X‐linked hypophosphatemic rickets: Description of seven new variants in patients followed up in reference hospitals in Rio de Janeiro

Abstract

Background X‐linked hypophosphatemic rickets (XLHR) is a rare genetic disease, often delayed in diagnosis due to the low degree of suspicion and limited access to sophisticated diagnostic tools that confirm the diagnosis, such as genetic testing. Methods Through a cross‐sectional and observational study, 26 patients with a previously presumptive diagnosis of X‐linked hypophosphatemic rickets (based on clinical history, laboratory findings, and physical examination), were followed for approximately 12 months. During 12 months of follow‐up, only 16 patients underwent genetic testing and enrolled in the study. Previous data were analyzed, such as clinical history (e.g., gender, current age, age of clinical diagnosis, age of admission to hospital, family history, and previous orthopedic surgery), physical exam, imaging tests (e.g., radiological changes) and laboratory tests (e.g., tubular maximum reabsorption rate of phosphate to glomerular filtration rate, alkaline phosphatase, and phosphate levels) at the time of the patient’s admission to IEDE and UFRJ, to corroborate and substantiate our research. These data were extracted from the medical records of the patients. Results Among the 16 patients analyzed by molecular biology techniques, the new generation sequencing (NGS), using DNA samples from oral swabs, we obtained seven variants never previously described, which were verified by Sanger sequencing. Among the seven variants never previously described, the most common coding impact was the nonsense mutation. We found two frameshift, one intronic splicing variant, three nonsense, and one deletion splice junction loss. Among patients with new mutations who presented data in the medical record, 100% showed a reduction in TmP/GFR (average of 1.98 mg/dl), the most sensitive laboratory parameter at the time of diagnosis, as well as serum phosphorus (100% had hypophosphatemia on arrival at the referral hospitals––average of 2.4 mg/dl and median 2.3 mg/dl). We also performed NGS on three mothers of the patients with identified mutations. Among these mothers, only one tested negative for the mutation and no family history was reported as well. This mother had serum phosphate of 3.5 mg/dl (normal range: 2.5–4.5 mg/dl) at the time of genetic test collection. The others had a positive test, low serum phosphorus at the time of the molecular test, in addition to a positive family history. Conclusion This study describes seven new variants in the PHEX gene and aims to increase the knowledge of the scientific community about the types of mutations involving this gene, increasing information on the genetic basis of this condition, enabling future considerations about genotype–phenotype correlation, in addition to diagnosis accurate and early.

A genetic study of a Brazilian cohort of patients with X-linked hypophosphatemia reveals no correlation between genotype and phenotype

“…A total of 23 different variants were distributed across the gene, and these variants have affected most exons or their adjacent introns (18). A major mutation density was found to be present from exon 15 to exon 22, corroborating with the findings of other studies (8,(26)(27)(28). Thus, the distribution in our cohort presents a lower mutation density in the first part of the gene according to PHEX mutation database (28).…”

“…In addition, the laboratory biomarkers were not strictly dependent on the type or site location of the variant. Popowska et al ( 27 ) found no relation between the severity of clinical symptoms and variant location. In concordance to that, no significant correlations were observed between the novel variant type and the serum concentrations of phosphate, PTH, or alkaline phosphatase at diagnosis, although one study reported that patients with truncating variants had lower serum phosphate concentration compared with patients without truncating variants ( 8 ).…”