Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort.

CONTEXT: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism. AIMS: To describe main phenotype patterns and their evolution through life. DESIGN: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. RESULTS: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. CONCLUSION: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature.

Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus. He developed epilepsy 2 years later. The temporal tumor was surgically resected because of increasing crises and worsening radiological signs. Microscopy showed nodules with specific glioneuronal elements or glial nodules, leading to the diagnosis of dysembryoplastic neuroepithelial tumor (DNT). Immunohistochemistry revealed positive nuclear staining with Olig2 and pERK in small cells. SHP2 plays a key role in RAS/MAPK pathway signaling which controls several developmental cell processes and oncogenesis. An amino-acid substitution in the N-terminal SHP2 domain disrupts the self-locking conformation and leads to ERK activation. Glioneuronal tumors including DNTs and pilocytic astrocytomas have been described in NS. This report provides further support for the relation of DNTs with RASopathies and for the implication of RAS/MAPK pathways in sporadic low-grade glial tumors including DNTs. © 2017 Wiley Periodicals, Inc.

Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature.

Noonan syndrome (NS), a genetic disease caused in half of cases by activating mutations of the tyrosine phosphatase SHP2 (PTPN11), is characterized by congenital cardiopathies, facial dysmorphic features, and short stature. How mutated SHP2 induces growth retardation remains poorly understood. We report here that early postnatal growth delay is associated with low levels of insulin-like growth factor 1 (IGF-1) in a mouse model of NS expressing the D61G mutant of SHP2. Conversely, inhibition of SHP2 expression in growth hormone (GH)-responsive cell lines results in increased IGF-1 release upon GH stimulation. SHP2-deficient cells display decreased ERK1/2 phosphorylation and rat sarcoma (RAS) activation in response to GH, whereas expression of NS-associated SHP2 mutants results in ERK1/2 hyperactivation in vitro and in vivo. RAS/ERK1/2 inhibition in SHP2-deficient cells correlates with impaired dephosphorylation of the adaptor Grb2-associated binder-1 (GAB1) on its RAS GTPase-activating protein (RASGAP) binding sites and is rescued by interfering with RASGAP recruitment or function. We demonstrate that inhibition of ERK1/2 activation results in an increase of IGF-1 levels in vitro and in vivo, which is associated with significant growth improvement in NS mice. In conclusion, NS-causing SHP2 mutants inhibit GH-induced IGF-1 release through RAS/ERK1/2 hyperactivation, a mechanism that could contribute to growth retardation. This finding suggests that, in addition to its previously shown beneficial effect on NS-linked cardiac and craniofacial defects, RAS/ERK1/2 modulation could also alleviate the short stature phenotype in NS caused by PTPN11 mutations.

Growth hormone treatment in children with Prader-Willi syndrome: safety and effectiveness data from the PATRO Children study.

Background: Recombinant human growth hormone (rhGH, somatropin) therapy is approved in children with Prader-Willi syndrome (PWS). Objectives: To report safety and effectiveness data for children with PWS treated with biosimilar rhGH (Omnitrope®, Sandoz) in the PAtients TReated with Omnitrope (PATRO) Children study. Design: PATRO Children was a multicenter, non-interventional, postmarketing surveillance study. Methods: Children with PWS received Omnitrope according to standard clinical practice. Adverse events (AEs) were monitored for the duration of Omnitrope treatment. Effectiveness outcomes were also assessed, including height standard deviation (SD) scores (HSDS). Results: As of July 2020 (study completion), 235 patients with PWS had been enrolled. At baseline, 95.7% (n = 225) of patients were prepubertal and 86.4% (n = 203) were rhGH treatment-naïve. At analysis, the median (range) treatment duration in the study was 56.8 (2.9-155.8) months. AEs were reported in 192 patients (81.7%) and were suspected as treatment-related in 39 patients (16.6%). Serious AEs (SAEs) were reported in 96 patients (40.9%) and were suspected as treatment-related in 22 patients (9.4%). The most frequent treatment-related SAEs were sleep apnea syndrome (n = 11; 4.7%), tonsillar hypertrophy (n = 4; 1.7%), and adenoidal hypertrophy (n = 4; 1.7%). Development of scoliosis was considered treatment-related in two patients; development of impaired glucose tolerance in one patient and type 2 diabetes mellitus in another patient were considered treatment-related. Effectiveness outcomes were primarily assessed in 153 patients who completed 3 years of treatment. Among the 151 prepubertal patients (135 treatment-naïve), mean (SD) change from baseline in HSDS after 3 years was +1.50 (1.07) across all patients and +1.57 (1.07) for treatment-naïve patients. Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in patients with PWS managed in real-life clinical practice. Patients with PWS should continue to be closely monitored for well-known safety issues (including respiratory, sleep, and glucose metabolism disorders, and scoliosis) during rhGH treatment.

A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone.

Growth hormone is used to increase height in short children who are not deficient in growth hormone, but its efficacy varies largely across individuals. The genetic factors responsible for this variation are entirely unknown. In two cohorts of short children treated with growth hormone, we found that an isoform of the growth hormone receptor gene that lacks exon 3 (d3-GHR) was associated with 1.7 to 2 times more growth acceleration induced by growth hormone than the full-length isoform (P < 0.0001). In transfection experiments, the transduction of growth hormone signaling through d3-GHR homo- or heterodimers was approximately 30% higher than through full-length GHR homodimers (P < 0.0001). One-half of Europeans are hetero- or homozygous with respect to the allele encoding the d3-GHR isoform, which is dominant over the full-length isoform. These observations suggest that the polymorphism in exon 3 of GHR is important in growth hormone pharmacogenetics.

OBSL1 mutations in 3-M syndrome are associated with a modulation of IGFBP2 and IGFBP5 expression levels.

3-M syndrome is an autosomal recessive disorder characterized by severe pre- and postnatal growth retardation and minor skeletal changes. We have previously identified CUL7 as a disease-causing gene but we have also provided evidence of genetic heterogeneity in the 3-M syndrome. By homozygosity mapping in two inbred families, we found a second disease locus on chromosome 2q35-36.1 in a 5.2-Mb interval that encompasses 60 genes. To select candidate genes, we performed microarray analysis of cultured skin fibroblast RNA from one patient, looking for genes with altered expression; we found decreased expression of IGFBP2 and increased expression of IGFBP5. However, direct sequencing of these two genes failed to detect any anomaly. We then considered other candidate genes by their function/location and found nine distinct mutations in the OBSL1 gene in 13 families including eight nonsense and one missense mutations. To further understand the links between OBSL1, CUL7, and insulin-like growth factor binding proteins (IGFBPs), we performed real-time quantitative PCR (RT-PCR) analysis for OBSL1, CUL7, IGFBP2, and IGFBP5, using cultured fibroblast RNAs from two patients with distinct OBSL1 mutations (p.F697G; p.H814RfsX15). We found normal CUL7 mRNA levels but abnormal IGFBP2 and IGFBP5 mRNA levels in the two patients, suggesting that OBSL1 modulates the expression of IGFBP proteins.

Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.

Necdin plays a role in the serotonergic modulation of the mouse respiratory network: implication for Prader-Willi syndrome.

Prader-Willi syndrome is a neurogenetic disease resulting from the absence of paternal expression of several imprinted genes, including NECDIN. Prader-Willi children and adults have severe breathing defects with irregular rhythm, frequent sleep apneas, and blunted respiratory regulations. For the first time, we show that Prader-Willi infants have sleep apneas already present at birth. In parallel, in wild-type and Necdin-deficient mice, we studied the respiratory system with in vivo plethysmography, in vitro electrophysiology, and pharmacology. Because serotonin is known to contribute to CNS development and to affect maturation and function of the brainstem respiratory network, we also investigated the serotonergic system with HPLC, immunohistochemistry, Rabies virus tracing approaches, and primary culture experiments. We report first that Necdin-deficiency in mice induces central respiratory deficits reminiscent of Prader-Willi syndrome (irregular rhythm, frequent apneas, and blunted respiratory regulations), second that Necdin is expressed by medullary serotonergic neurons, and third that Necdin deficiency alters the serotonergic metabolism, the morphology of serotonin vesicles in medullary serotonergic neurons but not the number of these cells. We also show that Necdin deficiency in neonatal mice alters the serotonergic modulation of the respiratory rhythm generator. Thus, we propose that the lack of Necdin expression induces perinatal serotonergic alterations that affect the maturation and function of the respiratory network, inducing breathing deficits in mice and probably in Prader-Willi patients.

Growth hormone in combination with leuprorelin in pubertal children with idiopathic short stature.

OBJECTIVE: There is a scarcity of data from randomised controlled trials on the association of growth hormone (GH) with gonadotrophin-releasing hormone agonists in idiopathic short stature (ISS), although this off-label use is common. We aimed to test whether delaying pubertal progression could increase near-adult height (NAH) in GH-treated patients with ISS. METHODS: Patients with ISS at puberty onset were randomised to GH with leuprorelin (combination, n = 46) or GH alone (n = 45). NAH standard deviation score (SDS) was the primary outcome measure. The French regulatory authority requested premature discontinuation of study treatments after approximately 2.4 years; patients from France were followed for safety. RESULTS: Mean (s.d.) baseline height SDS was -2.5 (0.5) in both groups, increasing at 2 years to -2.3 (0.6) with combination and -1.8 (0.7) with GH alone. NAH SDS was -1.8 (0.5) with combination (n = 19) and -1.9 (0.8) with GH alone (n = 16). Treatment-emergent adverse events and bone fractures occurred more frequently with combination than GH alone. CONCLUSION: Due to premature discontinuation of treatments, statistical comparison of NAH SDS between the two cohorts was not possible. During the first 2-3 years of treatment, patients treated with the combination grew more slowly than those receiving GH alone. However, mean NAH SDS was similar in the two groups. No new GH-related safety concerns were revealed. A potentially deleterious effect of combined treatment on bone fracture incidence was identified.

Genetic study of the melanin-concentrating hormone receptor 2 in childhood and adulthood severe obesity.

CONTEXT: The melanin-concentrating hormone receptor 2 (MCHR2) is a G protein-coupled receptor for melanin-concentrating hormone, a neuropeptide that plays an important role in feeding behaviors. MCHR2 maps on chromosome 6q16.3, in a susceptibility locus for childhood obesity. OBJECTIVE: The aim of this study was to investigate the association between MCHR2 variation and human obesity. DESIGN: Case control and family-based studies were performed. PARTICIPANTS: A total of 141 obese children and 24 nonobese adult subjects was sequenced, and case-control analyses were conducted using 628 severely obese children and 1,401 controls. RESULTS: There were 11 single nucleotide polymorphisms (SNPs) identified. We showed nominal association among -38,245 ATG A/G SNP (P = 0.03; 95% confidence interval 1.02-1.34; odds ratio 1.17), A76A T/C SNP (P = 0.03; 95% confidence interval 0.58-0.97; odds ratio 0.75), and childhood obesity. Analysis of 645 trios with childhood obesity supported further the A76A T/C association, showing an overtransmission to obese children of the at risk T allele (59.0%; P = 0.01), especially in children with most severe forms of obesity (Z score of body mass index > 4) (67.0%; P = 0.003). The A76A at risk T allele was also associated with overeating during meals (P = 0.02) in an additional group of 102 nonobese children. None of the MCHR2 variants, including the A76A SNP, showed association with adult severe obesity, although a trend for association of the T allele of this variant with food disinhibition (P = 0.06) and higher hunger (P = 0.09) was found. This variant was not associated with childhood obesity in an independent case-control study, including 1,573 subjects (P = 0.98). Moreover, the A76A SNP did not explain the linkage on the 6q locus. CONCLUSION: Our results altogether suggest that MCHR2 is not a major contributor to polygenic obesity and support a modest effect of the A76A SNP on food intake abnormalities in childhood.

No contribution of angiotensin-converting enzyme (ACE) gene variants to severe obesity: a model for comprehensive case/control and quantitative cladistic analysis of ACE in human diseases.

Candidate gene analyses are often inconclusive owing to genetic or phenotypic heterogeneity, low statistical power, selection of nonfunctional SNPs, and inadequate statistical analysis of the genetic architecture. Angiotensin-converting enzyme (ACE) is involved in adipocyte growth and function and the ACE-processed angiotensin II inhibits adipocyte differentiation. Associations between body mass index (BMI) and ACE polymorphisms have been reported in general populations, but the contribution to severe obesity of this gene, which is located under an obesity genome-scan linkage peak on 17q23, is unknown. ACE is one of the most studied genes and markers responsible for variation in circulating ACE enzyme levels have been extensively characterised. Eight of these variants were genotyped in 1054 severely obese cases and 918 nonobese controls, as well as 116 nuclear families from the genome scan (n=447), enabling the known clades to be inferred. Qualitative analysis of individual single-nucleotide polymorphisms (SNPs), haplotypes, clades, and diploclades demonstrated no significant associations (P<0.05) after minimal correction for multiple testing. Quantitative analysis of clades and diploclades for BMI, waist-to-hip ratio, or ZBMI in children were also not significant. This rigorous, large-scale study of common, well-defined, severe polygenic obesity provides strong evidence that functionally relevant sequence variation in ACE, whether it is defined at the level of SNPs, haplotypes, or clades, is not associated with severe obesity in French Caucasians. Such a study design exemplifies the strategy needed to clearly define the contribution of the ACE gene to the plethora of complex genetic diseases where weak associations have been previously reported.

Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients.

Context: LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism. Objective: The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4. Design and Patients: We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants. Results: We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant. Conclusion: This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.

Association of melanin-concentrating hormone receptor 1 5' polymorphism with early-onset extreme obesity.

Murine models have been highly effective in identifying the monogenic forms of human obesity discovered to date. Melanin-concentrating hormone receptor 1 (MCHR1) has been shown to be significant in the downstream orexigenic activity of the leptin-melanocortin pathway by such models. In this study, the human MCHR1 gene was extensively characterized by sequencing 3.5 kb of coding, untranslated and intronic regions plus 1 kb of putative promoter region in 180 morbidly obese adults and 87 morbidly obese children, a total of >2.4 Mb of sequencing. Thirty-nine single nucleotide polymorphisms (SNPs) were found, seven of which encode an amino acid change. One mutation, R248Q, appeared to cosegregate with the obesity trait in one pedigree but was also found to be a rare polymorphism in control samples. To investigate the possible polygenic role of MCHR1, the six common SNPs (minor allele frequency >5%) found in the sequenced regions were then screened in 557 morbidly obese adults, 552 obese children, and 1,195 nonobese nondiabetic control subjects. The plausible promoter SNP, rs133068, was found to be associated with protection against obesity in obese children only (allele frequency P = 0.006 and genotype frequency P = 0.004). Most significant results were found when using a dominant model (P = 0.001, odds ratio 0.695 [95% CI 0.560-0.863]). However, similar associations were found when both adults and children were analyzed together (P = 0.006, 0.783 [0.658-0.930]), suggesting that severe forms of obesity with early onset may be associated with SNPs in MCHR1.

Adult height and pubertal growth in Turner syndrome after treatment with recombinant growth hormone.

OBJECTIVE: The objective of this study was to evaluate factors affecting adult height (AH) in patients with Turner syndrome treated with GH. DESIGN: The study design was a population-based cohort study. SETTING: The setting was The StaTur Study, a register of patients treated in France between 1986 and 1997, followed for a mean of 9.3 yr. PATIENTS: We followed 704 of the 891 eligible patients (79%) to AH. INTERVENTION: GH (0.8 +/- 0.2 IU/kg.wk; 0.26 +/- 0.06 mg/kg.wk; mean +/- sd) was administered for 5.0 +/- 2.2 yr. Puberty was classified as spontaneous (10%), spontaneous with secondary estrogens (13%), or induced (77%). Estrogen treatment was initiated at 15.0 +/- 1.9 yr of age in those with induced puberty. MAIN OUTCOME MEASURE: The main outcome measure was multivariate analysis of AH after grouping potential predictors. RESULTS: The mean AH was 149.9 +/- 6.1 cm, 8.5 cm above projected height. The model explained 90% of the variance, with major effects of age at initiation and duration of treatment. Other factors included birth length, target height, bone age delay and weight at initiation of treatment, age at pubertal onset, GH dose, and number of injections per week. Age at introduction of estrogens was not a predictor, and the use of percutaneous vs. oral estrogens was associated with greater height (+2.1 cm; 95% confidence interval, 1.00-3.25). CONCLUSIONS: Our results support the early initiation of GH treatment and induction of puberty at a physiological age to achieve optimal AH. They suggest that GH should be injected daily, and percutaneous estrogens used. These results should be considered in the context of the lack of demonstrable influence of AH on psycho-social outcomes, uncertainties regarding long-term safety, and treatment cost.

Is glutamate decarboxylase 2 (GAD2) a genetic link between low birth weight and subsequent development of obesity in children?

Low birth weight is a risk factor for obesity and type 2 diabetes. The fetal insulin hypothesis proposes that low birth weight might be mediated partly by genetic factors that impair insulin secretion/sensitivity during the fetal stage, as shown for glucokinase, the ATP-sensitive K+ channel subunit Kir6.2, and the small heterodimer partner genes. Glutamic acid decarboxylase 2 gene (GAD2) overexpression impairs insulin secretion in animals. Recently, polymorphisms in the GAD2 gene were associated with adult morbid obesity. In the present study, we investigated potential effects of the functional -243 A-->G polymorphism in the 5' promoter region of the GAD2 gene on fetal growth, insulin secretion, food intake, and risk of obesity in 635 French Caucasian severely obese children from three different medical centers. The case/control study confirmed the association between the GAD2 single-nucleotide polymorphism (SNP) -243 A-->G and obesity (odds ratio, 1.25; P = 0.04). In addition, SNP -243 GG children carriers showed a 270 g lower birth weight and a 1.5 cm lower birth height compared with AA carriers (P = 0.009 and P = 0.013, respectively). The relation between birth weight and Z score of BMI was linear in AA carrier children (P = 0.00001) and quadratic (U-shaped curve) in AG/GG carrier children (P = 0.0009). G allele children carriers presented a trend toward lower insulinogenic index with 25% reduction of insulin secretion in response to glucose load compared with A carriers (P = 0.09). Eighteen percent of GG obese carriers vs. 5.7% of AA carriers reported binge eating phenotype (P = 0.04). These results confirm the association between GAD2-243 promoter SNP and the risk for obesity and suggest that GAD2 may be a polygenic component of the complex mechanisms linking birth weight to further risk for metabolic diseases, possibly involving the pleiotropic effect of insulin on fetal growth and later on feeding behavior.

Quality of life determinants in young women with turner's syndrome after growth hormone treatment: results of the StaTur population-based cohort study.

GH is used to increase adult height in children with Turner's syndrome with little knowledge of the impact on quality of life. We carried out a population-based cohort study of quality-of-life determinants in young women with Turner's syndrome, all previously treated with GH. Of 891 eligible women aged over 18 yr and recorded in the French Growth Hormone Register, 818 were available and 568 participated (69%). They were assessed for demographic characteristics, health status, sexual life, treatment expectations, scores for Medical Outcome Study Short Form 36 (SF-36), and General Health Questionnaire 12. Participants were 22.6 +/- 2.6 yr old (mean +/- sd), measured 150.9 +/- 5.6 cm, and had received GH for 4.8 +/- 2.2 yr. SF-36 scores were similar in participants and French women of the general population. Cardiac (12% of participants) or otological (26% of participants) involvement or induction of puberty after 15 yr of age was associated with lower scores for at least one of the SF-36 dimensions. Height and estimated height gain from treatment were not associated with quality-of-life scores. Higher expectations from treatment were associated with lower quality of life. We conclude that quality of life is normal and unaffected by height in young adults with Turner's syndrome treated with GH. These data emphasize the need to give appropriate attention to general health and otological care rather than focus on stature in the care of children with Turner's syndrome.

Implication of the Pro12Ala polymorphism of the PPAR-gamma 2 gene in type 2 diabetes and obesity in the French population.

BACKGROUND: The Pro12Ala Single Nucleotide Polymorphism (SNP) of the Peroxisome Proliferator-Activated Receptor gamma 2 (PPAR-gamma 2) has been associated with insulin resistance and type 2 diabetes (T2D) and also inconsistently with obesity. The aim of this study was to evaluate the impact of this SNP with regards to T2D and childhood and adult obesity in the French Caucasian population. METHODS: We conducted three independent case/control studies encompassing 2126 cases and 1124 controls. RESULTS: We found a significant association between PPAR-gamma 2 Pro12Ala SNP and T2D (p = 0.04, OR = 1.37), which was stronger when the T2D cohort was stratified according to the obesity status (p = 0.03, OR = 1.81 in obese T2D subjects). In contrast, there was no association between the Pro12Ala SNP and childhood and adulthood obesity. In normal glucose tolerant obese adults (but not in lean subjects), the Pro12 allele was associated with a significant increase in fasting insulin levels (p = 0.01), and in insulin resistance estimated by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (p = 0.003), after adjustment for age, gender and BMI. We didn't detect evidence for an interaction effect between the Pro12Ala SNP and the obesity status with respect to the HOMA-IR index in normal glucose tolerant children, but we found a borderline interaction (p = 0.06) in normal glucose tolerant adults. CONCLUSION: Our results showed that the Pro12Ala polymorphism is not associated with childhood or adult obesity in the French Caucasian population. In contrast, we confirm a contribution of the PPAR-gamma 2 Pro12 allele in the genetic risk forT2D, especially in obese subjects, where this allele worsens insulin resistanceand increases fasting insulin levels.

An N-terminal WT1 mutation (P181S) in an XY patient with ambiguous genitalia, normal testosterone production, absence of kidney disease and associated heart defect: enlarging the phenotypic spectrum of WT1 defects.

OBJECTIVE: This study reports the clinical and molecular data of an XY patient with a very unusual phenotype due to a Wilms' tumor-suppressor (WT1) gene mutation. The genotype-phenotype relationship of different WT1 mutations is then discussed. PATIENT: The patient presented at birth with micropenis, severe hypospadias and cryptorchidism. Normal androgen production and an absence of clinical response to a testosterone treatment trial suggested partial androgen resistance. Eventually, female sex of rearing was chosen. At the beginning of puberty, normal male androgen production occurred, and subsequent gonadectomy did not show gonadal dysgenesis. It is notable that the patient, now 20 years of age, has not developed kidney disease. In addition to the genital malformation, the patient displayed an associated congenital heart defect, consisting of a coarctation of the aorta and a patent ductus arteriosis (PDA). RESULTS: No mutations were detected in the androgen receptor or 5alpha-reductase genes. Direct sequencing of the WT1 gene identified a heterozygous proline to serine substitution at position 181 (P181S). The same heterozygous mutation was found in the mother. Interestingly, the mother shows no signs of kidney disease at her present age of 49. CONCLUSION: This is the first germline missense mutation in the N-terminal part of WT1 identified in a patient with the very particular phenotype of ambiguous genitalia with absence of gonadal dysgenesis and kidney disease. The possible molecular mechanisms leading to the patient's phenotype are considered. The high frequency of PDA in newborns and the absence of heart abnormalities in XX females carrying the P181S mutation, however, suggest that the heart defect was most likely a coincidental association. This case enlarges the clinical spectrum of WT1 defects and may provide new insights into the complex functions of WT1 in genital and kidney development.

Associations of glucocorticoid receptor and corticosteroid-binding globulin gene polymorphisms on fat mass and fat mass distribution in prepubertal obese children.

Previous studies conducted in adult obese patients have shown that glucocorticoid receptor and corticosteroid-binding globulin gene polymorphisms influence cortisol-driven obesity and metabolic parameters. We investigated the impact of these polymorphisms in prepubertal obese children that were thoroughly examined for hypothalamic-pituitary-adrenal axis activity and for metabolic and obesity parameters. Obese children carrier of the allele G of the BclI polymorphism within glucocorticoid receptor gene tend to present a higher percentage of fat mass as well as a decreased cortisol suppression after low-dose dexamethasone as found in adult studies. Additionally, these allele G carriers show a strong correlation between truncal fat mass distribution and cortisol response to a standardized lunch, whereas this correlation is weak in allele C carriers. No differences were found for obesity or metabolic parameters between genotypes at the corticosteroid-binding globulin locus. However, allele 90 carriers present increased 24-h free urinary cortisol. Overall, this study provides new data showing the influence of glucocorticoid receptor and corticosteroid-binding globulin genes in obesity and/or cortisol action in prepubertal obese children.