The IGSF1 Deficiency Syndrome May Present with Normal Free T4 Levels, Severe Obesity, or Premature Testicular Growth

Our objective is to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males, which so far includes congenital central hypothyroidism, disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index, decreased attentional control and a variable proportion of prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood. We present a family in which the proband was diagnosed with central hypothyroidism (CeH) and low serum prolactin. Severe weight gain started at 2 years, up to a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 ml, 3.8-4.3 SDS) started at 3 years. A pathogenic variant was found in the IGSF1 gene: c.3411_3412del, p.(Tyr1137*). His brother was referred for short stature at age 13 years and was diagnosed with CeH, normal serum prolactin and IGF-1, and disharmonious puberty. In the four male relatives (the proband's brother and three cousins) who carried the variant (one adult), FT4 was below the lower limit of the reference range in two, and just above this limit in the other two cases. Three were overweight or obese, adolescents had disharmonious pubertal development and the adult had profound macroorchidism. In conclusion, male hemizygous carriers of a pathogenic IGSF1 variant can present with FT4 levels above the lower limit of the reference range, and severe early onset obesity or premature testicular growth are part of the phenotypic spectrum.