We report a case of a 16-year-old male with normosmic hypogonadotropic hypogonadism and short stature, harboring a homozygous variant in the NR5A1 gene. The patient presented at 16 years of age with poor height and weight gain for the last 8 years along with delayed puberty and absence of secondary sexual characteristics. On examination, he had severe short stature, unambiguous external genitalia, micropenis, and prepubertal sexual maturation. Investigations revealed inappropriately normal gonadotropins with low testosterone, while other hormonal assessments were normal, including age- and sex-matched IGF-1. Magnetic resonance imaging of the hypothalamic-pituitary axis along with the olfactory system was normal. Whole-exome sequencing revealed a homozygous variant in the NR5A1 gene. This case suggests that NR5A1 can be associated with isolated congenital hypogonadotropic hypogonadism.

Kallmann syndrome (KS) is an uncommon genetic disorder characterized by isolated congenital hypogonadotropic hypogonadism (CHH) and anosmia/hyposmia. KS originates from abnormal embryonic migration of olfactory axons and gonadotropin-releasing hormone (GnRH)-synthesizing neurons. It can be challenging to diagnose due to its heterogeneous clinical presentation and genes implied. Herein, we report a rare phenotype of KS in two sisters accompanied by a variety of nonreproductive disorders such as hypoparathyroidism, hypercortisolism, atrophy of the cerebellum, intellectual disability, and remarkably, ovarian dysgenesis. Additionally, both subjects present muscle weakness, exercise intolerance, marked hypotonia and seizures, being suspected, although not fully confirmed, mitochondrial encephalomyopathy. These cases illustrate the heterogeneous clinical presentation and the diagnostic difficulties often found in patients suffering from this condition. These clinical features have never been described before as associated with KS; therefore, we decided to report this novel KS phenotype.

For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as  it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient's age, but diagnosis is often late. To evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development. This observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases-non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)-included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening. Median age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8-10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD. The early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes.

Kisspeptins are a family of hypothalamic neuropeptides that are essential for the regulation of reproductive physiology. Their importance in reproductive health became apparent in 2003, when loss-of-function variants in the gene encoding the kisspeptin receptor were reported to result in isolated congenital hypogonadotropic hypogonadism (CHH). It has since been ascertained that hypothalamic kisspeptin neurons regulate gonadotropin-releasing hormone (GnRH) secretion to thus stimulate the remainder of the reproductive endocrine axis. In this review, we discuss genetic variants that affect kisspeptin receptor signaling, summarize data on KISS1R agonists, and posit possible clinical uses of native and synthetic kisspeptin receptor agonists for the investigation and treatment of reproductive disorders.