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Congenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder that results in reproductive hormone deficiency and reduced potential for fertility in adult life. Discoveries of the genetic aetiology of CHH have advanced dramatically in the past 30 years, with currently over 40 genes recognised to cause or contribute to the development of this condition. The genetic complexity of CHH is further increased by the observation of di- and oligogenic, as well as classic monogenic, inheritance and incomplete penetrance. Very recently in the UK, a panel of 14 genes has been curated for the genetic diagnosis of CHH within the NHS Genomic Medicine Service programme. The aim of this review is to appraise the advantages and potential pitfalls of the use of a CHH panel in clinical endocrine diagnostics, and to consider the future avenues for developing this panel including the potential of whole exome or whole genome sequencing data analysis in this condition.

This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of Paediatric patients with differentiated thyroid carcinoma.

Gonadotropin releasing hormone (GnRH) deficiency is a disorder characterized by absent or delayed puberty, with largely unknown genetic causes. The purpose of this study was to obtain and exploit gene expression profiles of GnRH neurons during development to unveil novel biological mechanisms and genetic determinants underlying GnRH deficiency (GD). Here, we combined bioinformatic analyses of primary embryonic and immortalized GnRH neuron transcriptomes with exome sequencing from GD patients to identify candidate causative genes. Among differentially expressed and filtered transcripts, we found loss-of-function (LoF) variants of the autism-linked Neuroligin 3 (NLGN3) gene in two unrelated patients co- presenting with GD and neurodevelopmental traits. We demonstrated that NLGN3 is upregulated in maturing GnRH neurons and that NLGN3 wild type, but not mutant proteins, promotes neuritogenesis when overexpressed in developing GnRH cells. Our data represent proof-of-principle that this complementary approach can identify novel candidate GD genes and demonstrate that LoF NLGN3 variants may contribute to GD. This novel genotype- phenotype correlation implies common genetic mechanisms underlying neurodevelopmental disorders, such as GD and autistic spectrum disorder.

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., We assessed the contribution of rare variants in genes important in the timing of puberty and body mass regulation in the general population to the phenotype of familial delayed puberty.

Delayed pubertal onset has many etiologies, but on average two-thirds of patients presenting with late puberty have self-limited (or constitutional) delayed puberty. Self-limited delayed puberty often has a strong familial basis. Segregation analyses from previous studies show complex models of inheritance, most commonly autosomal dominant, but also including autosomal recessive, bilineal, and X-linked. Sporadic cases are also observed. Despite this, the neuroendocrine mechanisms and genetic regulation remain unclear in the majority of patients with self-limited delayed puberty. Only rarely have mutations in genes known to cause aberrations of the hypothalamic-pituitary-gonadal axis been identified in cases of delayed puberty, and the majority of these are in relatives of patients with congenital hypogonadotropic hypogonadism (CHH), for example in the FGFR1 and GNRHR genes. Using next generation sequencing in a large family with isolated self-limited delayed puberty, a pathogenic mutation in the CHH gene HS6ST1 was found as the likely cause for this phenotype. Additionally, a study comparing the frequency of mutations in genes that cause GnRH deficiency between probands with CHH and probands with isolated self-limited delayed puberty identified that a significantly higher proportion of mutations with a greater degree of oligogenicity were seen in the CHH group. Mutations in the gene IGSF10 have been implicated in the pathogenesis of familial late puberty in a large Finnish cohort. IGSF10 disruption represents a fetal origin of delayed puberty, with dysregulation of GnRH neuronal migration during embryonic development presenting for the first time in adolescence as late puberty. Some patients with self-limited delayed puberty have distinct constitutional features of growth and puberty. Deleterious variants in FTO have been found in families with delayed puberty with extremely low BMI and maturational delay in growth in early childhood. Recent exciting evidence highlights the importance of epigenetic up-regulation of GnRH transcription by a network of miRNAs and transcription factors, including EAP1, during puberty. Whilst a fascinating heterogeneity of genetic defects have been shown to result in delayed and disordered puberty, and many are yet to be discovered, genetic testing may become a realistic diagnostic tool for the differentiation of conditions of delayed puberty.