Congenital central hypothyroidism caused by a novel IGSF1 variant identified in a French family.

Introduction Central congenital hypothyroidism (CCH) is a rare disorder that can be caused by X-linked mutations in the immunoglobulin superfamily member 1 (IGSF1) gene. Here, we describe four familial cases with a variable presentation due to a novel IGSF1 pathogenic variant. Case presentation In the index case, investigation at birth of suspected brain-lung-thyroid syndrome surprisingly revealed a central hypothyroidism. Next-generation sequencing (NGS) uncovered a novel IGSF1 pathogenic variant: a hemizygous single base duplication (G) resulting in a premature stop codon (NM_001555.4: c.2485dup, p.Ala829Glyfs*15). Further family investigations revealed missed neonatal CCH for the older brother who presented with prolonged jaundice (TSH 3.06 mUI/L, FT4 9.4 pmol/L, FT3 4.2 pmol/L). It also led to the diagnosis of CCH at 11 months of age for the younger brother, whose thyroid function was considered normal at birth. Neuropsychological evaluations showed no cognitive impairment for the eldest two brothers, but a slightly reduced processing-speed index compared with the other parameters for the oldest. Furthermore, a maternal uncle was diagnosed with biochemical CCH at 34 years of age, despite having few symptoms, and a complete work-up revealed prolactin deficiency and macroorchidism. Discussion This report of a rare case of neonatal CCH caused by IGSF1 deficiency highlights the importance of recognizing the neonatal signs of hypothyroidism to diagnose CCH as early as possible. Our results also show the importance of performing family genetic screening if a pathogenic variant is identified, to properly monitor carriers as CCH may develop over time. We suggest that these families should be followed up in the long-term to better understand the natural history of this syndrome and evaluate the need for hormone substitution.