PSAT219 Renal Phosphate Wasting Caused by ENPP-1 mutation.
Authors: Madahar Inderpreet , Haider Adnan , Hardy Alexandra 
Published: November 2022

Background

Increased renal phosphate loss can be Fibroblast Growth Factor-23 (FGF-23) dependent or independent. FGF-23 reduces expression of Sodium-Phosphate co-transporters, responsible for phosphate reabsorption; and by inhibition of 1-alpha hydroxylation of 25-OH-D3. Reduced serum concentration of 1, 25-OH2-D3 results in secondary hyperparathyroidism. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) mutation is one of the rarest causes of hypophosphatemia, which causes FGF-23 dependent hypophosphatemia.

Case description

31-year-old female referred to endocrinology for evaluation of recurrent nephrolithiasis despite normalization of PTH and serum Calcium (Ca) after right inferior parathyroid adenoma resection. Repeated renal stone analysis revealed calcium phosphate as the major stone composition. Patient achieved mid parental height, denied history of calcium or phosphate metabolism disorders/ rickets in the family. Physical exam was not suggestive of rickets and skeletal survey showed normal bone mineralization. Initial labs following parathyroid adenoma resection showed normal Ca 9.7 mg/dl, PTH 47 pg/ml, Phosphorus (Ph) 2.3 mg/dl, 25-OH-D3 51 ng/ml, albumin 3.9 g/dl, Mg 1.8 mg/dl.

Repeat fasting labs six months later revealed Ca 9 mg/dl, Ph 1.7 mg/dl, 25-OH-D3 52 ng/ml, PTH 67.5 pg/ml and albumin 3.7 g/dl. Persistent low serum phosphate was evaluated further by a 24-hour urine collection which revealed high urine phosphate of 828 mg/day, Ca 181 mg/day, Mg 23 mg/day and creatinine was 1485 mg/day. Tubular reabsorption of phosphorus was 77% (normal: &gt;80%), indicating renal phosphate wasting. Serum FGF-23 on two different days was &gt;180 RU/ml. Next-generation sequencing tested positive for heterozygous ENPP-1 gene mutation variant c1441C&gt;T (p. Arg481Trp). Patient was started on oral Phosphorus supplementation & calcitriol. Repeat labs showed normalization of Ph 2.4 mg/dl. Audiology evaluation suggested mild sensorineural hearing loss. Heart calcium score was zero.

Discussion

ENPP1 gene mutation's clinical presentations can vary from no symptoms, hypophosphatemic rickets to death in the first six months of life from generalized arterial calcification. ENPP1 is an enzyme, which degrades ATP into adenosine monophosphate (AMP) and pyrophosphate (PPi). PPI is an inhibitor of hydroxyapatite crystallization in vascular tissue and organs, while Ph is a pro-mineralization factor. ENPP1 gene mutation results in a low concentration of PPi, predisposing the patient to pathological calcification. It is speculated that ENPP-1 modulates FGF-23 secretion. FGF-23 elevation in these patients is a protective response, as hypophosphatemia prevents pathological calcification. Treatment target is to keep phosphate at low end of normal. In our patient, ENPP- 1 mutation likely contributed to recurrent renal stones and possible parathyroid adenoma. Evaluation of genetic mutations is necessary to decide for or against FGF-23 antibody/Burosumab treatment. In ENPP-1 mutation. Burosumab should be avoided as it can bind to FGF-23 resulting in pathological calcification.

Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.