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Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing

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Correa, Fernanda A. [1] ; Franca, Marcela M. [1] ; Fang, Qing [2] ; Ma, Qianyi [2] ; Bachega, Tania A. [1] ; Rodrigues, Andresa [1] ; Ozel, Bilge A. [2] ; Li, Jun Z. [2] ; Mendonca, Berenice B. [1] ; Jorge, Alexander A. L. [3] ; Carvalho, Luciani R. [1] ; Camper, Sally A. [2] ; Arnhold, Ivo J. P. [1]
Número total de Autores: 13
Afiliação do(s) autor(es):
[1] Univ Sao Paulo HCFMUSP, Fac Med, Unidade Endocrinol Desenvolvimento, Hosp Clin, Lab Hormonios & Genet Mol LIM42, Disciplina Endocr, Sao Paulo, SP - Brazil
[2] Univ Michigan, Dept Human Genet, Med Sch, Ann Arbor, MI 48109 - USA
[3] Univ Sao Paulo HCFMUSP, Unidade Endocrinol Genet, Lab Endocrinol Celular & Mol LIM25, Disciplina Endocrinol, Hosp Clin, Fac Med, Sao Paulo, SP - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: ARCHIVES OF ENDOCRINOLOGY METABOLISM; v. 61, n. 6, p. 633-636, DEC 2017.
Citações Web of Science: 1

Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS -3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene. (AU)

Processo FAPESP: 13/03236-5 - Novas abordagens e metodologias na investigação genético-molecular dos distúrbios de crescimento e desenvolvimento puberal
Beneficiário:Alexander Augusto de Lima Jorge
Linha de fomento: Auxílio à Pesquisa - Temático