X-Linked Hypophosphatemia Caused by the Prevailing North American PHEX Variant c.*231A>G; Exon 13-15 Duplication Is Often Misdiagnosed as Ankylosing Spondylitis and Manifests in Both Men and Women.

Inactivating mutations of the gene coding for phosphate-regulating endopeptidase homolog X-linked (PHEX) cause X-linked hypophosphatemia (XLH). A novel PHEX variant, c.*231A>G; exon 13-15 duplication, has emerged as a common cause of XLH in North America, emphasizing the importance of delineating its clinical presentation. Here, a comprehensive description of a five-generation American kindred of 22 treatment-naïve individuals harboring the c.*231A>G; exon 13-15 duplication is provided. After XLH was diagnosed in the proposita, pro-active family members used social media to facilitate a timely assessment of their medical history. Most had normal height and 50% were normophosphatemic. Thirteen had been given a diagnosis other than XLH, most commonly ankylosing spondylitis, and XLH was only established after genetic testing. The prevalent phenotypic characteristics of c.*231A>G; exon 13-15 duplication were disorders of dentition (68.2%), enthesopathies (54.5%), fractures/bone and joint conditions (50%), lower-limb deformities (40.9%), hearing loss/tinnitus (40.9%), gait abnormalities (22.7%), kidney stones/nephrocalcinosis (18.2%), chest wall disorders (9.1%), and Chiari/skull malformation (4.5%). More affected males than females, respectively, had gait abnormalities (42.9% versus 13.3%), lower-limb deformities (71.4% versus 26.7%), and enthesopathies (85.7% versus 40%). Single phenotypes, observed exclusively in females, occurred in 22.7% and multiple phenotypes in 77.3% of the cohort. However, as many as six characteristics could develop in either affected males or females. Our findings will improve diagnostic and monitoring protocols for XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Urine phosphoethanolamine is a specific biomarker for hypophosphatasia in adults.

OBJECTIVES: We investigated the utility of urine phosphoethanolamine (PEA) as a marker to aid in diagnosing and/or confirming hypophosphatasia (HPP) in adults and for monitoring patients on enzyme replacement therapy (ERT). METHODS: Data was collected from seventy-eight adults who were referred to the Vanderbilt Program for Metabolic Bone Disease for evaluation of a possible or confirmatory HPP diagnosis between July 2014 through December 2019. Fifty-nine patients were diagnosed with HPP and nineteen were excluded from a diagnosis of HPP. The urine PEA results of those patients with a confirmed diagnosis of HPP and those patients with a diagnosis of HPP excluded were captured and compared to other laboratory and clinical parameters consistent with HPP, including alkaline phosphatase (ALP) activity, plasma pyridoxal 5'-phosphate (PLP), the presence of musculoskeletal abnormalities, and genetic testing for pathogenic mutations in ALPL. RESULTS: Initial urine PEA values in patients in our HPP cohort and not on ERT were significantly higher (median = 150.0 nmol/mg creatinine, IQR = 82.0-202.0) compared patients in our HPP negative group (median 18.0 nmol/mg creatinine, IQR = 14.0-30.0, p < 0.0001) and higher than patients on ERT (median 65.0 nmol/mg creatinine, IQR = 45.3-79.8). Patients who began ERT had a decline in urine PEA levels after treatment with a mean decrease of 68.1 %. Plasma ALP levels were significantly lower in the group of patients with HPP and not on ERT group (median = 24.0 U/L, IQR = 15.0-29.50) compared to the patients without HPP (median = 45.50 U/L, IQR = 34.0-62.0;) and plasma PLP levels were significantly higher in the HPP non-ERT group (median = 284.0 nmol/L, IQR = 141.0-469.4) compared to the patients without HPP (median = 97.5 nmol/L, IQR = 43.7-206.0;). The area under the curve (AUC) of urine PEA, ALP, and PLP to distinguish between HPP and non-HPP patients is 0.968, 0.927 and 0.781, respectively, in our cohort. Urine PEA had 100 % specificity (95 % CI of 83.2 % to 100.0 %) for diagnosing HPP at a value >53.50 nmol/mg creatinine with a sensitivity of 88.4 %; 95%CI 75.5 to 94.9 %. ALP had a 100 % specificity (95 % CI of 82.4 % to 100.0 %) for diagnosing HPP at a value <30.5 U/L with a sensitivity of 77.2 %; (95%CI 64.8 to 86.2 %). PLP had a 100 % specificity (95 % CI of 81.6 % to 100.0 %) for diagnosing HPP at a value >436 nmol/L with a sensitivity of 26.9 %; (95%CI 16.8 to 40.3 %). The most common pathogenic or likely pathogenic mutations in our cohort were c.1250A>G (p.Asn417Ser), c.1133A>T (p.Asp378Val), c.881A>C (p.Asp294Ala), c.1171C>T (p.Arg391Cys), and c.571G>A, (p.Glu191Lys). CONCLUSIONS: Urine PEA is a promising diagnostic and confirmatory marker for HPP in patients undergoing investigation for HPP. Urine PEA also has potential use as a marker to monitor ERT compliance. Future studies are necessary to evaluate the association between PEA levels and clinical outcomes.

Rare Diseases That Impersonate One Another: X-Linked Hypophosphatemia and Tumor-Induced Osteomalacia, a Retrospective Analysis of Discriminating Features.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disease characterized by frequent fractures, bone pain, muscle weakness, and affected gait. The rarity of TIO and similar presentation to other phosphate-wasting disorders contribute to a high misdiagnosis rate and long time to correct diagnosis. TIO is curable by tumor resection, so accurate diagnosis has significant impact on patients' emotional and economic burden. Current diagnostics for TIO rely on decades-old literature with poor phenotypic validation. Here, we identify salient clinical differences between rigorously validated cohorts of patients with TIO (n = 9) and X-linked hypophosphatemia (XLH; n = 43), a frequent misdiagnosis for patients with TIO. The TIO cohort had significantly elevated FGF23 (365 versus 95 RU/mL, p < 0.001) and alkaline phosphatase (282.8 versus 118.5 IU/L, p < 0.01) but significantly reduced phosphorus (1.4 versus 2.2 mg/dL, p < 0.05) and 1,25(OH)2 D (16.6 versus 59.8 pg/mL, p < 0.01). By contrast, total vitamin D was similar between the two groups. Dual-energy X-ray absorptiometry (DXA) scans reveal lower Z-scores in the hip (-1.6 versus 0.050, p < 0.01) and spine (0.80 versus 2.35, p < 0.05). TIO patients were more likely to have prior clinical diagnosis of osteoporosis (67% versus 0%), use assistive devices in daily living (100% versus 14%), and have received a knee arthroplasty (33% versus 7%). TIO patients lost an average of 1.5 cm over their disease course and had sustained an average of 8 fractures each, whereas fractures were rare in XLH. The XLH cohort had higher incidence of osteotomy (19% versus 0%), spinal stenosis (12% versus 0%), secondary dental abnormalities (95% versus 44%, p < 0.001), and depression and anxiety (46.5% versus 11%). These results deepen our understanding of the subtle differences present between diseases of phosphate wasting. They suggest several biochemical, clinical, and historical features that effectively distinguish TIO from XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Characterization of physical, functional, and cognitive performance in 15 adults with hypophosphatasia.

OBJECTIVE: Given the small but growing body of literature related to physical functioning and the scarce data related to fine motor and cognitive functioning in adults with hypophosphatasia (HPP), our objective was to characterize physical, functional, and cognitive performance in adults with HPP. A future objective is to utilize this characterization to develop guidelines for evaluation by physical therapists (PT), occupational therapists (OT), and speech-language pathologists (SLP). METHOD: We evaluated physical, functional, and cognitive performance in 15 adults with HPP through standardized assessments of mobility, balance, fine motor control, activities of daily living, cognition, and self-reported measures of health-related quality of life, fatigue, depression, and anxiety. The median age at enrollment was 44 years (range 26-79 years). Among the participants, 11 (73%) were women. Five participants (33%) were on enzyme replacement therapy. RESULTS: Compared with the general population, HPP participants traveled shorter distances on the Six-Minute Walk Test (420 m (m) [SD: 132] vs 620 m [SD: 49], p < 0.00005), had slower gait on the 10-Meter Walk Test [HPP men (3.71 ft/s (f/s) [SD: 0.77] vs 4.70 f/s [SD: 0.14], p < 0.00005) and HPP women (3.39 f/s [SD: 0.67] vs 4.56 f/s [SD: 0.09], p < 0.00005)]. HPP participants had decreased upper extremity (UE) dexterity by Nine Hole Peg Test [right UE in HPP men (22.7 s (s) [SD: 2.3] vs 19.0 s [SD: 3.9], p = 0.03), left UE in HPP men (23.3 s [SD: 0.7] vs 19.8 s [SD: 3.7], p = 0.03), right UE in HPP women (19.8 s [SD: 2.0] vs 17.7 s [SD: 3.2], p = 0.01), and left UE in HPP women (21.1 s [SD: 2.5] vs 18.9 s[SD: 3.4], p = 0.02)], and some had abnormally slow bilateral UE reaction times via Dynavision (0.9 s [0.85,0.96], functional speed <1.15 s). On the Short Form-36 (SF36), HPP patients reported worse energy/fatigue (30.4 [SD 22.7] vs 52.2 [SD: 22.4], p = 0.0001), social functioning (54.5 [SD: 34.2] vs 78.8 [SD: 25.5], p = 0.0002), pain (46.1 [SD: 27.3] vs 70.8 [SD: 25.5], p = 0.0001), general health (36.8 [SD: 24.0] vs 57.0 [SD: 21.1], p = 0.0002), and health change i.e. perception of health improvement (32.1 [SD: 15.3] vs 59.1 [SD: 23.1], p < 0.00005) than the general population. Fatigue Severity Scale scores were well above the median for a healthy population (5.21 [SD: 1.8] vs 2.3 [SD: 1.21], p < 0.00005), indicating significant fatigue. HPP participants had significantly higher DASS scores for depression (8.5 [SD: 6.5] vs 5.0 [SD: 7.5], p = 0.02), anxiety (7.9 [SD: 6.7] vs 3.4 [SD: 5.1], p = 0.00009), and stress (14.7 [SD: 12.4] vs 8.1 [SD: 8.4], p = 0.0003) compared to the general population. CONCLUSION: Objective functional assessments demonstrated defects in physical functioning, including decreased ability to walk distances, slow gait speed, and diminished ability to repeatedly rise from a sitting position. In addition, participants self-reported significant limitations due to physical dysfunction. Decreased upper extremity dexterity may indicate problems with activities of daily living and delayed reaction times can have safety implications. Some patients with HPP have increased difficulties with depression, anxiety, and stress. PT, OT, and SLP specialists can aid in establishing baseline assessment of impairment and objective metrics for assessing efficacy of treatment.

Rare Variants in the Gene ALPL That Cause Hypophosphatasia Are Strongly Associated With Ovarian and Uterine Disorders.

Context: Mutations in alkaline phosphatase (AlkP), liver/bone/kidney (ALPL), which encodes tissue-nonspecific isozyme AlkP, cause hypophosphatasia (HPP). HPP is suspected by a low-serum AlkP. We hypothesized that some patients with bone or dental disease have undiagnosed HPP, caused by ALPL variants. Objective: Our objective was to discover the prevalence of these gene variants in the Vanderbilt University DNA Biobank (BioVU) and to assess phenotypic associations. Design: We identified subjects in BioVU, a repository of DNA, that had at least one of three known, rare HPP disease-causing variants in ALPL: rs199669988, rs121918007, and/or rs121918002. To evaluate for phenotypic associations, we conducted a sequential phenome-wide association study of ALPL variants and then performed a de-identified manual record review to refine the phenotype. Results: Out of 25,822 genotyped individuals, we identified 52 women and 53 men with HPP disease-causing variants in ALPL, 7/1000. None had a clinical diagnosis of HPP. For patients with ALPL variants, the average serum AlkP levels were in the lower range of normal or lower. Forty percent of men and 62% of women had documented bone and/or dental disease, compatible with the diagnosis of HPP. Forty percent of the female patients had ovarian pathology or other gynecological abnormalities compared with 15% seen in controls. Conclusions: Variants in the ALPL gene cause bone and dental disease in patients with and without the standard biomarker, low plasma AlkP. ALPL gene variants are more prevalent than currently reported and underdiagnosed. Gynecologic disease appears to be associated with HPP-causing variants in ALPL.

Factors that influence parental attitudes toward enrollment in type 1 diabetes trials.

AIMS: To assess parental attitudes towards type 1 diabetes clinical trials (T1DCTs) and factors that impact willingness to enroll their children with and without diabetes. METHODS: A cross-sectional survey of parents of children with type 1 diabetes was administered at an academic clinic and a diabetes educational event. RESULTS: Survey response rate was 36%. Of 166 participating parents, 76% were aware of T1DCTs. More parents reported willingness to enroll children with diabetes (47%) than unaffected children (36%). Only 18% recalled being asked to enroll their children, and of these, 60% agreed to enroll at least some of those times. Less than 30% were comfortable with placebos. Factors predicting willingness to enroll children with diabetes included healthcare provider trust, comfort with consent by proxy, low fear of child being a "guinea pig," and comfort with placebo. Factors predicting willingness to enroll unaffected children were provider trust, comfort with consent by proxy, comfort with placebo, and perceived ease of understanding T1DCT information. CONCLUSIONS: Parents report moderate willingness to enroll children in T1DCTs. Willingness is diminished by common trial methodologies. Although most parents recalled receiving trial-related information, significantly fewer recalled being asked to participate. Efforts to optimize effective communication around identified areas of parental concern may increase T1DCT participation.