Long-term effect of conventional phosphate and calcitriol treatment on metabolic recovery and catch-up growth in children with PHEX mutation

Abstract

Objectives Hereditary hypophosphatemic rickets (HR) is conventionally treated with phosphate and calcitriol. Exploring genotype and phenotypic spectrum of X-linked hypophosphatemic rickets (XLHR), focusing on short-term, long-term, and pubertal impact of conventional treatment was aimed. Methods Sixteen patients from 12 unrelated families with HR were analyzed for phosphate regulating endopeptidase homolog X-linked (PHEX) mutation. Initially Sanger sequencing analysis was performed. If PHEX mutation was not detected, multiplex ligation-dependent probe amplification (MLPA) was performed. If molecular defect was detected, first-degree relatives were analyzed. Thirteen patients (81%) and five first-degree relatives with XLHR were evaluated for genotype–phenotype or gender-phenotype correlation. Clinical characteristics and response to conventional treatment were determined retrospectively. Results Nine different PHEX mutations were identified; four splice-site, three point mutations, and two single exon deletions. Four were novel mutations. Despite conventional treatment, median adult height was lower than median height on admission (−3.8 and −2.3 SDS, respectively), metabolic and radiographic recovery were not achieved, adherence was low (30%). Although mean adult height was better in compliant patients than noncompliants (−2.6 vs. −3.7 SDS, respectively), they were still short. Correlation between phenotype and genotype or gender could not be shown. Median phosphate decreased significantly throughout puberty (p=0.014). Median pubertal height was lower than prepubertal height (−4.4 vs. −3.6 SDS; respectively), pubertal growth spurt was not observed. Among five patients with a follow-up longer than five years, three had nephrocalcinosis (60%), two had hyperparathyroidism (40%), 4/6 (33%) required correction osteotomy. Conclusions Conventional treatment appears to have limited effect on metabolic, clinical and radiographic recovery in XLHR. Metabolic control and growth worsened during puberty. Although, long-term adverse effects are yet to be seen, introduction of burosumab as first-line treatment may be an alternative after infancy.

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

“…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. ( 23 , 46 ) Early diagnosis of XLH leads to prompt treatment and better outcomes.…”

“…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.…”

“…Reduced growth velocity and short stature (ie, height Z ‐score below −2 standard deviations) are found in 33%–92% of children with XLH. ( 35 , 36 , 38 , 39 , 40 , 41 , 42 , 43 , 48 ) Although children with XLH are born with average length, growth velocity begins to deviate from the norm at 6 months of age, and reduced growth is evident by 1 year and persists throughout childhood until final height. ( 32 , 49 ) Short stature is thus observed in more than 50% (56%–95%) of adults with XLH.…”

“…The majority of patients with XLH have lower limb deformities. ( 32 , 33 , 34 , 36 , 39 , 40 , 41 , 43 , 53 ) Genu/coxa varum or valgum is observed in more than 90% of most cohorts. ( 32 , 36 , 39 , 41 , 53 ) These deformities may be associated with intoeing or an unstable or abnormal gait and cause delayed onset, difficulty, or pain with walking and early fatigue.…”

“…(12) Other skeletal signs in children with XLH include enlarged wrists (46%), rachitic rosary (9% in treated cases and up to 38% in untreated cases), rib eversion (60%), pectus carinatum (47.7%), bracelet signs (64.6%), and skull malformations (7.9%-54%). (33,39,41,43,63) The latter include frontal bossing, square head, scaphocephaly, and craniosynostosis. (29,32,43,53,63,64) Specifically, craniosynostosis may be an early sign of XLH in infancy, presenting with an abnormal head shape.…”