Whole exome sequencing reveals a pathogenic homozygous CLDN16 mutation in a 17-year-old patient with familial hypomagnesemia with hypercalciuria and nephrocalcinosis: A case report

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive renal tubular disorder caused by mutations in the CLDN16 or CLDN19 genes. This case demonstrates the critical role of whole-exome sequencing (WES) in diagnosing FHHNC, particularly when novel mutations, such as the homozygous CLDN16 variant (c.351G > T, p.W117C) found in this patient, are identified, which expands the genetic understanding of this condition. A 17-year-old female presented with an 8-month history of persistent neck, shoulder, and upper limb pain that had worsened over the past month. Despite initial treatment for cervical degenerative disease at local hospitals, her symptoms showed minimal improvement. She also exhibited growth retardation, with a height of 145 cm (-2 SD), and experienced recurrent urinary tract infections, although she reported no visual disturbances or neurological symptoms. Laboratory tests revealed hypomagnesemia and elevated parathyroid hormone levels. Imaging studies confirmed bilateral nephrocalcinosis and a medullary sponge kidney. Genetic testing using WES identified a homozygous pathogenic mutation in CLDN16 (c.351G > T), which was further validated by Sanger sequencing in the patient and her heterozygous parents. During hospitalization, the patient received intravenous magnesium sulfate (2.5 g/day), oral calcium carbonate with vitamin D3 supplementation, and levofloxacin for urinary tract infection management. Upon discharge, she was maintained on oral magnesium oxide (500 mg twice daily) with regular monitoring of electrolyte levels and renal function. At the 2-year follow-up, the patient's serum magnesium levels improved but remained below the normal range. Hypercalciuria persisted, although her renal function was stable. Notably, there was no progression to end-stage renal disease, and her symptoms were better managed with ongoing treatment. This case underscores the importance of WES in the diagnosis of rare tubular disorders, especially when the clinical presentations are nonspecific. This finding highlights that CLDN16-related FHHNC can occur without ocular involvement, and this information may aid in differential diagnosis. Early and consistent magnesium supplementation appears to mitigate renal deterioration, emphasizing the need for prompt intervention. Additionally, this case reinforces the value of genetic counseling for families affected by autosomal recessive conditions.