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Genotype–Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism

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Abstract

Childhood and adolescent primary hyperparathyroidism (PHPT) is a very rare disease. Data on its molecular genetics are scarce. We performed a retrospective analysis (January 2000-January 2021) to determine the deleterious germline variants and genotype–phenotype correlations in children and adolescents < 20 years diagnosed with PHPT from a single referral center. Clinical features, biochemistry, imaging, management, and genetics (clinical exome analyzed for 11 PHPT and 7 pancreatitis-associated genes, MLPA for CDC73) were recorded. Thirty-six patients (20 males; median age 17 years) were classified into those with familial and/or syndromic (F/S) or apparently sporadic (AS) presentation. Sixteen (44.4%) harbored pathogenic/likely pathogenic germline variants in PHPT-associated genes. The genetic yield in F/S group was 90% (MEN1:8/10; CDC73:1/10), and AS group was 26.9% (CDC73:4/26; CASR:3/26). F/S group had frequent asymptomatic presentation (60% vs none; P < 0.001), lower serum PTH (237.5 vs 1369.1 pg/mL; P = 0.001), and maximum parathyroid dimension (0.9 vs 2.2 cm; P = 0.01) than AS group. Among the AS group, renal involvement was higher in those with molecular diagnoses (71.4% vs 10.5%; P = 0.01). All those with novel CASR variants (including one homozygous) had hypercalciuria and histology-proven parathyroid adenoma/carcinoma. A missense CTRC VUS occurred in one patient with chronic pancreatitis. In summary, Asian Indian children and adolescents with PHPT have high genetic yield, even with apparently sporadic presentation. The phenotypic spectrum of CASR variants is expanded to include childhood/adolescent PHPT with hypercalciuria and single gland neoplasia. The proposed roles for renal involvement to predict molecular diagnosis among those with apparently sporadic presentation require further elucidation.

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Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgements

We acknowledge Dr. Aparna Kamble for administrative help in the study’s conduct and Samiksha Chandrashekhar Hegishte for help in the review of genetic data.

Funding

No funding was received for conducting this study.

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Authors and Affiliations

  1. Department of Endocrinology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, 400012, India

    Anima Sharma, Saba Memon, Anurag R. Lila, Sneha Arya, Vikrant Gosavi, Manjiri Karlekar, Virendra Patil & Tushar Bandgar

  2. Department of Endocrinology, Vydehi Institute of Medical Sciences and Research Centre, Bengaluru, 560066, India

    Vijaya Sarathi

  3. Department of Endocrinology, Sapthagiri Institute of Medical Sciences and Research Centre, Bengaluru, 560090, India

    Swati S. Jadhav

  4. Department of Radiodiagnosis, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

    Priya Hira

  5. Department of Surgery, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India

    Mahadeo Garale

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  1. Anima Sharma
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Contributions

The corresponding author had full access to all of the data in the study and took responsibility for the decision to submit the article for publication. All authors participated in the study design, conducted the study, and contributed to data acquisition. AS, SM, ARL, VS, and TB interpreted the data and drafted the first manuscript. All authors revised the manuscript for important intellectual content and interpreted the data. All authors approved the final version of the manuscript and agree to be accountable for the work and to ensure that any questions relating to the accuracy and integrity of the paper are appropriately investigated and resolved.

Corresponding author

Correspondence to Tushar Bandgar.

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Conflict of interest

Anima Sharma, Saba Memon, Anurag R Lila, Vijaya Sarathi, Sneha Arya, Swati S Jadhav, Priya Hira, Mahadeo Garale, Vikrant Gosavi, Manjiri Karlekar, Virendra Patil, and Tushar Bandgar declare that they have no conflicts of interest.

Ethical Approval

The study was approved by the Institutional Ethics Committee [IEC(II)/OUT/175/2021 project number EC/OA-25/2021].

Informed Consent

Obtaining informed consent from participants was not applicable and was waived by Institutional Ethics Committee as this was a retrospective record study.

Human and Animal Rights

The research was performed in accordance with the Declaration of Helsinki and approved by the Institutional Ethics Committee [IEC(II)/OUT/175/2021 project number EC/OA-25/2021].

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Sharma, A., Memon, S., Lila, A.R. et al. Genotype–Phenotype Correlations in Asian Indian Children and Adolescents with Primary Hyperparathyroidism. Calcif Tissue Int 111, 229–241 (2022). https://doi.org/10.1007/s00223-022-00985-x

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