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.

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.

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.

Prevalence and clinical features of type 1.5 diabetes mellitus in children.

AIM: To classify children with diabetes mellitus as type 1, 1.5 or 2, based on strict criteria, and then compare their features and treatment. METHODS: In this retrospective study, all children with diabetes mellitus in our clinic with antibody status available (n = 120) were reclassified as type 1, 1.5 or type 2 based on status of antibodies to the pancreas and presence of obesity and/or acanthosis nigricans, and their features compared. RESULTS: Sixty-four percent of type 2 patients were reclassified as type 1.5. Type 1.5 patients had significantly lower BMI SDS, blood pressure and acanthosis nigricans than type 2 patients. They had a higher insulin requirement (0.82 +/- 0.44 U/kg/day) than type 1 (0.72 +/- 0.35 U/kg/day) or type 2 (0.28 +/- 0.3 U/kg/day) patients. Total cholesterol, HDL-cholesterol, ALT and AST significantly worsened from type 1 to 1.5 to type 2 patients. CONCLUSIONS: Type 1.5 diabetes mellitus should be considered among obese adolescents presenting as type 2, as their clinical course is more aggressive and insulin requirement higher.

Prevalence of vitamin D insufficiency in obese children and adolescents.

OBJECTIVE: Recent studies have shown a broad prevalence of vitamin D deficiency in adults. Serum 25-hydroxyvitamin D (25-OHD) levels were reported to be inversely related to body mass index (BMI) and body fat content and correlated directly with hypertension, degree of insulin resistance and progression to diabetes mellitus. We sought to determine the prevalence of vitamin D insufficiency and markers of metabolic syndrome in an obese pediatric population. METHODS: Charts of 217 obese (weight >95th percentile for age and sex) children (118 females, 99 males; mean BMI 32.2 +/- 6.4 kg/m2; mean age 12.9 2 5.5; age range 7-18 years) who had received a standard physical examination at the pediatric endocrine clinic of the Infants and Children's Hospital of Brooklyn at Maimonides, Brooklyn, NY, were retrospectively analyzed. Data obtained included age, sex, weight, BMI, height and systolic and diastolic blood pressure. The routine bloodwork panel for obesity at our pediatric endocrine facility includes fasting 25-OHD, total cholesterol, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides, ALT, AST, thyroid stimulating hormone (TSH), total T4, and insulin and glucose. Insulin sensitivity as calculated by quantitative insulin-sensitivity check index (QUICKI = 1/[log(I0) + log(G0)], where I0 is fasting insulin and G0 is fasting glucose) was computed following the visit. RESULTS: Overall, 55.2% of patients were vitamin D insufficient (25-OHD <20 ng/ml). Severely low vitamin D levels (25-OHD < or =10 ng/ml) were seen in 21.6% of 217 patients, which represents almost half of the insufficient group. In the 25-OHD <20 ng/ml group age, BMI, and SBP were significantly higher than in the 25-OHD 220 ng/ml group, while QUICKI (<0.35 is consistent with insulin resistance) was borderline low in the <20 ng/ml group. HDL-C was significantly lower in the 25-OHD < or =10 ng/ml group. The 25-OHD levels correlated negatively with BMI and positively with HDL-C. No other findings were significant. CONCLUSION: More than half of the obese children had vitamin D levels <20 ng/ml with equal gender distribution. Vitamin D insufficiency was associated with increased age, BMI, and SBP, and decreased HDL-C.

Altered glucose disposition and insulin sensitivity in peri-pubertal first-degree relatives of women with polycystic ovary syndrome.

BACKGROUND: 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. AIM: To study insulin dynamics parameters in the early adolescent FDR of women with PCOS. METHODS: 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. 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. CONCLUSION: 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.

Markers of ovarian reserve in young girls with Turner's syndrome.

We describe a preliminary report identifying markers of ovarian reserve to identify candidates for ovarian cryopreservation. Among 14 patients with Turner's syndrome, those with a poor probability of fertility had a significantly higher FSH, lower inhibin A, and lower AMH compared with those with a fair probability of fertility.