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Clinical characteristics, genetic profile and short-term outcomes of children with primary hyperoxaluria type 2: a nationwide experience

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Abstract

Background

Three types of primary hyperoxaluria (PH) are recognized. However, data on PH type 2 (PH2), caused by defects in the GRHPR gene, are limited.

Methods

We reviewed the medical records of patients < 18 years of age with genetically-proven PH2 from seven centres across India to identify the age of onset, patterns of clinical presentation, short-term outcomes and genetic profile, and to determine if genotype–phenotype correlation exists.

Results

We report 20 patients (all with nephrolithiasis or nephrocalcinosis) diagnosed to have PH2 at a median (IQR) age of 21.5 (7, 60) months. Consanguinity and family history of kidney stones were elicited in nine (45%) and eight (40%) patients, respectively. The median (IQR) serum creatinine at PH2 diagnosis was 0.45 (0.29, 0.56) mg/dL with the corresponding estimated glomerular filtration rate being 83 (60, 96) mL/1.73 m2/min. A mutational hotspot (c.494 G > A), rare in Caucasians, was identified in 12 (60%) patients. An intronic splice site variant (c.735-1G > A) was noted in five (25%) patients. Four (20%) patients required surgical intervention for stone removal. Major adverse kidney events (mortality or chronic kidney disease (CKD) stages 3–5) were noted in six (30%) patients at a median (IQR) follow-up of 12 (6, 27) months. Risk factors for CKD progression and genotype–phenotype correlation could not be established.

Conclusions

PH2 should no longer be considered an innocuous disease, but rather a potentially aggressive disease with early age of presentation, and possible rapid progression to CKD stages 3–5 in childhood in some patients. A mutational hotspot (c.494 G > A variant) was identified in 60% of cases, but needs further exploration to decipher the genotype–phenotype correlation.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable. Data subsets are available from the corresponding author.

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Funding

Next-generation sequencing for two patients enrolled in the study was funded by Department of Biotechnology (DBT), Government of India, via grant no. BT/PR25805/MED/12/771/2017 which is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India

    Sudarsan Krishnasamy, Bobbity Deepthi & Sriram Krishnamurthy

  2. Department of Pediatric Nephrology, St John’s Medical College Hospital, Bangalore, India

    Nivedita Kamath & Arpana Iyengar

  3. Department of Pediatric Nephrology, Government Medical College, Thiruvananthapuram, India

    Christy Cathreen Thomas & Susan Uthup

  4. Department of Pediatric Nephrology, Institute of Kidney Diseases and Research Centre, Ahmedabad, India

    Anshuman Saha

  5. Division of Pediatric Nephrology, Department of Pediatrics, Christian Medical College, Vellore, India

    Georgie Mathew & Indira Agarwal

  6. Division of Pediatric Nephrology, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India

    Karalanglin Tiewsoh

  7. Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh, India

    Nowneet Kumar Bhat

  8. Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

    Kausik Mandal

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  1. Sudarsan Krishnasamy
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Contributions

SuK, BD, NK, AI, CCT, SU, AS, GM, IA, KT, NKB and SK managed the patients. SuK prepared the study protocol, collected the data by coordinating with the participating centres, performed the statistical analysis and prepared the first draft. SK conceptualized the study, participated in protocol preparation, collected the data by coordinating with the participating centres, and critically revised the manuscript. KM interpreted next-generation sequencing results. All authors contributed to protocol preparation, data collection, data analysis and drafting of the manuscript, and approved the final version of the manuscript. SK shall act as the corresponding author and guarantor of the paper.

Corresponding author

Correspondence to Sriram Krishnamurthy.

Ethics declarations

Ethics approval

The study was approved by the Institute Ethics Committee (JIP/IEC-OS/2022/380 dated February 10, 2023).

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The authors affirm that human research participants provided informed consent.

Conflict of interest

The authors declare no competing interests.

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Krishnasamy, S., Deepthi, B., Kamath, N. et al. Clinical characteristics, genetic profile and short-term outcomes of children with primary hyperoxaluria type 2: a nationwide experience. Pediatr Nephrol 39, 1093–1104 (2024). https://doi.org/10.1007/s00467-023-06200-9

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  • DOI: https://doi.org/10.1007/s00467-023-06200-9

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