Recent advances in central congenital hypothyroidism.

Central congenital hypothyroidism (CCH) may occur in isolation, or more frequently in combination with additional pituitary hormone deficits with or without associated extrapituitary abnormalities. Although uncommon, it may be more prevalent than previously thought, affecting up to 1:16 000 neonates in the Netherlands. Since TSH is not elevated, CCH will evade diagnosis in primary, TSH-based, CH screening programs and delayed detection may result in neurodevelopmental delay due to untreated neonatal hypothyroidism. Alternatively, coexisting growth hormones or ACTH deficiency may pose additional risks, such as life threatening hypoglycaemia. Genetic ascertainment is possible in a minority of cases and reveals mutations in genes controlling the TSH biosynthetic pathway (TSHB, TRHR, IGSF1) in isolated TSH deficiency, or early (HESX1, LHX3, LHX4, SOX3, OTX2) or late (PROP1, POU1F1) pituitary transcription factors in combined hormone deficits. Since TSH cannot be used as an indicator of euthyroidism, adequacy of treatment can be difficult to monitor due to a paucity of alternative biomarkers. This review will summarize the normal physiology of pituitary development and the hypothalamic-pituitary-thyroid axis, then describe known genetic causes of isolated central hypothyroidism and combined pituitary hormone deficits associated with TSH deficiency. Difficulties in diagnosis and management of these conditions will then be discussed.This work was supported by funding from the Wellcome Trust (Grant 100585/Z/12/Z, to N.S., Grant 095564/Z/11/Z, to K.C.)This is the final version of the article. It first appeared from Society for Endocrinology via http://dx.doi.org/10.1530/JOE-15-034

Identification of genetic variants and phenotypic characterization of a large cohort of patients with congenital hypopituitarism and related disorders

PURPOSE: Congenital hypopituitarism (CH) disorders are phenotypically variable. Variants in multiple genes are associated with these disorders, with variable penetrance and inheritance. METHODS: We screened a large cohort (N = 1765) of patients with or at risk of CH using Sanger sequencing, selected according to phenotype, and conducted next-generation sequencing (NGS) in 51 families within our cohort. We report the clinical, hormonal, and neuroradiological phenotypes of patients with variants in known genes associated with CH. RESULTS: We identified variants in 178 patients: GH1/GHRHR (51 patients of 414 screened), PROP1 (17 of 253), POU1F1 (15 of 139), SOX2 (13 of 59), GLI2 (7 of 106), LHX3/LHX4 (8 of 110), HESX1 (8 of 724), SOX3 (9 of 354), OTX2 (5 of 59), SHH (2 of 64), and TCF7L1, KAL1, FGFR1, and FGF8 (2 of 585, respectively). NGS identified 26 novel variants in 35 patients (from 24 families). Magnetic resonance imaging showed prevalent hypothalamo-pituitary abnormalities, present in all patients with PROP1, GLI2, SOX3, HESX1, OTX2, LHX3, and LHX4 variants. Normal hypothalamo-pituitary anatomy was reported in 24 of 121, predominantly those with GH1, GHRHR, POU1F1, and SOX2 variants. CONCLUSION: We identified variants in 10% (178 of 1765) of our CH cohort. NGS has revolutionized variant identification, and careful phenotypic patient characterization has improved our understanding of CH. We have constructed a flow chart to guide genetic analysis in these patients, which will evolve upon novel gene discoveries

Key features of puberty onset and progression can help distinguish self-limited delayed puberty from congenital hypogonadotrophic hypogonadism

IntroductionDelayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development.MethodsThis was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed.Results78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay.DiscussionKey clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment.

Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective

BACKGROUND: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. OBJECTIVE: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. METHODS: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. RESULTS: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. CONCLUSIONS: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored

ChIP-on-chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor-1 (SF-1, NR5A1) in the human adrenal gland

The nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) is a key regulator of adrenal and gonadal biology. Disruption of SF-1 can lead to disorders of adrenal development, while increased SF-1 dosage has been associated with adrenocortical tumorigenesis. We aimed to identify a novel subset of SF-1 target genes in the adrenal by using chromatin immunoprecipitation (ChIP) microarrays (ChIP-on-chip) combined with systems analysis. SF-1 ChIP-on-chip was performed in NCI-H295R human adrenocortical cells using promoter tiling arrays, leading to the identification of 445 gene loci where SF-1-binding regions were located from 10 kb upstream to 3 kb downstream of a transcriptional start. Network analysis of genes identified as putative SF-1 targets revealed enrichment for angiogenic process networks. A 1.1-kb SF-1-binding region was identified in the angiopoietin 2 (Ang2, ANGPT2) promoter in a highly repetitive region, and SF-1-dependent activation was confirmed in luciferase assays. Angiogenesis is paramount in adrenal development and tumorigenesis, but until now a direct link between SF-1 and vascular remodeling has not been established. We have identified Ang2 as a potentially important novel target of SF-1 in the adrenal gland, indicating that regulation of angiogenesis might be an important additional mechanism by which SF-1 exerts its actions in the adrenal gland

Treatment Burden of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Randomized Study

Context: Somatrogon is a long-acting recombinant human growth hormone treatment developed as a once-weekly treatment for pediatric patients with growth hormone deficiency (GHD). / Objective: Evaluate patient and caregiver perceptions of the treatment burden associated with the once-weekly somatrogon injection regimen vs a once-daily Somatropin injection regimen. / Methods: Pediatric patients (≥3 to <18 years) with GHD receiving once-daily somatropin at enrollment were randomized 1:1 to Sequence 1 (12 weeks of once-daily Somatropin, then 12 weeks of once-weekly somatrogon) or Sequence 2 (12 weeks of once-weekly somatrogon, then 12 weeks of once-daily Somatropin). Treatment burden was assessed using validated questionnaires completed by patients and caregivers. The primary endpoint was the difference in mean overall life interference (LI) total scores after each 12-week treatment period (somatrogon vs Somatropin), as assessed by questionnaires. / Results: Of 87 patients randomized to Sequence 1 (n = 43) or 2 (n = 44), 85 completed the study. Once-weekly somatrogon had a significantly lower treatment burden than once-daily Somatropin, based on mean overall LI total scores after somatrogon (8.63) vs Somatropin (24.13) treatment (mean difference -15.49; 2-sided 95% CI -19.71, -11.27; P < .0001). Once-weekly somatrogon was associated with greater convenience, higher satisfaction with treatment experience, and less LI. The incidence of treatment-emergent adverse events (TEAEs) for Somatropin and somatrogon was 44.2% and 54.0%, respectively. No severe or serious AEs were reported. / Conclusion: In pediatric patients with GHD, once-weekly somatrogon had a lower treatment burden and was associated with a more favorable treatment experience than once-daily Somatropin

Loss-of-Function Variants in TBC1D32 Underlie Syndromic Hypopituitarism

Context: Congenital pituitary hormone deficiencies with syndromic phenotypes and/or familial occurrence suggest genetic hypopituitarism; however, in many such patients the underlying molecular basis of the disease remains unknown. Objective: To describe patients with syndromic hypopituitarism due to biallelic loss-of-function variants in TBC1D32, a gene implicated in Sonic Hedgehog (Shh) signaling. Setting: Referral center. Patients: A Finnish family of 2 siblings with panhypopituitarism, absent anterior pituitary, and mild craniofacial dysmorphism, and a Pakistani family with a proband with growth hormone deficiency, anterior pituitary hypoplasia, and developmental delay. Interventions: The patients were investigated by whole genome sequencing. Expression profiling of TBC1D32 in human fetal brain was performed through in situ hybridization. Stable and dynamic protein-protein interaction partners of TBC1D32 were investigated in HEK cells followed by mass spectrometry analyses. Main Outcome Measures: Genetic and phenotypic features of patients with biallelic loss-offunction mutations in TBC1D32. Results: The Finnish patients harboured compound heterozygous loss-of-function variants (c.1165_1166dup p.(Gln390Phefs*32) and c.2151del p.(Lys717Asnfs*29)) in TBC1D32; the Pakistani proband carried a known pathogenic homozygous TBC1D32 splice-site variant c.1372 + 1G > A p.(Arg411_Gly458del), as did a fetus with a cleft lip and partial intestinal malrotation from a terminated pregnancy within the same pedigree. TBC1D32 was expressed in the developing hypothalamus, Rathke's pouch, and areas of the hindbrain. TBC1D32 interacted with proteins implicated in cilium assembly, Shh signaling, and brain development. Conclusions: Biallelic TBC1D32 variants underlie syndromic hypopituitarism, and the underlying mechanism may be via disrupted Shh signaling.Peer reviewe

Key features of puberty onset and progression can help distinguish self-limited delayed puberty from congenital hypogonadotrophic hypogonadism

Introduction: Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development. Methods: This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed. Results: 78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay. Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment.  

Analysis of LIN28A in early human ovary development and as a candidate gene for primary ovarian insufficiency

Lin28 proteins are emerging as important regulators of microRNAs in endocrine systems. Lin28a regulates primordial germ cell development and puberty timing in mice, whereas the related protein LIN28B is associated with age at menarche in genome-wide association studies in humans. Here, we studied expression of LIN28A and LIN28B in early human gonad development. LIN28A increased in the developing ovary between 6 and 9 weeks post conception, but not in the developing testis. Immunohistochemistry demonstrated LIN28A in peripheral germ cells. LIN28B was expressed at lower levels in both tissues and did not increase with time. As disruption of Lin28a affects germ cell development in mice, LIN28A was considered a candidate gene for primary ovarian insufficiency (POI) in humans. However, no significant changes were found in 50 women studied. These findings show LIN28A is strongly expressed in germ cells during early human ovary development, but disruption of LIN28A is not a common cause of POI

ZSWIM7 Is associated with human female meiosis and familial primary ovarian insufficiency

Background Primary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. A genetic cause for POI can be found in up to 30% of women, elucidating key roles for these genes in human ovary development. Objective We aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree. Methods Genome sequencing and variant filtering using an autosomal recessive model was performed in the 2 affected sisters and their unaffected family members. Quantitative reverse transcriptase PCR (qRT-PCR) and RNA sequencing were used to study the expression of key genes at critical stages of human fetal gonad development (Carnegie Stage 22/23, 9 weeks post conception (wpc), 11 wpc, 15/16 wpc, 19/20 wpc) and in adult tissue. Results Only 1 homozygous variant cosegregating with the POI phenotype was found: a single nucleotide substitution in zinc finger SWIM-type containing 7 (ZSWIM7), NM_001042697.2: c.173C > G; resulting in predicted loss-of-function p.(Ser58*). qRT-PCR demonstrated higher expression of ZSWIM7 in the 15/16 wpc ovary compared with testis, corresponding to peak meiosis in the fetal ovary. RNA sequencing of fetal gonad samples showed that ZSWIM7 has a similar temporal expression profile in the developing ovary to other homologous recombination genes. Main conclusions Disruption of ZSWIM7 is associated with POI in humans. ZSWIM7 is likely to be important for human homologous recombination; these findings expand the range of genes associated with POI in women