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Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features

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Abstract

Biallelic loss of function mutations in the CLDN16 gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of CLDN16 variants (c.715G>A, p.G239R; and novel c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in CLDN16. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.

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Acknowledgements

The authors wish to express their gratitude to the parents and the patient who participated in this study.

Funding

This study did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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Author notes

  1. Mehmet Eltan and Zehra Yavas Abali have contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Endocrinology and Diabetes, School of Medicine, Marmara University, Fevzi Çakmak Mahallesi, Muhsin Yazıcıoglu Caddesi, No:10, 34899, Pendik Istanbul, Turkey

    Mehmet Eltan, Zehra Yavas Abali, Saygın Abali, Tarik Kirkgoz, Tulay Guran, Abdullah Bereket & Serap Turan

  2. Department of Medical Genetics, School of Medicine, Marmara University, Istanbul, Turkey

    Ayberk Turkyilmaz, Ceren Alavanda & Ahmet Arman

  3. Department of Pediatric Nephrology, School of Medicine, Marmara University, Istanbul, Turkey

    Ibrahim Gokce

  4. Department of Pediatric Endocrinology and Diabetes, School of Medicine, Koc University, Istanbul, Turkey

    Sukru Hatun

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  1. Mehmet Eltan
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Contributions

Study design: ME, ZYA, ST. Study conduct: all authors. Data collection: ME, ZYA, IG, SA, CA, AA, ST. Data analysis: all authors. Drafting manuscript: ME, ZYA, IG, AT, CA, and ST. Revising manuscript content: all authors. Critical reading and evaluation of the manuscript: AB, ST. Approving final version of manuscript: all authors. ME, AB, and ST take responsibility for the integrity of the data.

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Correspondence to Serap Turan.

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Conflict of interest

Mehmet Eltan, Zehra Yavas Abali, Ayberk Turkyilmaz, Ibrahim Gokce, Saygın Abalı, Ceren Alavanda, Ahmet Arman, Tarik Kirkgoz, Tulay Guran, Sukru Hatun, Abdullah Bereket, and Serap Turan declare that they have no conflict of interests.

Human and Animal Rights

All procedures performed in the study involving human participants were in accordance with the ethical standards of the National Research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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The patients and their healthy family members signed a written informed consent for the participation to the study.

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Supplementary Information

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223_2021_928_MOESM1_ESM.pptx

Supplementary Figure 1: IGV (Integrative Genomics View) visualization of the CLDN16 gene variants in Pt #1 and chromatogram of parental segregation analyses. A) The previously reported heterozygous missense (NM_006580: c.715G>A, p.Gly239Arg) variant. B) The novel heterozygous nonsense (NM_006580: c.360C>A, p.Cys120*) variant were detected in CLDN16 gene. C) The heterozygous nonsense (NM_006580: c.360C>A, p.Cys120*) variant was detected in the father. D) The heterozygous missense (NM_006580: c.715G>A, p.Gly239Arg) variant was detected in the mother. Supplementary file1 (PPTX 112 KB)

223_2021_928_MOESM2_ESM.pptx

Supplementary Figure 2: IGV sequence data of the mutation detected in Pt #2 and his parents. A) The recurrent homozygous missense variant (NM_006580: c.602G>A , p.Gly201Glu) in the CLDN16 gene. B-C) The heterozygous missense variant (NM_006580: c.602G>A, p.Gly201Glu) was detected both in the father and the mother. Supplementary file2 (PPTX 637 KB)

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Eltan, M., Yavas Abali, Z., Turkyilmaz, A. et al. Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features. Calcif Tissue Int 110, 441–450 (2022). https://doi.org/10.1007/s00223-021-00928-y

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