Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) Presenting with Genu Valgum Deformity: Treatment with Phosphate Supplementation and Surgical Correction

We describe a case of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) in a 32-year-old female with short stature, chronic pathologic genu valgum deformity, and knee pain who was referred to endocrinology clinic after previous inconclusive workups. We present imaging spanning 10 years of untreated disease. Biochemical studies showed hypophosphatemia with undetectable fibroblast growth factor 23 (FGF23.) Renal ultrasound revealed bilateral medullary nephrocalcinosis despite no apparent hypercalciuria. Due to concern for HHRH, genetic testing was performed that determined this patient to be homozygous in the SLC34A3 gene for a previously described missense variant (c.1402C \u3e T, p.Arg468Trp). There was no known family history of rickets. A bone biopsy with metabolic studies was performed for diagnostic and prognostic reasons. The histopathological findings along with tetracycline uptake studies were consistent with a diagnosis of HHRH. Treatment with phosphorous supplementation and surgical correction of her valgum deformity resulted in resolution of pain, but no change in bone histomorphometry

X-linked hypophosphatemia caused by the prevailing North American PHEX variant c.*231A\u3eG; 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 nove

Growth and disease burden in children with hypophosphatasia

Hypophosphatasia, an inborn error of metabolism characterized by impaired bone mineralization, can affect growth. This study evaluated relationships between anthropometric parameters (height, weight, and body mass index) and clinical manifestations of hypophosphatasia in children. Design: Data from children (aged < third percentile) and those with normal stature. Methods: Anthropometric parameters were evaluated by age group (< third percentile) and those with normal stature. Results: This analysis included 215 children (54.4% girls). Short stature presented in 16.1% of children aged<2 years and 20.4% of those aged≥2 years at assessment. Among those with available data (n = 62), height was below the target height (mean: −0.66 standard deviations). Substantial worsening of growth (mean delta height z score: −1.45; delta weight z score: −0.68) occurred before 2 years of age, while in those aged≥2 years, anthropometric trajectories were maintained (delta height z score: 0.08; delta weight z score: 0.13). Broad-ranging hypophosphatasia manifestations (beyond dental) were observed in most children. Conclusions: Short stature was not a consistent characteristic of children with hypophosphatasia, but growth impairment was observed in those aged<2 years, indicating that hypophosphatasia might affect growth plate activity during infancy. In addition, a broad range of clinical manifestations occurred in those above and below the third percentile for height, suggesting that height alone may not accurately reflect hypophosphatasia disease burden and that weight is less affected than longitudinal growt

Impact of muscular symptoms and/or pain on disease characteristics, disability, and quality of life in adult patients with hypophosphatasia: A cross-sectional analysis from the Global HPP Registry

IntroductionHypophosphatasia (HPP) manifests in adults as fractures/pseudofractures, pain, muscle weakness, and other functional impairments. Better phenotypic disease characterization is needed to help recognize disability and treat patients with HPP.MethodsBaseline/pretreatment demographic, clinical characteristic, and patient-reported disability/health-related quality-of-life (HRQoL) data from adults (≥18 y) in the Global HPP Registry (NCT02306720) were stratified by presence of overt skeletal manifestations (skeletal group) versus muscular/pain manifestations without skeletal manifestations (muscular/pain group) and summarized descriptively. Disability was measured using the Health Assessment Questionnaire–Disability Index (HAQ-DI), and HRQoL using the 36-item Short Form Health Survey (SF-36v2).ResultsOf 468 adults, 300 were classified into the skeletal group and 73 into the muscular/pain group. The skeletal group had a higher median age at baseline (50.1 vs 44.4 y; P=0.047) but a lower median age at first HPP manifestation (12.3 vs 22.1 y; P=0.0473), with more signs and symptoms (median, 4 vs 3; P&lt;0.0001) and involved body systems (median, 3 vs 2; P&lt;0.0001) than the muscular/pain group. More patients in the skeletal group required any use of mobility aids (22.6% vs 3.5%, respectively; P=0.001). Six-Minute Walk test distances walked were similar between groups. SF-36v2 and HAQ-DI scores were similar between groups for physical component summary (n=238; mean [SD]: 40.2 [11.0] vs 43.6 [11.2]; P=0.056), mental component summary (n=238; mean [SD]: 43.6 [11.3] vs 43.8 [11.8]; P=0.902), and HAQ-DI (n=239; median [minimum, maximum]: 0.4 [0.0, 2.7] vs 0.3 [0.0, 2.1]; P=0.22).ConclusionAdults with HPP experience similar QoL impairment regardless of skeletal involvement.Registrationhttps://clinicaltrials.gov/ct2/show/NCT02306720 and https://www.encepp.eu/encepp/viewResource.htm?id=47907, identifier NCT02306720; EUPAS13514

Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa.

Hypophosphatasia (HPP) is a rare, inherited, systemic, metabolic disorder caused by autosomal recessive mutations or a single dominant-negative mutation in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). The disease is associated with a broad range of signs, symptoms, and complications, including impaired skeletal mineralization, altered calcium and phosphate metabolism, recurrent fractures, pain, respiratory problems, impaired growth and mobility, premature tooth loss, developmental delay, and seizures. Asfotase alfa is a human, recombinant enzyme replacement therapy that is approved in many countries for the treatment of patients with HPP. To address the unmet need for guidance in the monitoring of patients receiving asfotase alfa, an international panel of physicians with experience in diagnosing and managing HPP convened in May 2016 to discuss treatment monitoring parameters. The panel discussions focused on recommendations for assessing and monitoring patients after the decision to treat with asfotase alfa had been made and did not include recommendations for whom to treat. Based on the consensus of panel members, this review provides guidance on the monitoring of patients with HPP during treatment with asfotase alfa, including recommendations for laboratory, efficacy, and safety assessments and the frequency with which these should be performed during the course of treatment. Recommended assessments are based on patient age and include regular monitoring of biochemistry, skeletal radiographs, respiratory function, growth, pain, mobility and motor function, and quality of life. Because of the systemic presentation of HPP, a coordinated, multidisciplinary, team-based, patient-focused approach is recommended in the management of patients receiving asfotase alfa. Monitoring of efficacy and safety outcomes must be tailored to the individual patient, depending on medical history, clinical manifestations, availability of resources in the clinical setting, and the clinician's professional judgment

Priorities and interactions of Sustainable Development Goals (SDGs) with focus on wetlands

Wetlands are often vital physical and social components of a country's natural capital, as well as providers of ecosystem services to local and national communities. We performed a network analysis to prioritize Sustainable Development Goal (SDG) targets for sustainable development in iconic wetlands and wetlandscapes around the world. The analysis was based on the information and perceptions on 45 wetlandscapes worldwide by 49 wetland researchers of the GlobalWetland Ecohydrological Network (GWEN). We identified three 2030 Agenda targets of high priority across the wetlandscapes needed to achieve sustainable development: Target 6.3-'Improve water quality'; 2.4-'Sustainable food production'; and 12.2-'Sustainable management of resources'. Moreover, we found specific feedback mechanisms and synergies between SDG targets in the context of wetlands. The most consistent reinforcing interactions were the influence of Target 12.2 on 8.4-'Efficient resource consumption'; and that of Target 6.3 on 12.2. The wetlandscapes could be differentiated in four bundles of distinctive priority SDG-targets: 'Basic human needs', 'Sustainable tourism', 'Environmental impact in urban wetlands', and 'Improving and conserving environment'. In general, we find that the SDG groups, targets, and interactions stress that maintaining good water quality and a 'wise use' of wetlandscapes are vital to attaining sustainable development within these sensitive ecosystems. © 2019 by the authors

Correction: Priorities and interactions of sustainable development goals (SDGs) with focus on wetlands. Water 2019, 11, 619 doi: 10.3390/w11030619

10.3390/w12010088Water (Switzerland)1218

Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) Presenting with Genu Valgum Deformity: Treatment with Phosphate Supplementation and Surgical Correction

We describe a case of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) in a 32-year-old female with short stature, chronic pathologic genu valgum deformity, and knee pain who was referred to endocrinology clinic after previous inconclusive workups. We present imaging spanning 10 years of untreated disease. Biochemical studies showed hypophosphatemia with undetectable fibroblast growth factor 23 (FGF23.) Renal ultrasound revealed bilateral medullary nephrocalcinosis despite no apparent hypercalciuria. Due to concern for HHRH, genetic testing was performed that determined this patient to be homozygous in the SLC34A3 gene for a previously described missense variant (c.1402C > T, p.Arg468Trp). There was no known family history of rickets. A bone biopsy with metabolic studies was performed for diagnostic and prognostic reasons. The histopathological findings along with tetracycline uptake studies were consistent with a diagnosis of HHRH. Treatment with phosphorous supplementation and surgical correction of her valgum deformity resulted in resolution of pain, but no change in bone histomorphometry

Phenotypic profiling in subjects heterozygous for 1 of 2 rare variants in the hypophosphatasia gene (ALPL)

CONTEXT: Hypophosphatasia (HPP) is a syndrome marked by low serum alkaline phosphatase (AlkP) activity as well as musculoskeletal and/or dental disease. While the majority of subjects with HPP carry a pathogenic variant in the METHODS: Through BioVU, a DNA biobank that pairs individuals\u27 genetic information with their de-identified medical records, we identified subjects with 2 rare variants with distinct reported clinical phenotypes (p.D294A and p.T273M). We then performed a manual review of these subjects\u27 de-identified medical records along with computational modeling of protein structure to construct a genetic, biochemical and clinical phenotype for each subject and variant. RESULTS: Twenty subjects with the p.D294A variant and 17 with the p.T273M variant had sufficient data for analysis. Among subjects in our cohort with the p.D294A variant, 6 (30.0%) had both clinical bone disease and serum AlkP activity below 40 IU/L while 4 subjects (23.5%) with the p.T273M variant met the same criteria despite the distinct clinical phenotypes of these variants. CONCLUSIONS: Given the loose genotype/phenotype correlation in HPP seen in our cohort, clinical context is crucial for the interpretation of genetic test results to guide clinical care in this population. Otherwise, over- or under-diagnosis may occur, resulting in misidentification of those who may benefit from additional screening and perhaps pharmacologic intervention