PHEX 30-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

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 30-UTR of PHEX was identified in XLH by other investigators. This c.∗231A>G mutation is 3-bp upstream of the putative pA signal (AATAAA) in PHEX. Accordingly, we investigated whether this 30-UTR defect accounted for HR in any of these 19 sporadic XLH patients. PCR amplification and sequencing of their 30-UTR region showed the c.∗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 30-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 30-UTR mutation presented an unexplained gender bias (p=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 30-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.∗231A>G can masquerade as sporadic or X-linked recessive HR.