Background: Type II isolated GH deficiency (IGHD type II) is caused by dominant negative splicing or point mutations of the GH-1 gene. Studies have suggested that dominant mutant GH forms prevent the secretion of wild-type GH, resulting in eventual cell death; surprisingly, some patients with these GH mutations develop other hormonal deficiencies (ACTH, TSH).
Subjects: The proband presented at the age of 2.3 years with IGHD. His father, also known to have been treated for IGHD as a child, had subsequently been lost to follow-up, having remained without treatment during this time. At re-evaluation at the age of 38 years, he complained of lack of stamina and poor libido. Clinical and biochemical assessment confirmed severe GHD, borderline ACTH insufficiency, suboptimal basal and stimulated gonadotropins, and a poor prolactin response to provocation. The basal testosterone concentration was low, and he complained of secondary infertility. Magnetic resonance imaging revealed anterior pituitary hypoplasia in both patients. Genetic testing revealed a heterozygous splicing mutation in GH-1 (intervening sequence-3 + 1G>A) in both patients, known to cause IGHD type II.
Interventions: The proband showed an excellent growth response to recombinant human GH (rhGH). His father, also treated with rhGH, showed improved quality of life on rhGH, but testosterone concentrations continued to decline, necessitating treatment with testosterone with symptomatic benefit but no improvement in semen quality.
Conclusions: This case supports recent experimental and clinical observations suggesting that the cytotoxicity associated with accumulation of dominant negative mutant 17.5 kDa GH causes a form of GHD that can evolve into multiple hormone deficiencies. Hence, patients diagnosed initially with IGHD type II require continued long-term clinical follow-up.