Endocrine. Feb. 2025;88:285-294

DOI: doi: 10.1007/s12020-024-04097-4

R. Chimenz, C. Columbu, F. Pugliese, A. Arena, L. Bonifazi Meffe, V. Carbone, D. Concolino, V. Guarnieri

Highlights:

This Italian multicentric study characterises the clinical and genetic spectrum of hypophosphatemic rickets in 24 patients, identifying pathogenic or likely pathogenic variants in PHEX, CYP27B1, and SLC34A3, including five large PHEX deletions and several novel alleles. The cohort was marked by frequent short stature, bone deformities, and musculoskeletal pain, and in over half the patients molecular confirmation came only in adulthood — sometimes decades after symptom onset — underscoring the diagnostic value of targeted NGS panels for earlier recognition and treatment (including burosumab) in genetic rickets.

Background:

Rickets is a rare bone disorder resulting from disturbed calcium, vitamin D, and phosphorus metabolism. While most cases are nutritional, around 13% have a genetic origin. Data on Italian cohorts of genetic rickets remain scarce, limiting understanding of the local mutational spectrum and clinical presentation.

Objective and methods:

The study aimed to provide a comprehensive clinical and molecular characterisation of an Italian cohort with hypophosphatemic rickets. Twenty-four unrelated patients with confirmed hypophosphataemia and reduced renal tubular phosphate reabsorption (TmPO4/GFR) were recruited from multiple tertiary centres between October 2018 and December 2023.

Material and Methods:

Clinical, anamnestic, and biochemical data (calcium, phosphorus, alkaline phosphatase, PTH, 25(OH)D3, 1,25(OH)2D3, creatinine, FGF23) were collected. DNA was analysed using a targeted NGS panel (SureSelect, Agilent) covering 16 genes associated with syndromic and non-syndromic rickets, sequenced on an Illumina NextSeq 500 (≥200x coverage). Patients negative on NGS were further screened for large genomic deletions using the CytoScan XON array. Variants were classified following ACMG/ClinGen guidelines.

Results:

Eight pathogenic, five likely pathogenic single-nucleotide variants, and three VUS (16 SNVs in total, plus five large genomic deletions) were identified in PHEX, corresponding to X-linked hypophosphataemia (XLH) in 20 of the 24 cases, alongside three CYP27B1-related VDDR1A cases and one SLC34A3-related HHRH case. Five large PHEX genomic deletions were detected via XON array. Eight of 21 PHEX variants and both SLC34A3 variants were novel; segregation analysis identified 11 familial and 3 de novo cases. Clinically, short stature (76.1%), bone deformities (85.7%), musculoskeletal pain (71.4%), and muscle weakness (55.5%) were the dominant features, with elevated alkaline phosphatase and low 25(OH)D3 commonly observed. Burosumab was started in 8 patients with favourable biochemical and symptomatic response. Notably, 54% of patients received molecular confirmation only in adulthood, in three cases after age 60–70.

Conclusion:

This study expands the known mutational spectrum of PHEX and SLC34A3 and confirms that hypophosphatemic rickets is frequently underdiagnosed until adulthood in Italy. The authors advocate for routine use of high-throughput targeted sequencing to enable earlier molecular diagnosis and more appropriate long-term management.

Keywords: Rickets, Hypophosphataemia, FGF23, PHEX, CYP27B1, SLC34A3