Context.IGSF1 deficiency was recently discovered as a novel X-linked cause of central hypothyroidism (CeH) and macroorchidism. However, clinical and biochemical data regarding growth, puberty, and metabolic outcome, as well as features of female carriers, are scarce.Objective.To investigate clinical and biochemical characteristics associated with IGSF1 deficiency in both sexes.Methods.All patients (n=42, 24 males) from 10 families examined in the university clinics of Leiden, Amsterdam, Cambridge, and Milan were included in this case series. Detailed clinical data were collected with an identical protocol and biochemical measurements were performed in a central laboratory.Results.Male patients (age 0-87 years, 17 index cases and 7 from family studies) showed CeH (100%), hypoprolactinemia (n=16, 67%) and transient partial growth hormone deficiency (GHD, n=3, 13%). Pubertal testosterone production was delayed, as were the growth spurt and pubic hair development. However, testicular growth started at a normal age and attained macroorchid size in all evaluable adults. BMI, fat percentage and waist circumference tended to be elevated. The metabolic syndrome was present in four out of five patients over 55 years. Heterozygous female carriers (age 32-80 years) showed CeH in 6 out of 18 cases (33%), hypoprolactinemia in 2 (11%), and GHD in none. As in men, BMI, fat percentage, and waist circumference were relatively high, and the metabolic syndrome was present in three cases.Conclusion.In males, the X-linked IGSF1 deficiency syndrome is characterized by CeH, hypoprolactinemia, delayed puberty, macroorchidism and increased body weight. A subset of female carriers also exhibits CeH.