What is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency? This study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency. Congenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD). The study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing. Genetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated. Cleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). FGFR1, ANOS1, and PROKR2 were most frequently mutated in KS, while GNRHR, FGFR1, and KISS1R predominated in nCHH. Oligogenic inheritance was detected in 15% of CHH cases, with variants in FGFR1 being most commonly involved. Importantly, a substantial proportion (14%) of CHH patients without a molecular diagnosis carried rare variants predicted to be P or LP in genes typically associated with CPHD (e.g. ROBO1, BRAF, FAT2, and DCHS2). Conversely, several CHH-associated genes such as FGFR1 and FGF8, already implicated in CPHD, were also identified in patients with CPHD and syndromic GN deficiency, further supporting a shared genetic architecture between CHH and CPHD. N/A. Non-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken. This study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency. This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B_201275 to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests.

Biallelic variants in the pro-opiomelanocortin gene (POMC) can cause hypocortisolism, hypopigmentation, and early-onset obesity. Following the identification of 2 patients of combined pituitary hormone deficiency (CPHD), we investigated the prevalence of this association among carriers of rare pathogenic or likely pathogenic (P/LP) POMC variants. This study is a case report and systematic literature review. Genetic analysis was conducted in a family with 2 cousins with childhood-onset obesity and CPHD. We assessed CPHD in carriers for biallelic pathogenic POMC variants using data from the literature and Human Gene Mutation Database. Clinical and biological data were collected, including pituitary axis involvement, obesity onset age, and pituitary imaging results. The 2 cousins, compound heterozygous for POMC variants, developed CPHD following initial hypocortisolism, with subsequent hypothyroidism, growth hormone deficiency, and hypogonadism. Among 41 patients with biallelic POMC variants identified in the literature, 20 had rare homozygous/compound heterozygous P/LP POMC variants and detailed endocrine evaluations. Of these, 40% presented with CPHD, always associated with early-onset severe obesity and hypocortisolism. Growth hormone deficiency was the most frequent (75%), followed by thyrotropic and gonadotropic deficiencies (62.5%). No anomalies were revealed in pituitary imaging. Two patients recovered the gonadotropic axis after treatment with the MC4R agonist. These findings underscore the potential for CPHD to occur in carriers of biallelic pathogenic POMC variants. Sequencing the full POMC, including coding and regulatory regions, is crucial in CPHD cases, alongside evaluating all pituitary axes in neonatal hypocortisolism. Beyond weight regulation, setmelanotide may modulate hypothalamic-pituitary function, with implications for fertility.

Mouse models of growth hormone deficiency (GHD) have provided important tools for uncovering the various actions of GH. Nearly 100 years of research using these mouse lines has greatly enhanced our knowledge of the GH/IGF-1 axis. Some of the shared phenotypes of the 5 "common" mouse models of GHD include reduced body size, delayed sexual maturation, decreased fertility, reduced muscle mass, increased adiposity, and enhanced insulin sensitivity. Since these common mouse lines outlive their normal-sized littermates-and have protection from age-associated disease-they have become important fixtures in the aging field. On the other hand, the 12 "uncommon" mouse models of GHD described herein have tremendously divergent health outcomes ranging from beneficial aging phenotypes (similar to those described for the common models) to extremely detrimental features (such as improper development of the central nervous system, numerous sensory organ defects, and embryonic lethality). Moreover, advancements in next-generation sequencing technologies have led to the identification of an expanding array of genes that are recognized as causative agents to numerous rare syndromes with concomitant GHD. Accordingly, this review provides researchers with a comprehensive up-to-date collection of the common and uncommon mouse models of GHD that have been used to study various aspects of physiology and metabolism associated with multiple forms of GHD. For each mouse line presented, the closest comparable human syndromes are discussed providing important parallels to the clinic.

Hypopituitarism (or pituitary deficiency) is a rare disease with an estimated prevalence of between 1/16,000 and 1/26,000 individuals, defined by insufficient production of one or several anterior pituitary hormones (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), in association or not with diabetes insipidus (antidiuretic hormone [ADH] deficiency). While in adults hypopituitarism is mostly an acquired disease (tumors, irradiation), in children it is most often a congenital condition, due to abnormal pituitary development. Clinical symptoms vary considerably from isolated to combined deficiencies and between syndromic and non-syndromic forms. Early signs are non-specific but should not be overlooked. Diagnosis is based on a combination of clinical, laboratory (testing of all hormonal axes), imaging (brain magnetic resonance imaging [MRI] with thin slices centered on the hypothalamic-pituitary region), and genetic (next-generation sequencing of genes involved in pituitary development, array-based comparative genomic hybridization, and/or genomic analysis) findings. Early brain MRI is crucial in neonates or in cases of severe hormone deficiency for differential diagnosis and to inform syndrome workup. This article presents recommendations for hormone replacement therapy for each of the respective deficient axes. Lifelong follow-up with an endocrinologist is required, including in adulthood, with multidisciplinary management for patients with syndromic forms or comorbidities. Treatment objectives include alleviating symptoms, preventing comorbidities and acute complications, and optimal social and educational integration.

The most commonly identified genetic cause of combined pituitary hormone deficiency (CPHD) is PROP1 gene mutations. The aim of the study was to compare selected clinical features of patients with CPHD caused by variants of the PROP1 gene (CPHD-PROP1) and patients with inborn CPHD of other etiology (CPHD-nonPROP1). The retrospective analysis included childhood medical records of 74 patients (32 female) with CPHD, including 43 patients (23 female) with the mutation in the PROP1 gene. Patients with CPHD-PROP1 compared to the CPHD-nonPROP1 presented with the following: significantly higher median birth weight (0.21 vs. - 0.29 SDS, p = 0.019), lower growth velocity within 3 years preceding growth hormone administration (- 2.7 vs. - 0.8 SDS, p < 0.001), higher mean maximal blood concentration of growth hormone within the stimulation process (1.2 vs. 1.08 ng/mL, p = 0.003), lower TSH (1.8 vs. 2.4 µIU/mL, p < 0.001), significantly lower prolactin concentrations (128 vs. 416.3 µIU/mL, p < 0.001), and less frequent typical signs of hypogonadism at birth in boys (n = 6; 30% vs. n = 12, 54%, p < 0.001). Secondary adrenal insufficiency was less frequent in CPHD-PROP1 (20 vs. 25 cases, p = 0.006) and occurred at a later age (13.4 vs. 10.4 years). MRI of the pituitary gland in CPHD-PROP1 revealed a small pituitary gland (21 cases), pituitary gland enlargement (eight cases), and one pituitary stalk interruption and posterior lobe ectopy, while it was normal in nine cases. Patients with the PROP1 mutations present a clinical picture significantly different from that of other forms of congenital hypopituitarism. Certain specific clinical results may lead to the successful identification of children requiring diagnostics for the PROP1 gene mutation.