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

Abstract

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.

Figure 1. ( A ) Genogram of the family of the patient with the growth hormone 1 ( GH1 ) c.291 + 1G> T mutation in heterozygosis; informed height measurements: I.2, II.3, II.4, II. ( B ) Immunohistochemistry analyses (×200 magnification) of the resected pituitary tumor revealed positive and diffuse adrenocorticotropic hormone (ACTH) staining. ( C ) GH1 Sanger sequencing showing c.291+1G>T germline GH1 variant in intron 3 (black arrow) from the peripheral blood DNA of our index patient (above) and wild type chromatogram (below). ( D ) USP8 sanger sequencing: first, no mutation is shown in our patient’s peripheral blood DNA, proving that it is not a germline mutation; second, the c.2159C>G/p.Pro720Arg mutation in the tumor DNA (black arrow); third, wild type chromatogram.

Figure 2. ( A, B ) A magnetic resonance image (MRI) in T1 post-contrast of the patient’s pituitary shows an intact pituitary stalk and normal adenohypophysis. Five years later, the pituitary MRI in coronal section in T1 before contrast ( C ) and in sagittal section in T1 post-contrast ( D ) shows a macroadenoma measuring about 2.0 × 1.7 × 1.3 cm and compressing the optic chiasma. The posterior pituitary lobe and the pituitary stalk are not visible.