SP913
HEPATOBLASTOMA IN A CHILD WITH FAMILIAL HYPOMAGNESAEMIA, HYPERCALCIURIA AND NEPHROCALCINOSIS CAUSED BY MUTATION IN CLDN16 GENE

Introduction and Aims: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC, MIM #248250) is a rare autosomal recessive tubular disorder caused by mutations in the CLDN16 gene, which encodes protein claudin-16. Claudins are integral membrane proteins are major structural components of the tight junction of all epithelial cells, which crucial for the paracellular flux of ions. Overexpression or downregulation of claudins is frequently observed in epithelial-derived cancers. Hepatoblastoma (HB) is the most common primary liver malignancy in childhood, which has not been reported previously in genetically confirmed FHHNC.

Methods: We report on a 19-month-old girl referred to our clinic with a history of nephrocalcinosis since age of 7 months.

Results: On admission laboratory and imaging tests revealed hypomagnesemia (0.6 mmol/L), hypercalciuria (3.3 mmol/mmol creatinine), increased PTH (149 pg/mL), eGFR 92.5 mL/min/1.73m2, and bilateral medullary nephrocalcinosis, stage 2. There was no failure to thrive, imbalance of other serum electrolytes and acid-base status,no rickets, ocular abnormalities or hearing impairment. The girl also had moderately elevated serum liver enzyme levels and α-fetoprotein (2984 IU/mL). Abdomen ultrasound showed a growth-like mass of 6.2х4.6 cm between right and left liver lobes. Spiral computed tomography scanning did not reveal any pulmonary or bone metastases. Liver biopsy identified HB, stage 1 with pure fetal subtype. The girl was treated with courses of chemotherapy according to SIOPEL-3, including carboplatin with lower nephrotoxic potential as alternative to cisplatin+doxorubicine+farmorubicin+epirubicin. Then extended left-side hemihepatectomy with cholecystectomy were performed. At the age of 8 years the girl was admitted again in remission from HB and along with hypomagnesemia (0.63 mmol/L), hypercalciuria (1.6 mmol/mmol creatinine), increased PTH (106 pg/mL) and nephrocalcinosis, grade 3, she also had polyuria, increased FEMg (11.9%), decreased eGFR 55.4 mL/min/1.73m2, and recurrent urolithiasis. Direct sequencing of the CLDN16 gene in the girl showed a homozygous mutation c.453G>T (p.L151F; rs104893729) in exon 3, which is the most common in Europe FHHNC-causing mutation that lead to partial loss of function of claudin-16. Her mother was heterozygous for this CLDN16 mutation. The girl was treated with oral Mg supplementation (1.5 mmol/kg/d), hydrochlorothiazide (1.5 mg/kg/d), and citrate substitution (1.0 mmol/kg/d). By the age of 9 years the girl had decreased eGFR 45.3 mL/min/1.73m2, which was significantly faster as expected in patients with residual function of claudin-16 in FHHNC.

Conclusions: We presented the first case of FHHNC caused by mutation in the CLDN16 associated with HB which might be related to the altered expression patterns of different claudin members. We speculated that used potential nephrotoxic chemotherapy for HB can be responsible for rapid progression of renal failure in index case.