ESPE Abstracts

Background: IGSF1 deficiency has been recently found to be a novel cause of x-linked central hypothyroidism, macroorchidism and delayed puberty.

Case presentation: We present a family, in which the proband was diagnosed with congenital central hypothyroidism by neonatal screening and treated accordingly. Further pituitary examination revealed an unmeasurable prolactin level, normal IGF1, normal cortisol and no abnormalities of the pituitary on MRI. The patient exhibited normal growth and bone age. However, the patient had excessive weight gain and remarkable testicular enlargement (5–6 cc). The enlargement was noticed first at 3.6 years of age and the macroorchidism was present at least until his last evaluation at age 12 years. At 6.3 years old, the patient still had a prepubertal LHRH stimulation and a pubertal LHRH was first observed at 10.3 years old, when his testicular size was 10–12 cc. The proband’s brother was referred for short stature at age 13 years and he was found to have congenital central hypothyroidism with a normal prolactin, normal GH secretion and low testosterone level for a testicular size of 25–28 cc (disharmonious pubertal development). His BMI was normal and besides poor growth, he did not have any of the manifestations of long standing untreated hypothyroidism. The family was referred for genetic evaluation, which revealed that the index patient, his brother, mother and maternal grandfather carry a nonsense mutation in the IGSF1 gene, specifically c.3411_3412del, p.Tyr1137*.

Conclusions: We present here a unique case of a family with IGSF1 deficiency. The proband presented with macroorchidism at an early age, which has not been previously documented. Also, other family members had congenital central hypothyroidism and did not present with classical manifestations of long standing hypothyroidism. Identification of this constellation of manifestations leading to mutational analysis of the IGSF1 gene is key. Further investigations into this family are still ongoing.