SOX2 Variant Resulting in Hypogonadotropic Hypogonadism, Learning Difficulties, and Ear (Rather Than Eye) Anomalies

Abstract

A 15-year-old female individual presented with primary amenorrhea and absence of pubertal signs. Her hormonal profile revealed isolated hypogonadotropic hypogonadism (IHH) with low levels of luteinizing hormone (LH), estradiol, and follicle-stimulating hormone (FSH), with a confirmatory luteinizing hormone-releasing hormone (LHRH) stimulation test. She has a background of global developmental delay and bilateral hearing loss, with computed tomography (CT) findings of an absent right incus lenticular process and a dilated right vestibule. Genetic testing revealed a heterozygous pathogenic variant c.152G>A (p.Trp51*) in the SOX2 gene. SOX2 (sex-determining region Y-box 2) is a transcription factor critical for early pituitary and hypothalamic development. However, the phenotype associated with SOX2 pathogenic variants remains incompletely defined due to its rarity and wide phenotypic variability. Our case uniquely highlights temporal bone anomalies and a comprehensive pituitary function workup, which may contribute to a clearer understanding of SOX2-related phenotypic presentations. This case underscores the need to consider SOX2 pathogenic variants in the genetic evaluation of IHH, even in the absence of ocular abnormalities.

Keywords: SOX2 variant; delayed puberty; hearing loss; hypogonadotropic hypogonadism; ocular anomalies.

Figure 1.

Centers for Disease Control and Prevention (CDC) height and weight chart. Abbreviation: THR, target height range.

Figure 2.

Left hand bone age: 13 years 6 months at chronological age of 15 years 9 months.

Figure 3.

Magnetic resonance imaging of pituitary gland. The pituitary gland is not enlarged and the normal T1W hyperintense posterior pituitary lobe is preserved. The pituitary stalk is thickened by 5 mm and there is a 4 × 5 × 7 mm nodular focus expanding the pituitary stalk with irregular enhancement (left picture, arrow). There is patchy enhancement of bulky pineal gland 5 × 7 mm. (right picture, arrow).

Figure 4.

Computed tomography scan of temporal bone with findings of an absent right incus lenticular process (not pictured), dilated right vestibule (orange arrow) with thickened and fore-shortened lateral semicircular canal (yellow arrow).

Figure 5.

Genes implicated in the development, secretion, and action of gonadotropin-releasing hormone (GnRH).