PHEX 3′-UTR c.*231A>G Near The Polyadenylation Signal Is a Relatively Common, Mild, American Mutation That Masquerades as Sporadic or X-Linked Recessive Hypophosphatemic Rickets

Abstract

Heritable forms of hypophosphatemic rickets (HR) include X-linked dominant (XLH), autosomal recessive, and autosomal dominant HR (from deactivating mutations in PHEX, DMP1 or ENPP1, and activating mutations in FGF23, respectively). Over 30 years, we have cared for 284 children with HR. For those 72 deemed sporadic XLH, we preliminarily reported mutation analysis for 30 subjects. Eleven had PHEX mutations. However, the remaining 19 lacked readily identifiable defects in PHEX, DMP1, or FGF23. In 2008, a novel singlebase change near the polyadenylation (pA) signal in the 3 0 -UTR of PHEX was identified in XLH by other investigators. This c. Ã 231A > G mutation is 3-bp upstream of the putative pA signal (AATAAA) in PHEX. Accordingly, we investigated whether this 3 0 -UTR defect accounted for HR in any of these 19 sporadic XLH patients. PCR amplification and sequencing of their 3 0 -UTR region showed the c.Ã 231A > G mutation in four unrelated boys. Then, among an additional 22 of our 72 "sporadic" XLH patients, one boy and one girl were found to have the 3 0 -UTR defect, totaling six patients. Among these 52 sporadic XLH patients with PHEX analysis, 36 were girls and 16 were boys; ie, a $2:1 gender ratio consistent with XLH. However, finding five boys and only one girl with this 3 0 -UTR mutation presented an unexplained gender bias (p ¼ 0.02). Haplotyping for the five boys, all reportedly unrelated, showed a common core haplotype suggesting a founder. Five of their six mothers had been studied clinically and biochemically (three radiologically). Remarkably, the seemingly unaffected mothers of four of these boys carried the 3 0 -UTR mutation. These healthy women had normal height, straight limbs, lacked the radiographic presentation of XLH, and showed normal or slight decreases in fasting serum Pi levels and/or TmP/GFR. Hence, PHEX c.Ã 231A > G can masquerade as sporadic or X-linked recessive HR.

X-Linked Hypophosphatemia: Uniquely Mild Disease Associated With PHEX 3′-UTR Mutation c.*231A>G (A Retrospective Case–Control Study)

“…Since 1983 at the Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children ‐ St. Louis, St. Louis, MO, USA (Research Center), we have diagnosed, treated, and investigated more than 300 children with XLH and studied many of their affected adult family members . Patient referrals were primarily from throughout the United States.…”

“…Informed written consent was obtained from all study participants as approved by the Human Research Protection Office at Washington University School of Medicine, St. Louis, MO, USA and more recently also by the Medical Research Department, Shriners Hospitals for Children, Tampa, FL, USA. Molecular confirmation of the diagnosis came primarily from our research laboratory that identifies PHEX mutations and can exclude DMP1 , FGF23 , ABCC6 , ENPP1 , GALNT3 , SLC34A3 , and VDR defects causing other heritable forms of hypophosphatemic rickets/osteomalacia …”

“…These five boys had higher fasting serum Pi and TmP/GFR compared to boys with mutations elsewhere in PHEX . This suggested they manifested a uniquely mild variant of XLH . Then, in two preliminary reports in 2016, we described two American kindreds manifesting mild XLH harboring this 3′‐UTR mutation…”

“…In 2015, we reported this PHEX 3′‐UTR mutation c.*231A>G in five boys and one girl among 52 seemingly “sporadic” XLH patients . Notably, four of the boys' mothers were then found to be healthy carriers with normal heights (two with average values) and straight limbs who lacked radiographic features of XLH and demonstrated normal or slightly low fasting serum Pi concentrations and/or renal tubular threshold maximum for phosphorus per glomerular filtration rate (TmP/GFR) . These five boys had higher fasting serum Pi and TmP/GFR compared to boys with mutations elsewhere in PHEX .…”

Rare, genetically conditioned forms of rickets: Differential diagnosis and advances in diagnostics and treatment

“…21 Other authors question this observation and claim that inheritance does have a dominant pattern but that in women the course of the disease is milder due to the presence of the second copy of the gene, and that, therefore, it may seem asymptomatic but in fact is oligosymptomatic but not adequately diagnosed. 22…”