Case Report and Review of Literature: Autosomal Recessive Hypophosphatemic Rickets Type 2 Caused by a Pathogenic Variant in ENPP1 Gene

Abstract

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is a rare form of hereditary rickets, which is characterized by defective bone mineralization and renal phosphate wasting due to a loss-of-function variant in the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene. Although pathogenic variant of ENPP1 has been known to manifest other phenotypes including arterial calcification, hearing loss, ossification of posterior longitudinal ligament, or pseudoxanthoma elasticum, there have been few reports including systematic examination in individuals diagnosed with ARHR2 to date. Herein, we report a case of ARHR2 with a bi-allelic pathogenic variant of ENPP1, in which the patient presented with gait abnormalities with severe genu varum at 26 months of age. Targeted gene panel sequencing was performed to investigate the genetic cause of rickets, and a homozygous nonsense variant in ENPP1, c.783C>G (p.Tyr261*), was identified. The patient was treated with oral phosphate and active vitamin D supplements and underwent corrective osteotomy for varus deformity. His phenotype was limited to rickets. A periodic systematic evaluation is needed to identify any comorbidities in ARHR2 patients since ENPP1 variants may present phenotypes other than rickets and symptoms may evolve or change over time.

Keywords: autosomal recessive hypophosphatemic rickets; case report; child; ectonucleotide pyrophosphatase phosphodiesterase 1; rickets.

Figure 1

Clinical photograph and radiological findings of the patient. (A) Photograph of the patient’s bowed legs at 24 months of age. (B) Plain radiograph of the lower extremities showing bilateral metaphyseal flaring of the distal femur and tibia, associated with varus deformity, at 30 months of age.

Figure 2

Genetic analysis of ENPP1 gene and pedigree of the family. (A) Genomic DNA sequences of the patient and his parents exhibiting either homozygous or heterozygous c.783C>G (p.Tyr261*) variant in the ENPP1 gene. (B) Pedigree of the family. The variants identified in the ENPP1 gene are indicated below each individual. The black arrow indicates the proband.