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Genetics, clinical features and outcomes of non-syndromic pituitary gigantism: experience of a single center from Sao Paulo, Brazil

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Abstract

Purpose

Non-syndromic pituitary gigantism (PG) is a very rare disease. Aryl hydrocarbon receptor-interacting protein (AIP) and G protein-coupled receptor 101 (GPR101) genetic abnormalities represent important etiologic causes of PG and may account for up to 40% of these cases. Here, we aimed to characterize the clinical and molecular findings and long-term outcomes in 18 patients (15 males, three females) with PG followed at a single tertiary center in Sao Paulo, Brazil.

Methods

Genetic testing for AIP and GPR101 were performed by DNA sequencing, droplet digital PCR and array comparative genomic hybridization (aCGH).

Results

Pathogenic variants in the AIP gene were detected in 25% of patients, including a novel variant in splicing regulatory sequences which was present in a sporadic male case. X-LAG due to GPR101 microduplication was diagnosed in two female patients (12.5%). Of interest, these patients had symptoms onset by age 5 and 9 years old and diagnosis at 5 and 15 years, respectively. X-LAG, but not AIP, patients had a significantly lower age of symptoms onset and diagnosis and a higher height Z-score when compared to non-X-LAG. No other differences in clinical features and/or treatment outcomes were observed among PG based on their genetic background.

Conclusion

We characterize the clinical and molecular findings and long-term outcome of the largest single-center PG cohort described so far.

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Funding

This work was in part funded by the intramural research program, NICHD, NIH, Bethesda, MD, USA (to CAS).

Author information

Authors and Affiliations

  1. Laboratorio de Endocrinologia Celular E Molecular/LIM25, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

    Ericka B. Trarbach, Isabella P. P. Grande, Alexander A. L. Jorge & Raquel S. Jallad

  2. Unidade de Neuroendocrinologia, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Av Dr Eneas de Carvalho Aguiar, 155, PAMB, 8 andar, São Paulo, SP, CEP 05403-010, Brazil

    Ericka B. Trarbach, Felipe H. G. Duarte, Marcello D. Bronstein & Raquel S. Jallad

  3. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA

    Giampaolo Trivellin & Constantine A. Stratakis

  4. Faculdade de Medicina, Instituto de Radiologia, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

    Felipe Barjud Pereira do Nascimento

  5. Divisao de Endocrinologia, Departamento de Clinica Medica, Faculdade de Ciencias Medicas da Universidade Estadual de Campinas (FCM-Unicamp), Campinas, SP, Brazil

    Heraldo M. Garmes

  6. Unidade de Diabetes, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

    Marcia Nery

  7. Unidade de Endocrinologia Do Desenvolvimento, Laboratorio de Hormonios E Genetica Molecular/LIM42, Disciplina de Endocrinologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil

    Berenice B. Mendonca

  8. Departamento de Radiologia E Diagnóstico Por Imagem, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

    Felipe Barjud Pereira do Nascimento

  9. Endocrinology Unit and Laboratory of Cellular and Molecular Endocrinology, Humanitas Clinical and Research Center-IRCCS, Rozzano, MI, Italy

    Giampaolo Trivellin

Authors
  1. Ericka B. Trarbach
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  2. Giampaolo Trivellin
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  3. Isabella P. P. Grande
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  4. Felipe H. G. Duarte
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  5. Alexander A. L. Jorge
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  6. Felipe Barjud Pereira do Nascimento
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  7. Heraldo M. Garmes
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  8. Marcia Nery
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  9. Berenice B. Mendonca
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  10. Constantine A. Stratakis
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  11. Marcello D. Bronstein
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  12. Raquel S. Jallad
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Corresponding author

Correspondence to Raquel S. Jallad.

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Conflicts of interest

EBT, IPPG, FHGD, AALJ, FBPN, HMG, MN, BBM, MDB and RSJ have nothing to declare. CAS and GT hold a patent on the GPR101 gene and its function and have received funding from Pfizer, Inc., on growth hormone and acromegaly research. CAS also holds patents on PRKAR1A and PDE11A genes and their function.

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This study was approved by the local Ethics Committee and an Informed Consent form was obtained from All Patients or their Legal Guardian.

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Trarbach, E.B., Trivellin, G., Grande, I.P.P. et al. Genetics, clinical features and outcomes of non-syndromic pituitary gigantism: experience of a single center from Sao Paulo, Brazil. Pituitary 24, 252–261 (2021). https://doi.org/10.1007/s11102-020-01105-4

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