Genotype and Phenotype Analysis in X-Linked Hypophosphatemia

Abstract

Background: X-linked hypophosphatemia (XLH) is the most frequent form of hypophosphatemic rickets and is caused by mutations in the PHEX gene. We analyzed genotype-phenotype correlations in XLH patients with proven PHEX mutations.Methods:PHEX mutations were detected in 55 out of 81 patients who clinically presented with hypophosphatemic rickets. The patients were grouped into nontruncating (n = 9) and truncating (n = 46) mutation groups; their initial presentation as well as long-term clinical findings were evaluated according to these groups.Results: Initial findings, including presenting symptoms, onset age, height standard deviation scores (SDS), and laboratory tests, including serum phosphate level and tubular resorption of phosphate, were not significantly different between the two groups (onset age: nontruncating mutation group, 2.0 years, truncating mutation group, 2.2 years; height SDS: nontruncating mutation group, −1.9, truncating mutation group, −1.7; serum phosphate: nontruncating mutation group, 2.5 mg/dL, truncating mutation group, 2.6 mg/dL). However, at their last follow-up, the serum phosphate level was significantly lower in patients with truncating mutations (nontruncating mutation group: 3.2 mg/dl, truncating mutation group: 2.3 mg/dl; P = 0.006). Additionally, 62.5% of patients with truncating mutations developed nephrocalcinosis at their last follow-up, while none of the patients with nontruncating mutations developed nephrocalcinosis (P = 0.015). Orthopedic surgery due to bony deformations was performed significantly more often in patients with truncating mutations (52.3 vs. 10.0%, P = 0.019).Conclusion: Although considerable inconsistency exists regarding the correlation of truncating mutations and their disease phenotype in several other studies, we cautiously suggest that there would be genotype-phenotype correlation in some aspects of disease manifestation after long-term follow-up. This information can be used when consulting patients with confirmed XLH regarding their disease prognosis.

Asia‐Pacific Consensus Recommendations on X‐Linked Hypophosphatemia: Diagnosis, Multidisciplinary Management, and Transition From Pediatric to Adult Care

“…A diagnosis of XLH is established via a combination of clinical, radiographic, biochemical, and genetic characteristics. The age of onset of clinical features of XLH in the majority of cases is between 1 and 2 years, ( 29 , 30 , 31 , 32 , 33 , 34 ) but diagnosis is established later between 2 and 3 years of age. ( 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ) This is because of the variable clinical phenotype of XLH, which may often lead to misdiagnosis or delay in diagnosis.…”

“…The most common initial manifestations of XLH include short stature, bone deformities, and radiologic signs of rickets ( 29 , 30 , 31 , 32 , 34 , 35 , 39 ) (Table 2 , Statement 2A). These clinical and radiologic features should prompt timely and appropriate referral for biochemical testing, early confirmation of the diagnosis, and initiation of treatment.…”

X-linked hypophosphatemia, fibroblast growth factor 23 signaling, and craniosynostosis

“…48 A phenotype–genotype correlation does not exist for any of the clinical features in XLH, although truncating mutations are predicted to cause more severe disease. 49,50 A phenotype–genotype correlation has not been demonstrated for craniosynostosis in patients with XLH. The average age at which craniosynostosis is evident clinically is presently unknown, nor whether the condition has its origin in utero or whether it tends to develop later in childhood.…”

Advances in understanding of phosphate homeostasis and related disorders

“…In patients with XLH, various types of variants have been identified in the PHEX gene, including missense variants, nonsense variants, frameshift variants, splicing variants, large deletions, and large duplications. More than 1,000 PHEX variants have been identified to date and are summarized in https://www.rarediseasegenes.com/: however, the genotype-phenotype relationship in XLH patients remains unclear [75]. We recently examined the genotype-phenotype relationship in 39 Japanese patients with XLH using 3-dimensional structure modeling.…”