Endocrine Abstracts

JOINT1485

Introduction: The SH2B1 gene encodes an important adaptor protein that is involved in the leptin-melanocortin pathway. Heterozygous variants of SH2B1 have been linked to various conditions, but homozygous variants have not been documented. This report presents a case of a homozygous SH2B1 variant associated with syndromic obesity and multiple pituitary hormone deficiencies.

Case: A fifteen-year 7-month-old female, presented with the absence of menstrual bleeding despite having started oral contraceptive therapy for primary amenorrhea. She had delayed neuromotor development. Parents were second degree cousins and were both obese. Mother’s and father’s body mass index (BMI) were 35.9 kg/m², 31.5 kg/m², respectively. Her target height was 152.5 cm (-1.8 SDS). On physical examination; weight was 63.65 kg (1.1 SDS), height was 147 cm (-2.57 SDS), and BMI was 29.46 kg/m² (2.45 SDS). Pubic hair stage was 4 and breast development was Tanner stage 1. The patient had acanthosis nigricans and central obesity, along with a low hairline, short neck, and micrognathia. Cataract, strabismus, amblyopia, myopia, astigmatism, and mild hearing loss were also detected. The WISC-R test indicated mild intellectual disability. Laborotory findings were as follows; TSH: 1.6 mU/l (0.51-4.17), fT4: 0.94 ng/dl (0.98-1.63), FSH: 8.6 mIU/mL (3.5-12.5), LH: 4.59 mIU/mL (2.4-12.6), estradiol (E2): <25 pg/mL (30.9-90.4), AMH: 0.26 ng/mL (1.9-8.3), ACTH: 28.1 ng/l (7.2-63.3), cortisol: 15.8 mg/dl (4.82-19.5), IGF-1: 147 mg/l (151-485), prolactin (PRL): 2.75 mg/l (4.79-23.3). In the LHRH test performed due to delayed puberty, peak FSH was 29.6 mIU/mL, LH 82.1 mIU/mL, with E2 <25 pg/mL. Puberty was delayed, and hormone levels indicated central hypothyroidism, hypoprolactinemia, and hypothalamic hypogonadotropic hypogonadism. Abdominal and pelvic ultrasound revealed grade 2 hepatosteatosis and a hypoplastic uterus with right ovary 1.8 cc, and left ovary 2.99 cc. Pituitary MRI was normal. Clinical exome panel for syndromic obesity revealed a homozygous c.2083G>A (p.Val695Met) pathogenic variant in SH2B1 gene. Both parents were heterozygous for the same variant.

Conclusion: The homozygous SH2B1 variant identified in this patient is associated with a novel syndrome characterized by obesity, short stature, intellectual disability, hearing loss, cataracts, and multiple pituitary hormone deficiencies. These findings have not been reported in heterozygous SH2B1 variants and provide new insights into the gene’s role. The SH2B1 gene may be important for defining an autosomal recessive syndrome with these features.

Keywords: Syndromic obesity, hypopituitarism, hypogonadism, SH2B1.