An Unusual Case of Delayed Puberty

Background: Kallmann syndrome (KS) is a rare congenital form of hypogonadotropic hypogonadism with anosmia/hyposmia.

Description: Female, 14 years old, without relevant personal or family history, referred because of pubertal delay (pubarche at age 13, without thelarche). She denied symptoms of neurological or other organs impairment, practice of strenuous physical exercise, restrictive eating behavior, illicit drug use and history of traumatic brain injury. The investigation performed before showed low estradiol levels and ultrasonography with small uterus, atrophic ovaries and horseshoe kidneys. She had good general condition, no dysmorphism, normal external genitalia and Tanner pubertal stage I (P3, B1, A3). Her growth velocity suffered progressive and slight slowdown after 10 years, but her height was still on the 50^th percentile. Complementary study showed low values of gonadotropins, 46XX karyotype and delayed bone age. LH-RH test revealed low values of FSH, LH and estradiol. KS was hypothesized and after a detailed inquiry anosmia/hyposmia was confirmed. Brain MRI showed bulbs and olfactory tracts atrophy and a small pituitary gland. Molecular analysis of the GnRHR and KAL1 gene by cyclic sequencing was normal, but the study proceeded to a Next Generation Sequencing (NGS) multigene panel approach that identified a heterozygous variant of uncertain significance in the KS gene FGF8 gene (c.283C>G, p.Gln95Glu). Pubertal induction was performed with transdermal estrogens, and after menarche combined hormonal therapy was started.

Conclusions: In pubertal delay with hypogonadotropic hypogonadism and despite its rarity KS should be considered and anosmia/hyposmia should be searched for. Brain MRI shows typical anomalies in most cases. The genetic cause is recognized in only 30% of cases. Early diagnosis and hormone replacement prevent the physical and psychological consequences of pubertal delay. NGS approaches will contribute to reveal the molecular basis of a larger number of cases and may bring better understanding and classification of these disorders.