Congenital hypogonadotropic hypogonadism (CHH) in infant boys is a rare disorder that can manifest as micropenis and/or cryptorchidism. Mini-puberty is considered a window of opportunity for CHH diagnosis and treatment. The lack of testosterone (T) elevation during this period is the gold standard for CHH diagnosis, but hormonal evaluation is not always available at this time. The aim was to compare inhibin B (INHB), anti-Müllerian hormone (AMH), T, LH, and FSH between infant boys (1 to 365 days) with micropenis and/or cryptorchidism due to isolated CHH (iCHH), CHH as part of combined pituitary hormone deficiency (CPHD), or of idiopathic origin (controls) and to determine discriminating cutoffs for CHH diagnosis based on sensitivity (Se) and specificity (Sp). This multicenter study from 7 University Hospitals in France included 138 boys aged 0 to 12 months (58 with iCHH, including 28 with a positive molecular diagnosis, 32 with CPHD, and 48 controls). Four periods of interest were studied: between 1 to 4 days, 15 to 65 days (early mini-puberty, corresponding to the T peak), 66 to 179 days (late mini-puberty), and 180 to 365 days (post mini-puberty). Out of mini-puberty, the best-discriminating hormones were INHB between 1 to 4 days (Se/Sp 100%/75% at 150 pg/mL and 89%/100% at 85 pg/mL) and INHB and AMH after 180 days (INHB: Se/Sp 100%/100% at 100 pg/mL; AMH: Se/Sp 100%/92% at 600 pmol/L, and 75%/100% at 370 pmol/L). INHB and/or AMH discriminating performances were good (area under the receiver operating characteristic curve ≥ 0.95) across all 4 periods. Inhibin B and/or AMH can be used to diagnose CHH in boys < 1 year of age.

46,XY disorders of sex development (DSD) present with diverse phenotypes and complicated genetic causes. Precise genetic diagnosis contributes to accurate management, and targeted next-generation sequencing (NGS) and whole-exome sequencing are powerful tools for investigating DSD. However, the prevalent variants resulting in 46,XY DSD remain unclear, especially those associated with mild forms, such as isolated hypospadias, inguinal cryptorchidism, and micropenis. From 2019 to 2021, 74 patients with 46,XY DSD (48 typical and 26 mild) from the First Affiliated Hospital of Sun Yat-sen University were enrolled in our cohort study for targeted NGS or whole-exome sequencing. Our targeted 46,XY DSD panel included 108 genes involved in disorders of gonadal development and differentiation, steroid hormone synthesis and activation, persistent Müllerian duct syndrome, idiopathic hypogonadotropic hypogonadism, syndromic disorder, and others. Variants were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign, or benign following the American College of Medical Genetics guidelines. As a result, 28 of 74 (37.8%) patients with pathogenic and/or likely pathogenic variants acquired genetic diagnoses. The Mild DSD patients acquired a diagnosis rate of 30.7%. We detected 44 variants in 28 DSD genes from 31 patients, including 33 novel and 11 reported variants. Heterozygous (65%) and missense (70.5%) variants were the most common. Variants associated with steroid hormone synthesis and activation were the main genetic causes of 46,XY DSD. In conclusion, 46,XY DSD manifests as a series of complicated polygenetic diseases. NGS reveals prevalent variants and improves the genetic diagnoses of 46,XY DSD, regardless of severity. Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt. IGD is typically diagnosed in adolescents presenting with absent or partial puberty using biochemical testing that reveals low serum testosterone or estradiol (hypogonadism) that results from complete or partial absence of GnRH-mediated release of LH and FSH (hypogonadotropic hypogonadism [HH]) in the setting of otherwise normal anterior pituitary anatomy and function and in the absence of secondary causes of HH. Pathogenic variants in more than 25 genes account for about half of all IGD; the genetic cause for the remaining cases of IGD is unknown. Treatment of manifestations: To induce and maintain secondary sex characteristics, gradually increasing doses of testosterone or human chorionic gonadotropin (hCG) injections in males or estrogen and progestin in females; to stimulate spermatogenesis or folliculogenesis, either combined gonadotropin therapy (hCG and human menopausal gonadotropins [hMG] or recombinant FSH) or pulsatile GnRH therapy. If conception fails despite spermatogenesis in a male or ovulation induction in a female, in vitro fertilization may be an option. Prevention of secondary complications: Optimal calcium and vitamin D intake should be encouraged and specific treatment for decreased bone mass as needed. Surveillance: For children of both sexes with findings suggestive of IGD, monitor at regular intervals after age 11 years: sexual maturation (by Tanner staging on physical examination); gonadotropin and sex hormone levels; bone age. In individuals with confirmed IGD, monitor at regular intervals: serum sex steroid levels (to guide optimal hormone replacement); bone mineral density. Evaluation of relatives at risk: If the pathogenic variant(s) in a family are known, genetic testing of prepubertal at-risk relatives may be indicated to clarify their genetic status. Because of variable expressivity, a prepubertal child with a known pathogenic variant may progress through puberty in a normal or delayed fashion, or not at all; therefore, clinical reevaluation over time is necessary. IGD can be inherited in an X-linked, autosomal dominant, or autosomal recessive manner. Almost all IGD-related genes have also been associated with indeterminate or oligogenic inheritance. Recurrence risk counseling is based on family history and the results of molecular genetic testing when available. Carrier testing for at-risk relatives in families with X-linked IGD or autosomal recessive IGD is possible if the pathogenic variant(s) in the family are known. Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) in the family are known.

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) pertains to a group of genetic disorders consisting of anosmic hypogonadotropic hypogonadism (Kallmann syndrome, KS) and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). KS is genetically heterogeneous. We hereby present 5 young male patients with GnRH deficiency caused by mutations in the KAL1 gene. Their ages ranged from 9 months to 16 years. They were referred to our department for an endocrine consultation for micropenis. Hormone assays showed low circulating gonadotropins and testosterone. Molecular studies revealed KAL1 mutations in all cases, three reported nonsense sequence variants in the KAL1 gene were detected in 4 patients, respectively (c.784C > T (p.Arg 262*), c.1267C > T (p.Arg423*), and c.1270C > T (p.Arg424*)), and one patient harbored a novel hemizygous sequence variant [c.227G > A (p.Trp76*)]. Only one patient presented short stature without growth hormone deficiency and anosmia. Another patient had bilateral eyelid ptosis, trichiasis, and refractive error. This is the first report on the co-occurrence of a KAL1 gene mutation and tent-like upper lip in four patients. All of our cases had normal olfactory bulbs and showed no renal agenesis, cleft lip/palate, and hearing impairment. These cases expand our knowledge of the phenotype associated with KAL1 sequence variations, although the precise mechanism by which KAL1 gene influences the development of this phenotype is still unknown.