X-linked IGSF1 (immunoglobulin superfamily, member 1) loss-of-function mutations in males are associated with central hypothyroidism, macroorchidism, and a variable spectrum of anterior pituitary dysfunction. Igsf1 deficient male mice also exhibit central hypothyroidism, however, the physiological and molecular function of IGSF1 in both species has not yet been elucidated. Although partial transient GH deficiency is a rare association of childhood IGSF1 deficiency, affected adults exhibit IGF-1 levels above the mean and are anecdotally reported to have acromegaloid features consistent with mild GH excess. We therefore evaluated the role of IGSF1 in human and murine somatotroph function, which is currently poorly-defined.
IGSF1 deficient adult men demonstrated acromegaloid facial features (52% vs. 19% controls P=0.024) and increased head circumference, HC (>2 SDS in 30% cases). Median basal (3.51 vs. 1.05 μg/L/24 h), pulsatile (34.18 vs. 18.99 μg/L/24 h,) and total GH secretion (36.00 vs. 20.83 μg/L/24 h) were elevated compared with controls (P≤0.01) and IGF-1 SDS was significantly elevated (1.0±1.4 SDS vs. −0.4±0.8 in controls P=0.043). HC was positively correlated with both pulsatile (r=0.911, P=0.011) and total GH secretion (r=0.893, P=0.017).
In comparison with wild type littermates, male Igsf1Δexon1 null mice demonstrated features of GH excess including comparative increases in mean lean mass (13%, P=<0.01) and skeletal dimensions (eg femoral length; 3.7%, P<0.001). Serum IGF-1 was elevated in 10 week-old knockout mice (mean 431±32 vs. 334±26 ng/ml, P=0.02) and correlated with final body weight (r=0.54, P=0.02). Although no difference in GH secretion was observed, assessment of a more recently generated knockout line (Igsf1Δ312) demonstrated enhanced pituitary Gh mRNA expression.
We delineate a somatotroph neurosecretory hyperfunction associated with IGSF1 deficiency in humans and mice. These observations substantiate a hitherto uncharacterized role for IGSF1 in somatotrophs and suggest that evaluation of patients with IGSF1 mutations for long-term consequences of increased GH exposure may be indicated.