Our objective was to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males. These characteristic include almost universal congenital central... Show moreOur objective was to further expand the spectrum of clinical characteristics of the IGSF1 deficiency syndrome in affected males. These characteristic include almost universal congenital central hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show 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 CeH and low serum prolactin. Severe weight gain started at two years old, with a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 mL, 3.8-4.3 standard deviation score) started aged three 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 four male relatives (the proband's brother and three cousins) with the variant (one adult), free thyroxine (fT4) was below the lower limit of the reference range in two, and just above this limit in the other two. 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 concentration above the lower limit of the reference range while severe early onset obesity or premature testicular growth are part of the phenotypic spectrum. Show less
In this thesis, we explored pituitary functioning and extra-pituitary implications of two pituitary disorders in humans. In part A, we focused on the long-term consequences of the diagnosis and... Show moreIn this thesis, we explored pituitary functioning and extra-pituitary implications of two pituitary disorders in humans. In part A, we focused on the long-term consequences of the diagnosis and treatment of nonfunctioning pituitary macroadenoma (NFMA) on hypothalamic regulation of circadian rhythmicity. These patients are at theoretical risk for damage of especially the hypothalamic suprachiasmatic nucleus (SCN), harboring the seat of the body’s central clock, and its projections. The studies aimed to explore symptoms of SCN dysfunctioning and their implications for patients, in order to formulate strategies to prevent or manage these long-term disabilities. In part B, we focused on the clinical characteristics and pathophysiology of the X-linked IGSF1 deficiency syndrome, in order to aid physicians in providing the necessary diagnostic procedures and long-term care for these patients, and to learn about IGSF1’s role in endocrine physiology. Show less
