ESPE Abstracts

Background: IGSF1, located on chromosome Xq26 and highly expressed in Rathke´s pouch, pituitary and testes, codes for a plasma membrane immunoglobulin superfamily-1 glycoprotein. Mutations in IGSF1, first described in 2012, lead to IGSF1-deficiency, a unique combination of mild central hypothyroidism (prevalence 100%), macroorchidism (80%) and hypoprolactinemia (60%). Additional symptoms comprise delayed pubertal testosterone rise (80%) and delayed adrenarche (50%) in adolescents. Furthermore, increased BMI (60%) and elevated IGF1 (20%) may develop in adulthood.

Case Report: A 16-year old boy presented with pubertal delay. At clinical investigation, disharmonic pubertal development with short stature (-2.2 SDS), bone age delay (-2.5 years) in the presence of large testicular volume (20ml) and advanced genital development (Tanner stage 4) but no voice break and only sparse pubic hair were striking. He was otherwise healthy and did not receive any medication, being a gifted scholar attending grammar school. Testosterone levels were low (0.6 ng/ml; LH 0.9 mU/ml and FSH 2.5 mU/ml) as were free T4 (0.85 ng/dl) and prolactin (0.1 ng/ml) at repeated measurements. IGF1, IGFBP3, ACTH and cortisol as well as brain MRI were normal. TRH test showed a normal rise of TSH (from 1.7 to 19.8 µU/ml), excluding a TRHR defect, and no prolactin response. Sanger sequencing of the IGSF1 gene revealed a hemizygous new mutation in the extracellular domain (c.2192T>C; p.Leu731Pro), that was deemed pathogenic.

Conclusion: IGSF1-deficiency represents a likely underdiagnosed cause for mild central hypothyroidism, commonly associated with macroorchidism and hypoprolactinemia. Pathogenetic mechanisms leading to this unique combination of symptoms have not been fully unravelled so far, but suppression of THRH, TSHB and inhibin action are likely to be involved. Given the overall mild course of IGSF1-deficiency and marked intra- and interfamilial phenotypic variability, IGSF1 seems to exert a modulatory rather than a vital physiological role.