IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction

J Clin Endocrinol Metab. 2020 Mar 1;105(3):e70-e84. doi: 10.1210/clinem/dgz093.


Context: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition.

Objective: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function.

Patients, design, and setting: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting.

Main outcome measures: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates.

Results: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels.

Conclusions: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.

Keywords: IGSF1; congenital hypopituitarism; growth hormone; pituitary.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Growth Hormone / biosynthesis
  • Humans
  • Immunoglobulins / deficiency
  • Immunoglobulins / physiology*
  • Insulin-Like Growth Factor I / analysis
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / physiology*
  • Mice
  • Middle Aged
  • Neurosecretion / physiology*
  • Somatotrophs / physiology*


  • IGSF1 protein, human
  • IGSF1 protein, mouse
  • Immunoglobulins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Insulin-Like Growth Factor I
  • Growth Hormone