ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2020) 17 4.12 | DOI: 10.1530/ey.17.4.12

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, Netherlands naaa2@cam.ac.uk


To read the full abstract: J Clin Endocrinol Metab, March 2020, 105(3):e70–e84

A cohort of 21 adult males (aged 19 to 89 years) harboring hemizygous pathogenic IGSF1 gene mutations underwent anthropometry, endocrine testing, testis ultrasonography, and body composition assessment to define the pathophysiological role of IGSF1 in influencing GH secretion. In addition, two lines of Igsf1 -deficient male mice were used to assess auxological parameters, organ sizes, bone features, pituitary GH content, GH secretion and IGF-I levels.

More than half of the human IGSF1 -deficient adults (52.4%) were classified as acromegalic and had increased head circumference SDS and finger soft-tissue thickness. They also had higher IGF-I levels and 7 patients showed GH hypersecretion on 24-hour GH secretion profiles. Some patients reported symptoms of GH excess, such as increasing shoe size, sleep apnea, acroparesthesia and oily skin. Consistently, IGSF1 -deficient animals had elevated IGF-I serum levels, pituitary GH protein levels, body weight, organ and skeletal size, and lean body mass.

The Immunoglobulin superfamily member 1 (IGSF1 ) gene encodes for a plasma transmembrane glycoprotein abundantly expressed in Rathke’s pouch and adult pituitary gland. Loss-of-function mutations or deletions of IGSF1 cause an X-linked syndrome with variable phenotypes. Heterozygous female carriers show either no endocrine anomalies, central hypothyroidism (33%) or hypoprolactinemia (11%). Affected males are characterized by central congenital hypothyroidism and macro-orchidism (1). Further features include prolactin deficiency (69%), disharmonious pubertal development (normal timing of testicular growth but delayed rise of testosterone), and increased body mass index (BMI) (2). IGF-I levels are within the normal range but a partial and transient GHD is present in approximately 13% of children (2). Interestingly, on retesting in young adults, GH secretion is normal with a tendency to increasing circulating IGF-I levels during adult life. Acromegalic signs occur in some patients (1)(3). In animals, Igsf1 -deficiency is associated with reduced pituitary and serum TSH concentrations, decreased serum T3, and increased body mass (1).

The mechanisms underlying IGSF1 mutations and their different clinical features are still unknown (4). The paucity of reliable antibodies for IGSF1 protein has hampered histo-chemical studies in human pituitary (5). Consistent with previous data, the current study shows that in adult IGSF1 deficiency is associated with symptoms typical of excessive GH secretion. These findings suggest that the effect of IGSF1 on pituitary GH-secreting cells axis is complex and likely variable throughout life.

References:

1. Joustra SD, Schoenmakers N, Persani L, Campi I, Bonomi M, Radetti G, et al. The IGSF1 deficiency syndrome: characteristics of male and female patients. J Clin Endocrinol Metab. 2013;98(12):4942–52.

2. Sun Y, Bak B, Schoenmakers N, van Trotsenburg AS, Oostdijk W, Voshol P, et al. Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement. Nat Genet. 2012;44(12):1375–81.

3. Joustra SD, Heinen CA, Schoenmakers N, Bonomi M, Ballieux BE, Turgeon MO, et al. IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management. J Clin Endocrinol Metab. 2016;101(4):1627–36.

4. Joustra SD, van Trotsenburg AS, Sun Y, Losekoot M, Bernard DJ, Biermasz NR, et al. IGSF1 deficiency syndrome: A newly uncovered endocrinopathy. Rare Dis. 2013;1:e24883.

5. Roche EF, McGowan A, Koulouri O, Turgeon MO, Nicholas AK, Heffernan E, et al. A novel IGSF1 mutation in a large Irish kindred highlights the need for familial screening in the IGSF1 deficiency syndrome. Clin Endocrinol (Oxf). 2018;89(6):813–23.

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