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Context Unlike homozygous variants, the implication of heterozygous variants on the leptin–melanocortin pathway in severe obesity has not been established. Objective To describe the frequency, the phenotype, and the genotype–phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. Methods In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. Results The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI. Conclusion Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.

Treatment for short stature in childhood has been recommended with the purpose of improving adult health-related quality of life (HRQoL). However, there are only limited data available concerning the consequences of body height for HRQoL in adulthood.Our objective was to investigate the relationship between body height and HRQoL.This national representative, cross-sectional household survey of the French general noninstitutionalized population included 8857 men and 9248 women, aged 18-50 yr, in 2003.Scores on the eight subscales of the Medical Outcomes Study 36-item Short Form (SF-36) were the primary outcomes. Univariate and multivariate linear regression analyses were used to evaluate the effect of height on HRQoL while controlling for age and various socioeconomic variables and pathological conditions.Height was found to be a very weak predictor of HRQoL both for men and women. Only heights lower than 149.2 and 136.0 cm and higher than 203.6 and 188.7 cm, in men and women, respectively, were associated with a clinically significant reduction in physical functioning. The effects of body height on other (mental and social) dimensions of HRQoL were negligible or undetectable.Height appears to have minimal consequences for physical functioning and negligible effects on other dimensions of HRQoL. These results contrast with widely popularized stereotypes and common beliefs and should be carefully considered to avoid further stigmatization and unnecessary medical care of individuals who are at the lower end of the growth distribution.

The prevalence of SHOX deficiency in children with short stature (SS) is variable in the literature and various genotypes have been identified.The aim of our study was to determine the frequency and distribution of SHOX genotypes in a large sample of children with SS in France.Children were enrolled in 38 French pediatric endocrinology centers and were either diagnosed with Leri-Weill syndrome (LWS), idiopathic short stature (ISS), or disproportionate short stature (DSS).SHOX analysis was performed centrally as part of the Genetics and Neuroendocrinology of Short Stature International Study observational study. We compared patients with (SHOX-D) and without SHOX deficiency (non-SHOX-D).Among the 537 patients tested [58.3% females, mean age 11.0 (4.2) yr], 27.7% had SHOX deficiency (LWS, 48.9%; ISS, 16.9%; DSS, 18.8%). Mean height [-2.3 (0.9) sd score] was similar in SHOX-D and non-SHOX-D patients. The majority of SHOX-D patients with LWS had either a deletion encompassing SHOX or a point mutation (69%), whereas 59% of those with ISS had a deletion downstream of SHOX in the enhancer region. The height of the parents carrying a deletion downstream of SHOX was higher than the height of the parents carrying the other gene anomalies.SHOX deletions and point mutations as well as downstream SHOX enhancer deletions were identified in almost one third of the patients tested. An anomaly in this latter region seemed to be linked to a milder phenotype. Although further confirmation is needed, we suggest that the enhancer region should be systematically analyzed in patients suspected of SHOX deficiency.

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/kgwk; 0.26 0.06 mg/kgwk; 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 percutaneousvs. 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. (J Clin Endocrinol Metab 90: 5197–5204, 2005)

Familial male-limited precocious puberty is a rare cause of precocious puberty due to activating mutations of the LH receptor, leading to early onset virilization and short stature. Two therapeutic approaches have been proposed: the P450 cytochrome inhibitor ketoconazole or combined treatment with spironolactone and testolactone. Results on adult heights have not been reported to date after these two treatments, and in this study we present results from five patients treated with ketoconazole at a median dose of 16.2 mg/kg.d for a median of 6.2 yr. Adult height was 173 cm (median; interquartile range, 14), similar to target height (175 cm; interquartile range, 9) and significantly higher than pretreatment predicted height (165 cm; interquartile range, 12; P < 0.01). During treatment, 39 of 58 (68%) testosterone measurements were less than 0.5 ng/ml (1.7 nmol/liter), nine of 58 (15%) were between 0.5 and 1 ng/ml (3.5 nmol/liter), and 10 of 58 (17%) were above 1 ng/ml. We observed a physiological increase in GnRH-stimulated LH levels after the age of 10 yr, and none of the patients had early activation of the gonadotropic axis. Liver tolerance was excellent, and only one patient had a transient and modest increase in serum transaminases. We conclude that ketoconazole is an efficient and well tolerated long-term treatment of familial male-limited precocious puberty that should be proposed as a first line therapy.

Klinefelter syndrome is a major cause of infertility in the male. Nevertheless, pregnancies were recently obtained by intracytoplasmic injection of sperm retrieved by surgery or ejaculation, underscoring the need to understand the role of Sertoli and Leydig cell secretions during development. In 18 infants with prenatally diagnosed homogenous 47,XXY karyotype, blood samples were taken from birth to 3 yr of age. Inhibin B (INHB), anti-Mullerian hormone (AMH), testosterone, FSH, and LH levels were compared with those in six adolescents with XXY karyotype and reference values established in 215 control infants. In XXY infants FSH, LH, INHB, and AMH did not differ from controls. Testosterone levels during the first trimester exhibited a physiological increase but were lower than in controls (P = 0.0001). Significant correlations were found between testosterone and LH (P < 0001), between INHB and FSH (P = 0.0011), and between AMH and INHB (P = 0.025). In XXY adolescents, AMH and INHB were undetectable. Our findings demonstrate that testosterone secretion is impaired in infants with Klinefelter syndrome. By contrast, INHB and AMH secretions were not altered, which raises the question of the mechanism(s) governing the decline of Sertoli cell function after puberty.

Androgen insensitivity syndromes (AIS) result from the incapacity for T and dihydrotestosterone to virilize male embryos and is mainly attributable to molecular defects of the AR gene. In normal males, T and LH rise during the first few months of life, and this physiological surge is commonly used to evaluate the gonadotropic axis at this age. This neonatal surge has not been evaluated in detail in newborns with AIS. We sequentially measured plasma T, LH, and FSH during the first 3 months of life in 15 neonates with AIS and AR mutation. A GnRH and an human CG stimulation test were also performed. Patients were divided in 2 groups with complete (n = 10) or partial (n = 5) AIS (CAIS or PAIS), based on the clinical phenotype. In patients with PAIS, T levels were in the high-normal range at d 30 (18.4 +/- 6.9 nM) and d 60 (12.8 +/- 3.8 nM). In contrast, plasma T values were below the normal range in 9 of 10 patients with CAIS at d 30 (1 +/- 0.3 nM) and d 60 (1.4 +/- 0.7 nM, both P0.004 vs. PAIS). Plasma LH values were low in CAIS at d 30 (0.7 +/- 0.1U/liter) and increased normally in PAIS (8.7 +/- 2.5 U/liter, P = 0.004). We conclude that the postnatal T and LH surge occurs expectedly in neonates with PAIS but is absent in those with CAIS and that the postnatal T rise requires the receptivity of the hypothalamo-pituitary axis to T.

GnRH agonists improve final height in girls with “true” precocious puberty. To test if a comparable effect can be obtained in older girls, we performed a long-term controlled study in 30 caucasian girls whose puberty started between 8.4 and 10 yr (9.4 ± 0.1 yr), a variant of normal called “advanced” puberty. At entry into trial, these girls had clinical, biological, and sonographic manifestations of puberty and a bone age greater than 10.9 yr. They were randomized 2:1 to receive 3.75 mg triptorelin im every 4 weeks for 2 yr (n = 20, group I) or no treatment (n = 10, group II). Mean height at inclusion was 135.2 ± 4.3 cm (+0.6 sds) in group I, 136.1 ± 4.2 cm (+0.8 sds ) in group II, with target height 157.6 ± 4.3 cm (group I) and 157.8 ± 4.7 cm (group II), and predicted height (Bayley-Pinneau) 154.1 ± 3.9 cm and 155.2 ± 3.7 cm. Although GnRH agonists transiently delayed sexual maturation as well as bone age and growth rate, they had no clear-cut long-standing effect, and final height was comparable in treated (157.6 ± 4.0 cm) and untreated girls (156.1 ± 5.3 cm) (NS).

Evaluation of GH secretion using pharmacological GH stimulation tests (GHST) remains a current practice, although the reliability of GHST has been questioned, and many pitfalls have been pointed out. We have analyzed all of the 6373 GH stimulation tests that led to the initiation of GH therapy in 3233 children treated in France from 1973-1989. Tests and GH measurements were performed by individual centers and collected by the Association France-Hypophyse. GH deficiency (GHD) was due to craniospinal irradiation (11%), was due to organic causes or associated with multiple deficiencies (22%), or was considered idiopathic (65%); 2% of the patients were considered non-GHD. Eleven different pharmacological tests were used, and 62 of the 66 theoretical pairs of tests were used at least once. The most frequent combination of tests (ornithine in one instance and insulin in another) was used in 12.7% of patients. The reliability of the GH peak measured by comparing the results of 2 tests in the same patient was poor, as measured by intraclass correlation coefficients below 0.8. Multivariate analysis identified several parameters positively or negatively associated with peak plasma GH: calendar year of initiation of treatment, etiology of GHD, height SD score, bone age SD score, puberty, weight SD score, genetic target height SD score, and the nature of the pharmacological agent used. We believe that several of these factors (weight SD score, genetic target height SD score, and nature of the agent) identify biases in the diagnosis of GHD. We conclude that GHST should be performed with a very limited number of agents, interpreted after the establishment of reference values in age-matched normal children, and associated with other clinical and biochemical parameters for establishing the diagnosis of GHD.

We observed four families with loss of function mutations of the TSH receptor gene. One patient had a homozygous Pro162 Ala substitution. The three other were compound heterozygotes: 1) Gln324--Stop and Asp410 Asn2), Cys41 Ser and Phe525 Leu, 3) Cys390 Trp and Trp546--Stop. In all patients, the plasma TSH concentration was increased, whereas T3 and T4 concentrations were normal. The TSH levels were normal in the heterozygous parents. These results confirmed the recessive character of TSH receptor defects. Expression of the various mutated receptors in transfected COS-7 cells demonstrated the impairment of their function. We studied the expression of the receptors on the cell surface by immunofluorescence, their ability to bind hormone, and their capacity to activate adenylate cyclase. Some mutations allowed us to identify sites that are especially important for receptor function. The substitution Cys390 Trp abolished high affinity hormone binding. Receptor mutated at Asp410 Asn bound the hormone normally, but failed to activate adenylate cyclase. This result underscores the role of this acidic extracellular residue, close to the first transmembrane segment, in signal transmission. The Phe525 Leu substitution also markedly impaired adenylate cyclase activation, underlining the importance of the second intracellular loop in receptor signaling.