Genetic and Environmental Influences on Chest Circumference during Infancy: A Longitudinal Study of Japanese Twins

Peer reviewe

Circulating luteinizing hormone receptor inhibitor(s) in boys with chronic renal failure

Circulating luteinizing hormone receptor inhibitor(s) in boys with chronic renal failure. Patients with chronic renal failure frequently have hypogonadism. To elucidate the molecular mechanisms involved, we tested the ability of serum from these patients to inhibit recombinant human luteinizing hormone receptors. Using a cell line expressing functional human luteinizing hormone receptors, we found that adenosine 3′,5′-monophosphate (cAMP) production was markedly inhibited by sera from the patients, but not by sera from healthy subjects. Inhibition of cAMP production was associated with inhibition of 125I-human chorionic gonadotropin binding. Inhibition of LH receptors by sera from patients correlated with the glomerular filtration rate and after renal allograft transplantation, decreased. Fractionation of serum samples indicated the receptor-inhibiting activity in proteins of molecular weights from 30,000 to 60,000 Daltons. When characterized and purified, the factor responsible may well be a new LH receptor antagonist of clinical significance

The Association Between Puberty Timing and Body Mass Index in a Longitudinal Setting : The Contribution of Genetic Factors

We analyzed the contribution of genetic factors on the association between puberty timing and body mass index (BMI) using longitudinal data and two approaches: (i) genetic twin design and (ii) polygenic scores (PGS) of obesity indices. Our data were derived from Finnish cohorts: 9080 twins had information on puberty timing and BMI and 2468 twins also had genetic data. Early puberty timing was moderately associated with higher BMI in childhood in both boys and girls; in adulthood these correlations were weaker and largely disappeared after adjusting for childhood BMI. The largest proportion of these correlations was attributable to genetic factors. The higher PGSs of BMI and waist circumference were associated with earlier timing of puberty in girls, whereas weaker associations were found in boys. Early puberty is not an independent risk factor for adult obesity but rather reflects the association between puberty timing and childhood BMI contributed by genetic predisposition.Peer reviewe

Early Detection of Abnormal Growth Associated with Juvenile Acquired Hypothyroidism

Context Development of the typical growth phenotype in juvenile acquired hypothyroidism (JHT), the faltering linear growth with increasing weight, has not been thoroughly characterized. Objective To describe longitudinal growth pattern in children developing JHT and investigate how their growth differs from the general population in systematic growth monitoring. Design Retrospective case-control study. Setting JHT cases from 3 Finnish University Hospitals and healthy matched controls from primary health care. Patients A total of 109 JHT patients aged 1.2 to 15.6 years (born 1983-2010) with 554 height and weight measurements obtained for 5 years preceding JHT diagnosis. Each patient was paired with 100 healthy controls (born 1983-2008) by sex and age. Longitudinal growth pattern was evaluated in mixed linear models. Growth monitoring parameters were evaluated using receiver operating characteristics analysis. Results At diagnosis, JHT patients were heavier (mean adjusted body mass index-for-age [BMISDS] difference, 0.65 [95% CI, 0.46-0.84]) and shorter (mean adjusted height-for-age deviation from the target height [(THSDS)-S-DEV] difference, -0.34 [95% CI, -0.57 to -0.10]) than healthy controls. However, 5 years before diagnosis, patients were heavier (mean BMISDS difference, 0.33 [95% CI, 0.12-0.54]) and taller (mean (THSDS)-S-DEV difference, 0.29 [95% CI, 0.06-0.52]) than controls. JHT could be detected with good accuracy when several growth parameters were used simultaneously in screening (area under the curve, 0.83 [95% CI, 0.78-0.89]). Conclusions Abnormal growth pattern of patients with JHT evolves years before diagnosis. Systematic growth monitoring would detect abnormal growth at an early phase of JHT and facilitate timely diagnosis of JHT.Peer reviewe

Letrozole Monotherapy in Pre- and Early-Pubertal Boys Does Not Increase Adult Height

Background: Aromatase inhibitors (Als) have been used in boys with idiopathic short stature (ISS) to promote growth despite the lack of actual data regarding treatment effect on adult height. In this study, we characterized adult heights and long-term follow-up in Al-treated boys with ISS. Methods: Adult heights and long-term follow-up data, including spine MRIs, of a randomized, double-blind, placebo-controlled trial of boys who were treated with letrozole (Lz) (2.5 mg/d) or placebo (PI) for 2 years during prepuberty and early puberty. The mean bone ages at treatment cessation were 10.2 and 10.8 years, respectively. Results: Adult heights were similar between the boys treated with Lz (n = 10) and those who received PI (n = 10) (164.8 +/- 4.0 vs. 163.7 +/- 3.7 cm, p = 0.49, respectively). In either group, the adult heights did not differ from predicted adult heights at start of the study [PI: 163.7 (3.7) cm vs. 166.9 (3.3), p = 0.06; Lz: 164.8 (4.0) cm vs. 167.6 (7.9), p = 0.20, respectively]. Long-term follow-up data showed that the frequency of subjects with a vertebral deformity was similar between the groups (Lz, 29% and PI, 22%, p = 0.20), and no single comorbidity was clearly enriched in either group. Conclusions: The Lz-treated boys had similar adult heights with the subjects who received PI for 2 years, which indicates that the treatment is not beneficial when given to pre- or early-pubertal boys. Previously observed vertebral deformities ameliorated during follow-up, which supports the skeletal safety of Lz therapy in children and adolescents.Peer reviewe

Postnatal Testicular Activity in Healthy Boys and Boys With Cryptorchidism

Cryptorchidism, or undescended testis, is a well-known risk factor for testicular cancer and impaired semen quality in adulthood, conditions which have their origins in early fetal and postnatal life. In human pregnancy, the interplay of testicular and placental hormones as well as local regulatory factors and control by the hypothalamic-pituitary (HP) axis, lead to testicular descent by term. The normal masculine development may be disrupted by environmental factors or genetic defects and result in undescended testes. Minipuberty refers to the postnatal re-activation of the HP-testicular (T) axis after birth. During the first weeks of life, gonadotropin levels increase, followed by activation and proliferation of testicular Leydig, Sertoli and germ cells. Consequent rise in testosterone levels results in penile growth during the first months of life. Testicular size increases and testicular descent continues until three to five months of age. Insufficient HPT axis activation (e.g., hypogonadotropic hypogonadism) is often associated with undescended testis and therefore minipuberty is considered an important phase in the normal male reproductive development. Minipuberty provides a unique window of opportunity for the early evaluation of HPT axis function during early infancy. For cryptorchid boys, hormonal evaluation during minipuberty may give a hint of the underlying etiology and aid in the evaluation of the later risk of HPT axis dysfunction and impaired fertility. The aim of this review is to summarize the current knowledge of the role of minipuberty in testicular development and descent

EAP1 regulation of GnRH promoter activity is important for human pubertal timing

The initiation of puberty is orchestrated by an augmentation of gonadotropin-releasing hormone (GnRH) secretion from a few thousand hypothalamic neurons. Recent findings have indicated that the neuroendocrine control of puberty may be regulated by a hierarchically organized network of transcriptional factors acting upstream of GnRH. These include enhanced at puberty 1 (EAP1), which contributes to the initiation of female puberty through transactivation of the GnRH promoter. However, no EAP1 mutations have been found in humans with disorders of pubertal timing. We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited delayed puberty (DP). Variants were analyzed for rare, potentially pathogenic variants enriched in case versus controls and relevant to the biological control of puberty. We identified one in-frame deletion (Ala221del) and one rare missense variant (Asn770His) in EAP1 in two unrelated families; these variants were highly conserved and potentially pathogenic. Expression studies revealed Eap1 mRNA abundance in peri-pubertal mouse hypothalamus. EAP1 binding to the GnRH1 promoter increased in monkey hypothalamus at the onset of puberty as determined by chromatin immunoprecipitation. Using a luciferase reporter assay, EAP1 mutants showed a reduced ability to trans-activate the GnRH promoter compared to wild-type EAP1, due to reduced protein levels caused by the Ala221del mutation and subcellular mislocation caused by the Asn770His mutation, as revealed by western blot and immunofluorescence, respectively. In conclusion, we have identified the first EAP1 mutations leading to reduced GnRH transcriptional activity resulting in a phenotype of self-limited DP.Peer reviewe

A Longitudinal Study of Urinary Phthalate Excretion in 58 Full-Term and 67 Preterm Infants from Birth through 14 Months

Reproduced with permission from Environmental Health PerspectivesDanish Agency for Science, Technology and Innovation (09-067180) and by Kuopio University Hospital, EVO funding, Finlan

HS6ST1 Insufficiency Causes Self-Limited Delayed Puberty in Contrast With Other GnRH Deficiency Genes

Context: Self-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified. Objective: To assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP. Design, Patients, and Setting: We performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro, and examined the tissue expression and functional requirement of the mouse homolog in vivo. Results: A potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (P = 3.01 x 10 -5 ). Biochemical analysis showed that this mutation reduced sulfotransferase activity in vitro. Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1 (+/-) and Hs6st1(+/+) mice, but vaginal opening was delayed in Hs6st1(+/-) mice despite normal postnatal growth. Conclusions: We have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene.Peer reviewe

Contributions of Function-Altering Variants in Genes Implicated in Pubertal Timing and Body Mass for Self-Limited Delayed Puberty

Context: Self-limited delayed puberty (DP) is often associated with a delay in physical maturation, but although highly heritable the causal genetic factors remain elusive. Genome-wide association studies of the timing of puberty have identified multiple loci for age at menarche in females and voice break in males, particularly in pathways controlling energy balance. Objective/Main Outcome Measures: We sought to assess the contribution of rare variants in such genes to the phenotype of familial DP. Design/Patients: We performed whole-exome sequencing in 67 pedigrees (125 individuals with DP and 35 unaffected controls) from our unique cohort of familial self-limited DP. Using a whole-exome sequencing filtering pipeline one candidate gene [fat mass and obesity-associated gene (FTO)] was identified. In silico, in vitro, and mouse model studies were performed to investigate the pathogenicity of FTO variants and timing of puberty in FTO+/- mice. Results: We identified potentially pathogenic, rare variants in genes in linkage disequilibrium with genome-wide association studies of age at menarche loci in 283 genes. Of these, five genes were implicated in the control of body mass. After filtering for segregation with trait, one candidate, FTO, was retained. Two FTO variants, found in 14 affected individuals from three families, were also associated with leanness in these patients with DP. One variant (p. Leu44Val) demonstrated altered demethylation activity of the mutant protein in vitro. Fto(+/-) mice displayed a significantly delayed timing of pubertal onset (P <0.05). Conclusions: Mutations in genes implicated in body mass and timing of puberty in the general population may contribute to the pathogenesis of self-limited DP.Peer reviewe