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Cushing disease due to a somatic USP8 mutation in a patient with evolving pituitary hormone deficiencies due to a germline GH1 splicing variant
Labello, Julia Haddad; Benedetti, Anna Flávia Figueredo; Azevedo, Bruna Viscardi; Jorge, Alexander Augusto de Lima; Cescato, Valter Angelo Sperling; Rosemberg, Sergio; Frasseto, Fernando Pereira; Arnhold, Ivo Jorge Prado; Carvalho, Luciani Renata Silveira de.
  • Labello, Julia Haddad; Faculdade de Medicina da Universidade de São Paulo. Disciplina de Endocrinologia e Metabologia. Hospital das Clínicas. São Paulo. BR
  • Benedetti, Anna Flávia Figueredo; Faculdade de Medicina da Universidade de São Paulo. Disciplina de Endocrinologia e Metabologia. Hospital das Clínicas. São Paulo. BR
  • Azevedo, Bruna Viscardi; Faculdade de Medicina da Universidade de São Paulo. Disciplina de Endocrinologia e Metabologia. Hospital das Clínicas. São Paulo. BR
  • Jorge, Alexander Augusto de Lima; Universidade de São Paulo. Faculdade de Medicina. Disciplina de Endocrinologia e Metabologia. São Paulo. BR
  • Cescato, Valter Angelo Sperling; Universidade de São Paulo. Faculdade de Medicina. Instituto de Psiquiatria. São Paulo. BR
  • Rosemberg, Sergio; Universidade de São Paulo. Faculdade de Medicina. Hospital das Clínicas. São Paulo. BR
  • Frasseto, Fernando Pereira; Universidade de São Paulo. Faculdade de Medicina. Hospital das Clínicas. São Paulo. BR
  • Arnhold, Ivo Jorge Prado; Faculdade de Medicina da Universidade de São Paulo. Disciplina de Endocrinologia e Metabologia. Hospital das Clínicas. São Paulo. BR
  • Carvalho, Luciani Renata Silveira de; Faculdade de Medicina da Universidade de São Paulo. Disciplina de Endocrinologia e Metabologia. Hospital das Clínicas. São Paulo. BR
Arch. endocrinol. metab. (Online) ; 66(1): 104-111, Jan.-Feb. 2022. tab, graf
Article in English | LILACS | ID: biblio-1364312
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.
Subject(s)

Full text: Available Index: LILACS (Americas) Main subject: Human Growth Hormone / Pituitary ACTH Hypersecretion / Dwarfism, Pituitary Type of study: Prognostic study Limits: Adult / Female / Humans Language: English Journal: Arch. endocrinol. metab. (Online) Journal subject: Endocrinology / Metabolism Year: 2022 Type: Article Affiliation country: Brazil Institution/Affiliation country: Faculdade de Medicina da Universidade de São Paulo/BR

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Full text: Available Index: LILACS (Americas) Main subject: Human Growth Hormone / Pituitary ACTH Hypersecretion / Dwarfism, Pituitary Type of study: Prognostic study Limits: Adult / Female / Humans Language: English Journal: Arch. endocrinol. metab. (Online) Journal subject: Endocrinology / Metabolism Year: 2022 Type: Article Affiliation country: Brazil Institution/Affiliation country: Faculdade de Medicina da Universidade de São Paulo/BR