 years of age. Subjects were enrolled in a cross-sectional study, and anthropometric measures were collected. They underwent fasting intravenous glucose tolerance tests (IVGTT), and glucose, insulin, lipids, IGFBP-1, adiponectin and inflammatory markers were collected. Results: The subjects were stratified into 3 groups based upon the BMI Z-score. Out of all the subjects, 65.3% were in the group with a BMI Z-score <1 SDS, 16.3% subjects were in the group with a BMI Z-score of 1 to 2 SDS, and 18.4% of the subjects were in the group with a BMI Z-score of more than 2 SDS. The group with a BMI Z-score of more than 2 SDS had increased waist circumference (WC), body fat, increased fasting insulin, and triglycerides (TG). This group had decreased levels of adiponectin and HDL and low IGFBP-1 as compared to the group with BMI <1 SDS. The group with a BMI Z-score of 1 to 2 SDS had a decreased level of IGFBP-1 as compared to the group with a BMI Z-score less than 1 SDS. IGFBP-1 inversely correlated with age, WC, BMI, body fat, TG, and insulin levels. IGFBP-1 positively correlated with adiponectin and HDL levels. Conclusion: IGFBP-1 in children can identify the presence of insulin resistance in the group with BMI 1 to 2 SDS, even before the known markers of insulin resistance such as elevated triglycerides and even before decreased HDL and adiponectin levels are identified.

Lack of GNAS Remethylation During Oogenesis May Be a Cause of Sporadic Pseudohypoparathyroidism Type Ib.

CONTEXT: Pseudohypoparathyroidism type Ib (PHP1B) is characterized by hypocalcemia and hyperphosphatemia due to parathyroid hormone resistance in the proximal renal tubules. Maternal pathogenic STX16/GNAS variants leading to maternal epigenetic GNAS changes impair expression of the stimulatory G protein alpha-subunit (Gsα) thereby causing autosomal dominant PHP1B. In contrast, genetic defects responsible for sporadic PHP1B (sporPHP1B) remain mostly unknown. OBJECTIVE: Determine whether PHP1B encountered after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) causes GNAS remethylation defects similar to those in sporPHP1B. DESIGN: Retrospective analysis. RESULTS: Nine among 36 sporPHP1B patients investigated since 2000, all with loss of methylation (LOM) at the 3 maternal GNAS differentially methylated regions (DMRs) and gain of methylation at the paternal NESP DMR, had been conceived through IVF or ICSI. Besides abnormal GNAS methylation, IVF/ICSI PHP1B cases revealed no additional imprinting defects. Three of these PHP1B patients have dizygotic twins, and 4 have IVF/ICSI-conceived siblings, all with normal GNAS methylation; 2 unaffected younger siblings were conceived naturally. CONCLUSION: Sporadic and IVF/ICSI-conceived PHP1B patients revealed indistinguishable epigenetic changes at all 4 GNAS DMRs, thus suggesting a similar underlying disease mechanism. Given that remethylation at the 3 maternal DMRs occurs during oogenesis, male factors are unlikely to cause LOM postfertilization. Instead, at least some of the sporPHP1B variants could be caused by a defect or defects in an oocyte-expressed gene that is required for fertility and for re-establishing maternal GNAS methylation imprints. It remains uncertain, however, whether the lack of GNAS remethylation alone and the resulting reduction in Gsα expression is sufficient to impair oocyte maturation.

Profile of Daughters and Sisters of Women With Polycystic Ovary Syndrome: The Role of Proband's Glucose Tolerance.

CONTEXT: First-degree relatives of women with polycystic ovary syndrome (PCOS) present hormonal and metabolic alterations compared to girls unrelated to PCOS. It is unknown whether glucose intolerance in the PCOS proband confers a more severe metabolic predisposition on their first-degree relatives. OBJECTIVE: To determine whether glucose tolerance status in women with PCOS is associated with worsened glucose metabolism and sex hormone levels in their peripubertal daughters or sisters. DESIGN: Cross-sectional study. SETTING: Seven academic centers in North America, South America, and Europe. PATIENTS: Sixty-four pairs of women with PCOS and their daughters or younger sisters aged between 8 and 14 years were recruited. Twenty-five mothers or older sisters with PCOS were glucose intolerant (GI) and 39 were normal glucose tolerant (NGT). MAIN OUTCOME MEASURES: Beta-cell function estimated by the insulin secretion-sensitivity index-2 (ISSI-2) during an oral glucose tolerance test and by the disposition index during a frequently sampled IV glucose tolerance test. Free testosterone and 17-hydroxyprogesterone (17-OHP) levels. RESULTS: Being related to a GI PCOS proband was associated with a lower ISSI-2 (P-value = 0.032) after adjusting for ethnicity, body mass index z-score, and pubertal stage. They also had higher free testosterone (P-value = 0.011) and 17-OHP levels compared to girls with an NGT proband, the latter becoming significant after adjusting for confounders (P-value = 0.040). CONCLUSIONS: Compared to first-degree female relatives of women with PCOS and NGT, first-degree relatives of women with PCOS and GI display lower beta-cell function and hyperandrogenemia, putting them at higher risk of GI and PCOS development.

Isolated mild clitoral hypertrophy may reveal 46,XY disorders of sex development in infancy due to 17ßHSD-3 defect confirmed by molecular analysis.

AIMS: 17-ß-Hydroxysteroid dehydrogenase type 3 (17ßHSD-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 17ß HSD-3 enzyme. METHODS: 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 17ßHSD-3 (HSD17B3) were sequenced. RESULTS: 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. CONCLUSIONS: A low T/Δ4 ratio is indicative of 17ßHSD-3 deficiency and associated with isolated clitoromegaly. The R80 site is critical for NADPH binding, thus the mutation at this site leads to 17ßHSD-3 deficiency presenting as 46,XY disorder of sex development.

The prevalence of non-alcoholic fatty liver disease and metabolic syndrome in obese children.

BACKGROUND AND AIM: 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. METHODOLOGY: Retrospective chart analysis of 700 obese children was done for their anthropometric and biochemical investigations. RESULTS: 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%). CONCLUSION: 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.

Retinol binding protein 4 is associated with adiposity-related co-morbidity risk factors in children.

OBJECTIVE: In adults, elevated levels of retinol binding protein 4 (RBP4) have been associated with biochemical markers of adiposity-related co-morbidities including insulin resistance, dyslipidemia, hypertension, and abdominal obesity. This study examined the relationship between RBP4 and risk factors for co-morbidities of adiposity in a population of ethnically diverse children in early- to mid-adolescence in the public school system of New York City. MATERIALS/METHODS: We analyzed anthropometric (body mass index, % body fat, waist circumference), metabolic (lipids, glucose), and inflammatory (TNF-alpha, interleukin-6, C-reactive protein, adiponectin) markers for adiposity-related co-morbidities and serum alanine aminotransferase (ALT) in 106 school children (65 males, 41 females) 11-15 years of age (mean +/- SD = 13.0 +/- 0.1 years) who were enrolled in the Reduce Obesity and Diabetes (ROAD) project. Insulin sensitivity was assessed by quantitative insulin sensitivity check index. Insulin secretory capacity was measured as acute insulin response and glucose disposal index. RESULTS: Serum RBP4 was significantly correlated directly with ALT, triglycerides, and triglyceride z-score, and inversely correlated with adiponectin. Correlations with ALT and adiponectin remained significant when corrected for % body fat, age, and gender. There were significant ethnic differences in the relationship of RBP4 to ALT, glucose disposal index and adiponectin. CONCLUSIONS: In early- to mid-adolescents, circulating concentrations of RBP4 are correlated with multiple risk factors for adiposity-related co-morbidities. The observation that many associations persisted when corrected for % body fat, suggests that RBP4 can be viewed as an independent marker of adiposity-related co-morbidity risk in children.

Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic.

PURPOSE: Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown. METHODS: We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups. RESULTS: First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband's condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01). CONCLUSION: Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.

Glucocorticoid Resistance in Premature Adrenarche and PCOS: From Childhood to Adulthood.

CONTEXT: We hypothesize that impaired glucocorticoid sensitivity (GC sensitivity) plays a role in the development of premature adrenarche (PA) and polycystic ovarian syndrome (PCOS) by increasing androgen synthesis. OBJECTIVE: To study glucocorticoid sensitivity in vitro in subjects with PA and PCOS. PATIENTS AND METHODS: Fourteen subjects (10 girls, 4 boys, 6.9 ± 0.6 years) with PA; 27 subjects with PCOS (17 ± 2.5 years) and 31 healthy controls were enrolled in the study. All subjects and controls underwent GC sensitivity analysis in vitro using a fluorescein labeled-dexamethasone (F-DEX) assay. A GC sensitivity index (GCSI) was calculated as area under the curve of the F-DEX assay results. Subjects were classified as GC resistant if the GCSI ≤ 264 and GC sensitive if the GCSI ≥ 386. RESULTS: In the PA group, 8 of 14 subjects were resistant with GCSI of 179.7 ± 39.9, 4 were within the normal range with GCSI of 299.6 ± 27.9, and 2 had increased GC sensitivity with GCSI of 423.5 ± 47.9. In the PCOS group, 18 of 27 subjects were GC-resistant with GCSI of 180.9 ± 58.2, 8 were within the normal range with GCSI of 310.7 ± 26.4, and 1 had increased GCSI of 395.4. In the PCOS GC-resistant subgroup, cortisol was higher compared with PCOS with normal GCSI (P < 0.05). In the combined PCOS plus female control group, GCSI correlated negatively with cortisol and testosterone (P < 0.05). CONCLUSION: GC resistance was found in more than 50% of patients with PCOS and PA. The findings strongly suggest that GC resistance is associated with states of PA and PCOS.

Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation.

CONTEXT: Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24). OBJECTIVE: The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy. DESIGN AND PATIENT: The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3-7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts. RESULTS: LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase. CONCLUSION: Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.

Radioimmunoassay for autoantibodies against interferon omega; its use in the diagnosis of autoimmune polyendocrine syndrome type I.

Patients with the autoimmune polyendocrine syndrome I (APS I) have high titers of neutralizing IgG autoantibodies against type I interferons (IFNs), in particular IFN-omega. Until now, the most specific assay has been the antiviral interferon neutralizing assay (AVINA), which has the drawbacks of requiring a cytolytic virus, being cumbersome and difficult to standardise. We have developed a fast and reliable immunoassay based on radiolabelled IFN-omega for quantifying anti-IFN-omega antibodies. Sera from 48 APS I patients were analysed together with those from 5 control groups. All sera from APS I patients were positive for anti-IFN-omega, while, except one serum, all sera from the controls were negative. This method has the advantage over bioassays that it is readily adapted to high throughput. It provides an alternative, sensitive and specific diagnostic test for APS I, and an ideal screening tool to precede mutational analyses of the AIRE gene in suspected APS I cases.

Insulin receptor autoimmunity and insulin resistance.

The frequency of insulin receptor autoantibodies (IR-ab) was determined among adolescents and young adults with documented insulin resistance syndrome (IRS) with and without concomitant autoimmunity. The study population was comprised of 61 patients with obesity, acanthosis nigricans and insulin resistance (simple IRS); 12 with IRS and other autoimmune problems (lupus erythematosus, rheumatoid arthritis, dermatomyositis) (type B insulin resistance); six with autoimmune polyglandular syndrome type 2; and 40 healthy controls. Using our newly developed radiobinding assay system, we found no control positive while 25% of the patients with type B IRS (3/12) were positive, as expected. However, we found that 9.8% of the patients with simple IRS (6/61) were also reproducibly positive. All the latter patients with positive IR-ab were female with ovarian hyperandrogenism. The phenotype of those affected was otherwise unremarkably different from those without IR-ab. Our findings suggest that autoimmunity to insulin receptors may be causal in IRS especially for females with ovarian hyperandrogenism, and that IR-ab may be found in IRS besides those previously defined by the type B phenotype. Determining the level of IR-ab in childhood onset IRS may provide mechanistic insights into the genesis of insulin resistance and lead to novel treatment approaches.

Resting energy expenditure in insulin resistance falls with decompensation of insulin secretion in obese children.

BACKGROUND: Low resting energy expenditure (REE) and respiratory quotient (RQ) have been shown in adults to predispose to obesity and diabetes mellitus. AIM: 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. DESIGN: 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). RESULTS: 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. CONCLUSIONS: Findings in the CIR and DIR groups support the correlation of REE with metabolic changes consistent with an increased risk of diabetes mellitus.

Novel mutation in cytochrome P450c17 causes complete combined 17alpha-hydroxylase/17,20-lyase deficiency.

BACKGROUND: 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. PATIENT: 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. METHODS: 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. RESULTS: 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. CONCLUSION: This patient is a compound heterozygote for nonsense mutations in the CYP17 gene, which confirms the diagnosis of 17OHD.

Baseline IGFBP - 3 as the Key Element to Predict Growth Response to Growth Hormone and IGF - 1 Therapy in Subjects with Non - GH Deficient Short Stature and IGF - 1 Deficiency.

BACKGROUND: Short stature in children represents a heterogeneous group with different etiologies. Primary Insulin like growth factor 1 (IGF - 1) deficiency in short stature can present with normal or elevated growth hormone (GH) production. Currently there is no model that can reliably predict response to recombinant (r)GH therapy and/or rIGF - 1 therapy in children with non - GH deficient short stature. HYPOTHESIS: Baseline Insulin like growth factor binding protein 3 (IGFBP - 3) along with ∆ IGF - 1 in the first 3 months of GH therapy level can be a marker of growth response to the rGH and/or rIGF - 1 therapy in children with non - growth hormone deficiency short stature. OBJECTIVES: To study the relationship between baseline IGFBP - 3 and IGF - 1 levels and the response to rGH and rIGF - 1 therapy in children with short stature, normal GH secretion and low IGF - 1 SDS. METHODS: 43 children, age 9.07 ± 2.75 years with height -2.72 ± 0.7 SD and baseline IGF - 1 of -2.76 ± 0.58 SD, who passed the growth hormone releasing hormone (GHRH) stimulation test were included in a retrospective chart review. They were treated with rGH therapy with a mean dose of 0.46 ± 0.1 mg/kg/week. Growth velocity (GV), IGF - 1 and IGFBP - 3 levels were done at 3 and 6 months of therapy. Subjects with poor response to rGH after 6 months of therapy were switched to rIGF - 1 therapy at 0.24 mg/kg/day for the next 6 months. Subjects were divided according to their growth rate into responders to rGH (N = 23); non - responders to rGH, responders to rIGF - 1 (N = 14) and non - responders to rGH and rIGF-1 (N = 6). RESULTS: There was no correlation between GV and peak GH level at GHRH test. Growth velocity positively correlated with ΔIGF - 1 SD among subjects treated with rGH therapy. Height SD positively correlated with IGFBP - 3 SD. Baseline IGFBP - 3 also inversely correlated with GH peak during GHRH test. CONCLUSIONS: In subjects with short stature and low IGF - 1 level, baseline IGFBP - 3 levels can predict the growth response to rGH and/or rIGF - 1 therapy.

Phenotypic spectrum and responses to recombinant human IGF1 (rhIGF1) therapy in patients with homozygous intronic pseudoexon growth hormone receptor mutation.

BACKGROUND: Patients with homozygous intronic pseudoexon GH receptor (GHR) mutations (6Ψ) have growth hormone insensitivity (GHI) (growth failure, IGF1 deficiency and normal/elevated serum GH). We report 9 patients in addition to previously described 11 GHR 6Ψ patients and their responses to rhIGF1 therapy. METHODS: 20 patients (12 males, 11 families, mean age 4.0 ± 2.2 years) were diagnosed genetically in our centre. Phenotypic data and responses to rhIGF1 treatment were provided by referring clinicians. Continuous parametric variables were compared using Student t-test or ANOVA. RESULTS: 10/20 (50%) had typical facial features of GHI, 19/20 (95%) from consanguineous families and 18/20 (90%) of Pakistani origin. At diagnosis, mean height SDS: -4.1 ± 0.95, IGF1 SDS: -2.8 ± 1.4; IGFBP3 SDS: -3.0 ± 2.1 and mean basal and peak GH levels: 11.9 µg/L and 32.9 µg/L, respectively. 1/12 who had IGF1 generation test, responded (IGF1: 132-255 ng/mL). 15/20 (75%; 11M) received rhIGF1 (mean dose: 114 µg/kg twice daily, mean duration: 5.3 ± 2.5 years). Mean baseline height velocity of 4.7 ± 1.1 cm/year increased to 7.4 ± 1.8 cm/year (P = 0.001) during year 1 of therapy. Year 3 mean height SDS (-3.2 ± 1.0) was higher than pre-treatment height SDS (-4.3 ± 0.8) (P = 0.03). Mean cumulative increase in height SDS after year 5 was 1.4 ± 0.9. Difference between target height (TH) SDS and adult or latest height SDS was less than that of TH SDS and pre-treatment height SDS (2.1 ± 1.2 vs 3.0 ± 0.8; P = 0.02). CONCLUSION: In addition to phenotypic heterogeneity in the cohort, there was mismatch between clinical and biochemical features in individual patients with 6Ψ GHR mutations. rhIGF1 treatment improved height outcomes.

Role of a founder c.201_202delCT mutation and new phenotypic features of congenital lipoid adrenal hyperplasia in Palestinians.

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.

Multiple immuno-regulatory defects in type-1 diabetes.

Susceptibility to immune-mediated diabetes (IMD) in humans and NOD mice involves their inherently defective T cell immunoregulatory abilities. We have followed natural killer (NK) T cell numbers in patients with IMD, both by flow cytometry using mAbs to the characteristic junctions found in the T cell receptors of this cell subtype, and by semiquantitative RT-PCR for the corresponding transcripts. Both before and after clinical onset, the representation of these cells in patients' PBMCs is reduced. We also report low numbers of resting CD4(+) CD25(+) T cells in IMD patients, a subset of T cells shown to have important immunoregulatory functions in abrogating autoimmunities in 3-day thymectomized experimental mice. Whereas a biased Th1 to Th2 cytokine profile has been suggested to underlie the pathogenesis of IMD in both species, we found defective production of IFN-gamma in our patients after in vitro stimulation of their PBMCs by phorbol-myristate acetate and ionomycin and both IFN-gamma and IL-4 deficiencies in V(alpha)24(+) NK T-enriched cells. These data suggest that multiple immunoregulatory T (Treg) cell defects underlie islet cell autoimmunity leading to IMD in humans and that these lesions may be part of a broad T cell defect.

Childhood obesity and insulin resistance.

Insulin resistance (IR) in childhood has importance to the understanding and prevention of the growing epidemic of insulin resistance syndrome (IRS) in adults with attendant obesity, type 2 diabetes (T2DM), atherosclerotic diseases, hypertension, gout, non-alcoholic, steato-hepatitis (NASH), gall bladder disease, nephropathy, polycystic ovarian disease (PCOS), infertility and premature senility. The severity of IR and its' complications in children unfortunately and usually progresses in their pubertal transition to adulthood; affected young children are more likely than adults to have underlying causal monogenic disorders; the sequence of natural history and events give insights into disease pathogeneses, and optimal life style choices that last are best made during the early formative years. Some features of IR in children discussed herein are: a strong tendency to low birth weight for gestational age, adverse effects of adrenarche and therapeutic steroid therapy, predisposition to premature pubarche, acanthosis nigricans, tall stature despite pituitary GH suppression, allergic diathesis, hyperandrogenism and PCOS, dyslipidemia and fatty liver disease, and diagnosis by clinical and biochemical markers of IR including insulin regulated hepatic hormonal binding proteins such as IGFBP-1. The national preoccupation with the "metabolic syndrome" T2DM and obesity, should be appropriately directed to an improved understanding of IR in children and their management, if the looming health crisis in affected adults is to be seriously addressed. The nation is facing its' first generation of children who will be less healthy and die younger than the previous generation (Marks (2005) Presentation to the American Association of Diabetes Educators 32nd Annual Meeting and Exhibition, August 10-13, Washington, DC).