Autosomal Dominant Hypophosphatemic Rickets: A Case Report and Review of the Literature

Chiara Mameli,Gian Vincenzo Zuccotti,Elisa Cattaneo,Valeria Colombo,Mirko Gambino,Arianna Sangiorgio,Luigina Spaccini

doi:10.3390/ijerph18168771

Abstract

Autosomal dominant hypophosphatemic rickets (ADHR) is an extremely rare form of genetic rickets caused by mutations in the fibroblast growth factor 23 gene. ADHR is characterized by hypophosphatemia secondary to isolated renal phosphate wasting. Only a few cases of ADHR have been reported in the literature to date. We describe the case of a 17-month-old girl who presented with severe failure to thrive (length: −4.08 standard deviation (SD), weight: −2.2 SD) and hypotonia. Hypophosphatemia, decreased tubular phosphate reabsorption (69%), and rachitic lesions were found. Genetic analysis showed the heterozygous variant c.536G>A (NM_020638.3:c.536G>A) in exon 3 of the FGF23 gene, leading to the diagnosis of ADHR. She was treated with phosphate salts and oral alfacalcidol. After 4 years of treatment, at 5 years of age, the patient’s ADHR resolved spontaneously. Considering the lack of knowledge regarding ADHR, we reviewed the literature to describe the features of this rare and poorly understood disease. Eleven ADHR pediatric cases have been described thus far, with cases tending to be more common in females than males. Similar to the general population, two groups of patients with ADHR can be described depending on the mutations present: patients with an R179 and R176 mutation have early-onset of disease and higher frequency of rickets, and a milder and late-onset of disease, respectively. Symptoms and disease severity may fluctuate. Spontaneous remission may occur during the pediatric age.

Highlights

Rickets is a systemic disease that occurs during developmental ages
autosomal recessive hypophosphatemic rickets (ARHR) and XLHR are caused by loss-of-function mutations in the genes DMP1/ENPP1 and PHEX, respectively, which encode for proteins involved in fibroblast growth factor 23 (FGF23) production in osteocytes
We review the pediatric cases of autosomal dominant hypophosphatemic rickets (ADHR) described in the literature so far to help clinicians in the management of this rare disease

Summary

Introduction

Rickets is a systemic disease that occurs during developmental ages. It originates from an abnormal differentiation and maturation of chondrocytes, resulting in a lack of mineralization of the growth plate cartilage and bone deformity [1,2]. ARHR and XLHR are caused by loss-of-function mutations in the genes DMP1/ENPP1 and PHEX, respectively, which encode for proteins involved in FGF23 production in osteocytes. Their loss-of-function increases FGF23 production, leading to hypophosphatemia. FGF23 reduces intestinal phosphate absorption by enhancing CYP24A1, which encodes for the 24-hydroxylase that is responsible for 1.25 (OH) D metabolic inactivation [2] These mutations result in enhanced FGF23 bioactivity and lead to isolated renal phosphate wasting, hypophosphatemia, and impaired bone mineralization [3,5,6]. We review the pediatric cases of ADHR described in the literature so far to help clinicians in the management of this rare disease

Case Report

Narrative Review of Literature and Discussion

Findings

Conclusions