Cushing disease due to a somatic USP8 mutation in a patient with evolving pituitary hormone deficiencies due to a germline GH1 splicing variant

Author(s)

Julia Haddad Labello ^[1] ; Anna Flávia Figueredo Benedetti ; Bruna Viscardi Azevedo ^[3] ; Alexander Augusto de Lima Jorge ^[4] ; Valter Angelo Sperling Cescato ^[5] ; Sergio Rosemberg ^[6] ; Fernando Pereira Frasseto ^[7] ; Ivo Jorge Prado Arnhold ^[8] ; Luciani Renata Silveira de Carvalho ^[9]

Affiliation

^[1] Faculdade de Medicina da Universidade de São Paulo. Disciplina de Endocrinologia e Metabologia. Hospital das Clínicas - Brasil

^[3] Faculdade de Medicina da Universidade de São Paulo. Disciplina de Endocrinologia e Metabologia. Hospital das Clínicas - Brasil

^[4] Universidade de São Paulo. Faculdade de Medicina. Disciplina de Endocrinologia e Metabologia - Brasil

^[5] Universidade de São Paulo. Faculdade de Medicina. Instituto de Psiquiatria - Brasil

^[6] Universidade de São Paulo. Faculdade de Medicina. Hospital das Clínicas - Brasil

^[7] Universidade de São Paulo. Faculdade de Medicina. Hospital das Clínicas - Brasil

^[8] Faculdade de Medicina da Universidade de São Paulo. Disciplina de Endocrinologia e Metabologia. Hospital das Clínicas - Brasil

^[9] Faculdade de Medicina da Universidade de São Paulo. Disciplina de Endocrinologia e Metabologia. Hospital das Clínicas - Brasil

• Document type: Journal article
• Source: ARCHIVES OF ENDOCRINOLOGY METABOLISM; v. 66, n. 1, p. 104-111, 2022-01-17.

Abstract

SUMMARY We present the unique case of an adult Brazilian woman with severe short stature due to growth hormone deficiency with a heterozygous G to T substitution in the donor splice site of intron 3 of the growth hormone 1 (GH1) gene (c.291+1G>T). In this autosomal dominant form of growth hormone deficiency (type II), exon 3 skipping results in expression of the 17.5 kDa isoform of growth hormone, which has a dominant negative effect over the bioactive isoform, is retained in the endoplasmic reticulum, disrupts the Golgi apparatus, and impairs the secretion of other pituitary hormones in addition to growth hormone deficiency. This mechanism led to the progression of central hypothyroidism in the same patient. After 5 years of growth and thyroid hormone replacement, at the age of 33, laboratory evaluation for increased weight gain revealed high serum and urine cortisol concentrations, which could not be suppressed with dexamethasone. Magnetic resonance imaging of the sella turcica detected a pituitary macroadenoma, which was surgically removed. Histological examination confirmed an adrenocorticotropic hormone (ACTH)-secreting pituitary macroadenoma. A ubiquitin-specific peptidase 8 (USP8) somatic pathogenic variant (c.2159C>G/p.Pro720Arg) was found in the tumor. In conclusion, we report progression of isolated growth hormone deficiency due to a germline GH1 variant to combined pituitary hormone deficiency followed by hypercortisolism due to an ACTH-secreting macroadenoma with a somatic variant in USP8 in the same patient. Genetic studies allowed etiologic diagnosis and prognosis of this unique case. (AU)

• FAPESP's process: 17/04294-0 - Role of GH use in the development of ACTH-producing macroadenoma in a patient with hypopituitarism due to mutation in the GH1 c.291 + 1G> T gene in heterozygosis
• Grantee: Julia Haddad Labello
• Support Opportunities: Scholarships in Brazil - Scientific Initiation