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Cited by 95Sexual Differentiation and DisordersAdrenal Hormones and DisordersMetabolism and Genetic Disorders

The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency

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Pignatelli, Duarte, Carvalho, Berta L., Palmeiro, Aida, Barros, Alberto, Guerreiro, Susana G., Macut, Djuro·2019·Frontiers in Endocrinology
DOI 10.3389/fendo.2019.00432PMC PMC6620563
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Abstract

pathogenic variants is a rather frequent disease with serious consequences, going from a real mortality risk to infertility and to milder symptoms, nevertheless important for affecting the patients' self-esteem. In the most severe cases life-threatening adrenal salt wasting crises may occur. Significant morbidity including the possibility of mistaken gender determination, precocious puberty, infertility and growth arrest with consequent short stature may also affect these patients. In the less severe cases milder symptoms like hirsutism will likely affect the image of the self with strong psychological consequences. Its diagnosis is confirmed by 17OH-progesterone dosages exceeding the cut-off value of 10/15 ng/ml but genotyping is progressively assuming an essential role in the study of these patients particularly in confirming difficult cases, determining some aspects of the prognosis and allowing a correct genetic counseling. Genotyping is a difficult process due to the occurrence of both a gene and a highly homologous pseudo gene. However, new tools are opening new possibilities to this analysis and improving the chances of a correct diagnosis and better understanding of the underlying mechanisms of the disease. Beyond the 10 classic pathogenic variants usually searched for in most laboratories, a correct analysis of 21OH-deficiency cases implies completely sequencing of the entire gene and the determination of gene duplications. These are now recognized to occur frequently and can be responsible for some false positive cases. And finally, because gene conversions can include several pathogenic variants one cannot be certain of identifying that both alleles are affected without studying parental DNA samples. A complete genotype characterization should be considered essential in the preparation for pregnancy, even in the case of parents with milder forms of the disease, or even just carriers, since it has been reported that giving birth to progeny with the severe classic forms occurs with a much higher frequency than expected.

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  • The simulation results provided qualitative, yet quantitatively characterized, agreement with the reported clinical phenotype of CAH patients: mild CAH patients have often been reported to be asymptomatic or to have signs of androgen excess with around 10-fold higher ACTH morning peak, while severe CAH patients have even more pronounced excess androgen production with around 100-fold higher ACTH.

    “Patients with mild CAH have been often reported to be asymptomatic (cortisol concentrations following similar trajectories throughout the day) or with signs of androgen excess (increased ACTH, around 10-fold higher morning peak), while for patients with severe CAH excess androgen production was even more pronounced (increased ACTH, around 100-fold higher morning peak) [4, 6, 31, 32].”

    From A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy (2024) · cites this paper as [4]

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Authors
Pignatelli, D., Carvalho, B. L., Palmeiro, A., Barros, A., Guerreiro, S. G., & Macut, D.
Affiliations
Universidade do Porto (PT)
Corresponding author
Pignatelli, Duarte
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2019-07-04
Volume
10
Pages
432-432
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2019.00432
PMC
PMC6620563
OpenAlex
W2954367909
Cited by
95
References
110
Citations by year
2026: 10 · 2025: 12 · 2024: 20 · 2023: 17 · 2022: 11 · 2021: 13 · 2020: 11 · 2018: 1
FWCI
0.77
Type
journal article
Language
en
Update notices
corrigendum (2020-03-04)
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Ministerio de Economía y Competitividad
  • Fundação para a Ciência e a Tecnologia (PTDC/MEC-ONC/31384/2017, /2017)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
congenital adrenal hyperplasia, 21-hydroxylase deficiency, genotyping, CYP21, pseudogenes, gene duplication, false positives, gene conversion, genetic counseling, infertility, adrenal crisis, 17-hydroxyprogesterone, carrier screening, prenatal diagnosis

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