Detection of hypophosphatasia in hospitalised adults in rheumatology and internal medicine departments: a multicentre study over 10 years.

INTRODUCTION: Hypophosphatasia (HPP) is a rare genetic disease caused by loss-of-function mutations in the ALPL gene encoding the tissue non-specific alkaline phosphatase (ALP). Mild HPP is usually misdiagnosed in adult age. While an elevated serum ALP value draws more attention than a low value, low serum ALP should be better recognised and may lead to HPP detection. METHODS: Patients were selected from the records of the biochemistry department of six University Hospitals in France. Patients were hospitalised in the departments of rheumatology and internal medicine between 2007 and 2017. RESULTS: 56 321 hospitalised patients had at least 2 serum ALP dosages and 664 of these patients had at least 2 low serum ALP≤35 UI/L. Among these 664 patients, 482 (72.6%) had fluctuating low values (mean age 62.9 years; 60% of women) and 182 patients (27.4%) had persistent low values below 35 IU/L (mean age 53.4 years; 67% of women). Among patients with persistent hypophosphatasaemia treated with bisphosphonates, 70.8% never had ALP measurement before treatment and 20.8% were treated despite an abnormal decrease of ALP. Genetic testing was performed in 18 patients and was positive in 11. Genetic diagnosis of HPP was at least 6.0% in persistent hypophosphatasaemia and at least 15.9% in patients with at least three symptoms suggestive of HPP. CONCLUSION: In this 10-year retrospective study, 0.32% of adult patients hospitalised in the rheumatology and internal medicine departments had persistently low serum ALP, and among them, 6% had genetically proven HPP. Reported hypophosphatasaemia represented only 3.6% of hospitalised patients.

The challenge of hypophosphatasia diagnosis in adults: results from the HPP International Working Group Literature Surveillance.

Hypophosphatasia (HPP) is an inborn error of metabolism caused by reduced or absent activity of the tissue non-specific alkaline phosphatase (TNSALP) enzyme, resulting from pathogenic variants in the ALPL gene. Clinical presentation of HPP is highly variable, including lethal and severe forms in neonates and infants, a benign perinatal form, mild forms manifesting in adulthood, and odonto-HPP. Diagnosis of HPP remains a challenge in adults, as signs and symptoms may be mild and non-specific. Disease presentation varies widely; there are no universal signs or symptoms, and the disease often remains underdiagnosed or misdiagnosed, particularly by clinicians who are not familiar with this rare disorder. The absence of diagnosis or a delayed diagnosis may prevent optimal management for patients with this condition. Formal guidelines for the diagnosis of adults with HPP do not exist, complicating efforts for consistent diagnosis. To address this issue, the HPP International Working Group selected 119 papers that explicitly address the diagnosis of HPP in adults through a Medline, Medline In-Process, and Embase search for the terms "hypophosphatasia" and "HPP," and evaluated the pooled prevalence of 17 diagnostic characteristics, initially selected by a group of HPP clinical experts, in eligible studies and in patients included in these studies. Six diagnostic findings showed a pooled prevalence value over 50% and were considered for inclusion as major diagnostic criteria. Based on these results and according to discussion and consideration among members of the Working Group, we finally defined four major diagnostic criteria and five minor diagnostic criteria for HPP in adults. Authors suggested the integrated use of the identified major and minor diagnostic criteria, which either includes two major criteria, or one major criterion and two minor criteria, for the diagnosis of HPP in adults.

Mild hypophosphatasia may be twice as prevalent as previously estimated: an effective clinical algorithm to detect undiagnosed cases.

OBJECTIVES: Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented. METHODS: Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario Clínico San Cecilio in the period June 2018 - December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal-5'-phosphate (PLP) and genetic study of ALPL gene. RESULTS: Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∼40 %). CONCLUSIONS: This new algorithm was effective in detecting previously undiagnosed cases of HPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder.

Clinical and molecular description of the first Italian cohort of 33 subjects with hypophosphatasia.

Introduction: Hypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on Italian HPP surveys. Methods: There were 30 suspected HPP patients recruited from different Italian tertiary cares. Biological samples and related clinical, biochemical, and anamnestic data were collected and the ALPL gene sequenced. Search for large genomic deletions at the ALPL locus (1p36) was done. Phylogenetic conservation and modeling were applied to infer the effect of the variants on the protein structure. Results: There were 21 ALPL variants and one large genomic deletion found in 20 out of 30 patients. Unexpectedly, NGS-driven differential diagnosis allowed uncovering three hidden additional HPP cases, for a total of 33 HPP subjects. Eight out of 24 coding variants were novel and classified as "pathogenic", "likely pathogenic", and "variants of uncertain significance". Bioinformatic analysis confirmed that all the variants strongly destabilize the homodimer structure. There were 10 cases with low ALP and high VitB6 that resulted negative to genetic testing, whereas two positive cases have an unexpected normal ALP value. No association was evident with other biochemical/clinical parameters. Discussion: We present the survey of HPP Italian patients with the highest ALPL mutation rate so far reported and confirm the complexity of a prompt recognition of the syndrome, mostly for HPP in adults. Low ALP and high VitB6 values are mandatory for the genetic screening, this latter remaining the gold standard not only to confirm the clinical diagnosis but also to make differential diagnosis, to identify carriers, to avoid likely dangerous therapy in unrecognized cases.

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.

Introduction: Hypophosphatasia (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. Methods: Baseline/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). Results: Of 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<0.0001) and involved body systems (median, 3 vs 2; P<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). Conclusion: Adults with HPP experience similar QoL impairment regardless of skeletal involvement. Registration: https://clinicaltrials.gov/ct2/show/NCT02306720 and https://www.encepp.eu/encepp/viewResource.htm?id=47907, identifier NCT02306720; EUPAS13514.

Clinical and Genetic Characteristics of Hypophosphatasia in Chinese Adults.

Hypophosphatasia (HPP) is an inherited disease caused by ALPL mutation, resulting in decreased alkaline phosphatase (ALP) activity and damage to bone and tooth mineralization. The clinical symptoms of adult HPP are variable, making diagnosis challenging. This study aims to clarify the clinical and genetic characteristics of HPP in Chinese adults. There were 19 patients, including 1 with childhood-onset and 18 with adult-onset HPP. The median age was 62 (32-74) years and 16 female patients were involved. Common symptoms included musculoskeletal symptoms (12/19), dental problems (8/19), fractures (7/19), and fatigue (6/19). Nine patients (47.4%) were misdiagnosed with osteoporosis and six received anti-resorptive treatment. The average serum ALP level was 29.1 (14-53) U/L and 94.7% (18/19) of patients had ALP levels below 40 U/L. Genetic analysis found 14 ALPL mutations, including three novel mutations-c.511C>G (p.His171Ala), c.782C>A (p.Pro261Gln), and 1399A>G (p.Met467Val). The symptoms of two patients with compound heterozygous mutations were more severe than those with heterozygous mutations. Our study summarized the clinical characteristics of adult HPP patients in the Chinese population, expanded the spectrum of pathogenic mutations, and deepened clinicians' understanding of this neglected disease.

Identifying adult hypophosphatasia in the rheumatology unit.

BACKGROUND: The most frequent manifestation in adult hypophosphatasia (HPP) is musculoskeletal pain. The unspecific nature of its clinical presentation may prevent correct diagnosis. The aim of the study was to assess the prevalence of ALPL mutations in adult patients treated in rheumatological outpatient facilities with evident musculoskeletal symptoms typical for HPP. METHODS: Over a period of 10 years 9,522 patients were screened in the rheumatology outpatient clinic of the Hanusch hospital Vienna. Serum ALP levels ≤ 40 U/L were found in 524 patients. After screening for secondary causes, 73 patients were invited for clinical evaluation. Genetic testing was performed in 23 patients with suspected HPP. Logistic regression models with Firth penalisation were used to estimate the unadjusted and BMI-adjusted association of each clinical factor with HPP. RESULTS: Mutations in the ALPL gene were observed in 57% of genetically screened patients. Arthralgia, fractures, and pain were the leading symptoms in individuals with ALPL mutation. Chondrocalcinosis (OR 29.12; 95% CI 2.02-1593.52) and dental disease (OR 8.33; 95% CI 0.93-143.40) were associated with ALPL mutation, independent of BMI. Onset of symptoms in patients with ALPL mutation was at 35.1 (14.3) years, with a mean duration from symptoms to diagnosis of 14.4 (8.1) years. Bone mineral density (BMD) and trabecular bone score (TBS) as well as bone turnover markers were not indicative for HPP or ALPL mutation. CONCLUSION: HPP can mimic rheumatologic diseases. Thus, HPP should be considered as a possible diagnosis in adult patients presenting with musculoskeletal pain of unknown origin in rheumatology outpatient clinics. In patients with persistently low ALP serum levels and unclear musculoskeletal pain, HPP as the underlying cause has to be considered.

Oral health status of adult hypophosphatasia patients: A cross-sectional study.

AIM: This study evaluated the oral health status of adult patients with hypophosphatasia (HPP). MATERIALS AND METHODS: Parameters of oral health assessment comprised decayed/missing/filled teeth (DMFT) index, probing pocket depth and clinical attachment level (CAL) as well as documentation of tooth loss and periodontal health status according to CCD/AAP criteria. Findings were compared with national reference data (DMS V survey) reporting oral health status in age-related controls. Within-group comparisons were made between the HPP patients harbouring one versus two alkaline phosphatase liver/bone/kidney type (ALPL) gene variants. RESULTS: Of 80 HPP patients (64 female) with a mean age of 46.4 years (range 24-78) and one (n = 55) or two (n = 18) variants (n = 7 lacking testing) within the ALPL gene, those with two variants displayed substantially higher tooth loss rate (14.0 ± 9.3) than those affected by only one ALPL variant (4.1 ± 5.4), who did not differ substantially from healthy DMS V controls. While DMFT score and severe periodontal diseases (PDs) of HPP patients with one variant only increased with progressing age, the two-variant sub-cohort age independently exhibited increased DMFT scores and a higher rate of severe PDs. CONCLUSIONS: HPP patients affected by two variants of the ALPL gene exhibited a higher risk of periodontitis and tooth loss than the general population, while patients with one variant developed clinically relevant oral disease symptoms with progressing ageing. CLINICALTRIALS: gov identifier: NCT02291497.

Biochemical and clinical manifestations in adults with hypophosphatasia: a national cross-sectional study.

Hypophosphatasia (HPP) is a rare disease affecting bone mineralization. Adults with HPP have an increased occurrence of low-energy fractures, which cannot be explained by reduced bone mass assessed by dual energy X-ray absorptiometry. The bone phenotype in adults with HPP requires further studies investigating bone strength and bone structural parameters. INTRODUCTION: Hypophosphatasia (HPP) is a rare inherited disorder of bone and mineral metabolism, characterized by broad-ranging clinical manifestations and severity. However, studies investigating the clinical spectrum in adults with HPP compared to a control group are scarce. The aim of this study was to evaluate biochemical and clinical characteristics as well as bone health in a Danish cohort of adults with HPP. METHODS: We conducted a cross-sectional study assessing biochemical parameters, fracture prevalence, bone mineral density (BMD), bone turnover markers, physical performance and pain characteristics in 40 adults with HPP and 40 sex-, age-, BMI- and menopausal status-matched healthy controls. RESULTS: Patients with HPP had a significantly higher prevalence of non-vertebral, low-energy fractures (p = < 0.001). BMD at the lumbar spine, total hip, femoral neck, forearm and whole body did not differ between the groups. Low levels of the bone-specific alkaline phosphatase correlated significantly with higher BMD at the lumbar spine and femoral neck in both groups. The bone formation marker N-terminal propeptide of type 1 procollagen was significantly lower in patients with HPP than healthy controls (p = 0.006). Adults with HPP had significantly reduced walking capability (p = < 0.001) and lower body strength (p = < 0.001). Chronic pain was significantly more prevalent in adults with HPP than the control group (p = 0.029). CONCLUSIONS: The increased occurrence of low-energy fractures in adults with HPP is not explained by low BMD. Adults with HPP have reduced physical performance when compared with healthy controls.

Biochemical algorithm to identify individuals with ALPL variants among subjects with persistent hypophosphatasaemia.

BACKGROUND: Hypophosphatasia (HPP) is a rare and underdiagnosed condition characterized by deficient bone and teeth mineralization. The aim of this study was first, to evaluate the diagnostic utility of employing alkaline phosphatase (ALP) threshold levels to identify adults with variants in ALPL among individuals with persistently low ALP levels and second, to determine the value of also including its substrates (serum pyridoxal-5'-phosphate-PLP-and urinary phosphoetanolamine-PEA) for this purpose in order to create a biochemical algorithm that could facilitate the diagnostic work-up of HPP. RESULTS: The study population comprised 77 subjects with persistent hypophosphatasaemia. They were divided into two groups according to the presence (+GT) or absence (-GT) of pathogenic ALPL variants: 40 +GT and 37 -GT. Diagnostic utility measures were calculated for different ALP thresholds and Receiver Operating Characteristic (ROC) curves were employed to determine PLP and PEA optimal cut-off levels to predict the presence of variants. The optimal threshold for ALP was 25 IU/L; for PLP, 180 nmol/L and for PEA, 30 µmol/g creatinine. Biochemical predictive models were assessed using binary logistic regression analysis and bootstrapping machine learning technique and results were then validated. For ALP < 25 UI/L (model 1), the area under curve (AUC) and the 95% confidence intervals (CI) was 0.68 (95% CI 0.63-0.72) and it improved to 0.87 (95% CI 0.8-0.9), when PEA or PLP threshold levels were added (models 2 and 3), reaching 0.94 (0.91-0.97) when both substrates were included (model 4). The internal validation showed that the addition of serum PLP threshold levels to the model just including ALP improved significantly sensitivity (S) and negative predictive value (NPV) - 100%, respectively- with an accuracy (AC) of 93% in comparison to the inclusion of urinary PEA (S: 71%; NPV 75% and AC: 79%) and similar diagnostic utility measures as those observed in model 3 were detected when both substrates were added. CONCLUSIONS: In this study, we propose a biochemical predictive model based on the threshold levels of the main biochemical markers of HPP (ALP < 25 IU/L and PLP > 180 nmol/L) that when combined, seem to be very useful to identify individuals with ALPL variants.

Prevalence of Low Serum Alkaline Phosphatase and Hypophosphatasia in Adult Patients with Atypical Femur Fractures.

Hypophosphatasia (HPP) is a rare genetic disorder characterized by low serum alkaline phosphatase (ALP), its manifestations may include atypical femoral fractures (AFF). However, the prevalence of low serum ALP and HPP in patients with AFF remains unknown. We retrospectively analyzed ALP levels and clinical manifestations compatible with HPP in 72 adult patients with confirmed AFF by chart review. ALP values were compared with those of a control group of patients with prior proximal femoral fracture during antiresorptive treatment (n = 20). Among the AFF patients, 18 (25%) had at least one serum ALP value ≤ 40 IU/L, although in all but one case, at least one ALP value > 40 IU/L was also detected at another time point. Most low ALP values were associated with antiresorptive treatment (P = 0.049) and lowest levels of ALP did not differ between the AFF and the control groups (P = 0.129). However, low ALP values among AFF patients were associated with a higher rate of bilateral AFF (50% vs 22%, P = 0.025), metatarsal fracture (33% vs 7%, P = 0.006), and with trends for more frequent use of glucocorticoid (22% vs 8%, P = 0.089) and proton pump inhibitor (61% vs 44%, P = 0.220). In one AFF patient with low ALP and clinical suspicion of HPP, a rare pathogenic heterozygous variant of the ALPL gene was identified. In conclusion, low ALP values are common among subjects with AFF and mainly related to concomitant antiresorptive medication. Hence, low serum ALP has low specificity for HPP among AFF patients.

[Prevalence of hypophosphatasia in adult patients in rheumatology]. / Prävalenz der Hypophosphatasie bei adulten Patienten in der Rheumatologie.

BACKGROUND: Hypophosphatasia (HPP) is a genetic disorder caused by one or more mutations in the alkaline phosphatase (ALP) gene, responsible for encoding tissue-specific ALP and for the mineralization process. OBJECTIVE: Identification of the prevalence of HPP in rheumatology patients. MATERIAL AND METHODS: Medical records of all adult rheumatology patients with pathologically low total ALP levels (<35 U/L) treated in the Department of Rheumatology at the Clinic of Internal Medicine III, University Hospital Bonn between January 2017 and June 2019, were retrospectively examined for clinical signs as well as for results of genetic tests for HPP. RESULTS: In 60 out of 2289 patients (2.62%) pathologically low ALP levels were detected. Of these 30 (1.31%) were found to have persistently low ALP levels. Genetic testing for ALP gene mutations was performed in 19 of these 30 patients and 7 of the 19 patients (36.84%) had HPP signs (insufficiency fractures, or bad dental status since childhood), all with pathologic ALP mutations. Of these patients 3 (15.78%) each had a history of insufficiency fracture with normal bone densitometry. Overall, 13 out of the 19 patients (68.42%) had mutations in the ALP gene. Interestingly, no association with chondrocalcinosis was detected in any of the patients. CONCLUSION: The HPP seems to be an underdiagnosed disease with a higher proportion of affected rheumatology patients. Therefore, future studies should aim to develop a diagnostic protocol in the clinical practice.

[Periodontal status evaluation in adolescents with hereditary rickets-like diseases]. / Otsenka sostoyaniya tkanei parodonta u podrostkov s nasledstvennymi rakhitopodobnymi zabolevaniyami.

BACKGROUND: Hypophosphatemic rickets (HPPR) and hypophosphatasia (HPP) are hereditary pathologies accompanied by phosphorus metabolism problems and rickets deformities of the skeleton. Periodontal diseases, their diagnostic methods and factors affecting the progress of periodontal tissue damage are the least studied among the dental manifestations of HPPR and HPP. OBJECTIVE: The aim of present cohort study was evaluation of periodontal tissue status in adolescents with HPPR and HPP. MATERIALS AND METHODS: A dental examination of 20 adolescents aged 12 to 18 years with genetically and biochemically confirmed hereditary rickets-like diseases (E83.3 Disorders of phosphorus metabolism and phosphatases: hypophosphatemic rickets (HPPR) and hypophosphatasia (HPP)) was performed at the Pediatric Dentistry Department of Moscow State University of Medicine and Dentistry. In the present study clinical examination and cone-beam computed tomography (CBCT) data of patients were analyzed. RESULTS: According to the clinical examination data, a strong direct correlation was found between patient's age and the periodontal diseases severity (correlation coefficient r=0.87) in the study group. CBCT revealed the significant alveolar bone hypomineralization in adolescents with HPPR and HPP in comparison to control group (p<0.05). According to the measurement results obtained a strong inverse correlation between alveolar bone mineral density and alveolar bone reduction (correlation coefficient r= -0.74) in adolescents with hereditary rickets-like diseases was revealed. CONCLUSION: The diagnostic options of CBCT allow to begin comprehensive dental treatment of patients with HPPR and HPP at an early stage of periodontal disease preventing further development of pathology.

Prevalence of low alkaline phosphatase activity in laboratory assessment: Is hypophosphatasia an underdiagnosed disease?

BACKGROUND: Tissue-nonspecific alkaline phosphatase (TNSALP) encoded by the ALPL gene is of particular importance for bone mineralization. Mutation in the ALPL gene can lead to persistent low ALP activity resulting in the rare disease Hypophosphatasia (HPP) that is characterized by disturbed bone and dental mineralization. While severe forms are extremely rare with an estimated prevalence of 1/100.000, recent studies suggest that moderate form caused by heterozygous mutations are much more frequent with an estimated prevalence of 1/508. The purpose of this study was to estimate the prevalence of low AP levels in the population based on laboratory measurements. METHODS: In this study, the prevalence of low AP activity and elevated pyridoxal-5-phosphate (PLP) levels was analyzed in 6.918.126 measurements from 2011 to 2016 at a single laboratory in northern Germany. Only laboratory values of subjects older than 18 years of age were included. Only the first measurement was included, all repeated values were excluded. RESULTS: In total, 8.46% of the measurements of a total of 6.918.126 values showed a value < 30 U/L. 0.59% of the subjects with an ALP activity below 30 U/L had an additional PLP measurement. Here, 6.09% showed elevated pyridoxal-5-phosphate (PLP) levels. This suggest that 0.52% (1:194) of subjects show laboratory signs of HPP. CONCLUSION: These data support the genetic estimation that the prevalence of moderate forms of HPP may be significantly higher than expected. Based on these data, we recommend automatically measurement of PLP in the case of low ALP activity and a notification to the ordering physician that HPP should be included in the differential diagnosis and further exploration is recommended.

The Occurrence and Burden of Hypophosphatasia in an Ambulatory Care Endocrinology Practice.

OBJECTIVE: Hypophosphatasia (HPP) is an inherited disease resulting from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase. The presentation and severity of the disease are highly variable, ranging from perinatal onset with high mortality rates to adult identification with low mortality rates and symptoms ranging from minimal to severe. Moderate forms of HPP typically manifest during middle age and are often undiagnosed. The objective of this study was to determine the occurrence and burden of HPP in an ambulatory care endocrinology practice. METHODS: Potential subjects were identified with a computerized text search of patient electronic medical records. Search terms included serum alkaline phosphatase (ALP) levels of ≤40 U/L. Records of patients with at least 2 low ALP levels were reviewed manually to identify potential patients with a history consistent with hypophosphatasia. RESULTS: In total, 315 patients with ALP levels ≤40 U/L were identified from an estimated 20 000 patient records. Fifty-six patients with a single low level were excluded from further review. The remaining 259 patients were reviewed, 10 of whom had histories consistent with HPP. None of the identified 10 patients was currently being treated or had previously been treated for HPP. Information about these patients was shared with their respective providers, along with the recommendation to proceed with further evaluation to confirm the diagnosis of HPP. CONCLUSION: Hypophosphatasia is an uncommon condition with variable presentation, often resulting in a missed diagnosis. Surveillance of practices by identifying patients with low ALP levels is a rational screening approach to identifying potential patients with HPP.

Hypophosphatasia.

Hypophosphatasia (HPP) is a group of inherited disorders characterised by the impaired mineralisation of bones and/or teeth and low serum alkaline phosphatase (ALP) activity. It is caused by a mutation in the ALPL gene encoding the tissue-non-specific isoenzyme of ALP (TNSALP) resulting in a loss of function. The disease is highly heterogenous in its clinical expression ranging from stillbirth without mineralised bone to the mild form of late adult onset with symptoms and signs such as musculoskeletal pain, arthropathy, lower-extremity fractures, premature loss of teeth or an incidental finding of reduced serum ALP activity. A classification based on the age at diagnosis and the presence or absence of bone symptoms was historically used: perinatal, prenatal benign, infantile, childhood, adult and odontohypophosphatasia. These subtypes are known to have overlapping signs and complications. Three forms of HPP distinguishable by their genetic characteristics have been described: severe, moderate and mild. Severe forms of HPP (perinatal and infantile severe) are recessively inherited, whereas moderate HPP may be dominantly or recessively inherited. The biochemical hallmark of HPP is persistently low serum ALP for age and increase in natural substrates of TNSALP, pyridoxal 5'-phosphate and phosphoethanolamine supported by radiological findings. The diagnosis is confirmed by ALPL sequencing. A multidisciplinary team of experts is essential for the effective management. Calcium restriction is recommended in infants/children to manage hypercalcaemia. A targeted enzyme replacement therapy for HPP has become available and correct diagnosis is crucial to allow early treatment.

Clinical and genetic characteristics of hypophosphatasia in Chinese children.

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited disorder, which is caused by loss-of-function mutations in the ALPL gene. HPP is a heterogeneous disease that has a wide spectrum of phenotypes. Few studies were carried out in the Chinese population with HPP, especially in children. METHODS: The clinical and genetic characteristics of 10 Chinese children with HPP who were referred to the Beijing Children's Hospital were described. Previously reported HPP cases of children in China were also reviewed. RESULTS: A total of 33 cases were identified, which included 2 perinatal lethal HPP, 10 infantile HPP, 10 childhood HPP, and 11 odonto HPP. The male-to-female ratio was 24:9. The average age at onset was 0.69 years (ranged from 2 h after birth to 14 years), while the average age at clinical diagnosis was 3.87 years (ranged from 2 h after birth to 19 years). Serum alkaline phosphatase (ALP) levels were significantly decreased in patients with perinatal lethal/infantile HPP when compared with those with the mild forms of HPP childhood/odonto HPP (P < 0.01). Although serum phosphate levels were not different (P > 0.05), serum calcium levels were elevated, and serum intact parathyroid hormone levels were decreased in patients with perinatal lethal/infantile HPP in comparison with those with the childhood/odonto HPP (P all < 0.01). Genetic analyses identified 40 mutations in 31 HPP cases, including 28 missense mutations, 9 frameshift mutations, 2 splice junction alterations, and 1 regulatory mutation. Of which, 5 novel mutations were identified in our present study: 2 frameshift mutations (p.Arg138GlyfsTer27, p.Leu511Profs*272); 2 missense mutations (p.Ala176Val, p.Phe268Leu), and 1 splice junction alteration (c.297+5G>A). Compound heterozygous mutations accounted for 80.6% of all variants. No mutational "hot-spot" was found. Most mutations of ALPL were located in exons 5, 7, 10, and 3. Notably, subjects that carrying single heterozygous mutations showed milder phenotypes of HPP, while subjects with nonsense mutations were associated with a severer phenotype. CONCLUSIONS: HPP is a rare disease with often delayed diagnosis, and the incidence of HPP in China may be seriously underestimated. The present study expands the phenotypic and genotypic spectrum and the understanding of HPP in Chinese children. These findings will be useful for clinical assessment and shorten the diagnosis time for pediatric HPP in China.

Burden of Illness in Adults With Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry.

Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by deficient tissue non-specific alkaline phosphatase activity. This study aims to assess patient-reported pain, disability and health-related quality of life (HRQoL) in a real-world cohort of adults with HPP who were not receiving asfotase alfa during the analysis. Adults (≥18 years old) with HPP (confirmed by ALPL gene mutation and/or low serum alkaline phosphatase activity for age/sex) were identified from the Global HPP Registry (NCT02306720). Demographics, clinical characteristics, and data on patient-reported pain, disability, and HRQoL (assessed by Brief Pain Inventory Short Form [BPI-SF], Health Assessment Questionnaire Disability Index [HAQ-DI], and 36-Item Short-Form Health Survey version 2 [SF-36v2], respectively) were stratified by pediatric- and adult-onset HPP and summarized descriptively. Of the 304 adults included (median [min, max] age 48.6 [18.8, 79.8] years; 74% women), 45% had adult-onset HPP and 33% had pediatric-onset HPP (unknown age of onset, 22%). Of those with data, 38% had experienced ≥5 HPP manifestations and 62% had a history of ≥1 fracture/pseudofracture. Median (Q1, Q3) BPI-SF scores were 3.5 (1.5, 5.3) for pain severity and 3.3 (0.9, 6.2) for pain interference. Median (Q1, Q3) disability on the HAQ-DI was 0.3 (0.0, 0.7). Median (Q1, Q3) physical and mental component summary scores on the SF-36v2 were 42.4 (32.7, 49.9) and 45.3 (36.3, 54.8), respectively. Greater numbers of HPP manifestations experienced/body systems affected correlated significantly with poorer scores on the BPI-SF, HAQ-DI, and SF-36v2 (all p < 0.05). No significant differences between adults with pediatric- and adult-onset HPP were observed for patient-reported outcomes, except for disability and the BPI-SF question "pain at its worst," which were significantly higher among adults with pediatric- versus adult-onset HPP (p = 0.03 and 0.04, respectively). These data from the Global HPP Registry show that adults with HPP have a substantial burden of illness that is associated with reduced patient-reported HRQoL, regardless of age of disease onset. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment.

This article provides an overview of the current knowledge on hypophosphatasia-a rare genetic disease of very variable presentation and severity-with a special focus on adolescents and adults. It summarizes the available information on the many known mutations of tissue-nonspecific alkaline phosphatase (TNSALP), the epidemiology and clinical presentation of the disease in adolescents and adults, and the essential diagnostic clues. The last section reviews the therapeutic approaches, including recent reports on enzyme replacement therapy (EnzRT).

Clinical Significance of Hypophosphatasemia in Children.

Low serum alkaline phosphatase (sALP)-hypophosphatasemia-is a characteristic of hypophosphatasia (HPP), but related to several clinical conditions. Here, we evaluated the frequency, persistency and the etiology of hypophosphatasemia in children. In retrospective analyses of sALP measurements from children, evaluated according to in-house constructed age- and sex-specific reference ranges, patients with no normal sALP measurement (Unresolved hypophosphatasemia) were invited for reanalysis. Prospectively, ALP substrates, pyridoxal-5-phosphate (PLP), and phosphoethanolamine (PEA) were measured in patients with persistent hypophosphatasemia. Radiographs and ALPL gene sequencing for HPP were performed to the cases with elevated PEA and/or PLP. From 130,340 sALP measurements of 93,162 patients, hypophosphatasemia was detected in 1404 samples from 867 patients (0.9%). Among them, 745 had at least one normal sALP values in laboratory records, grouped as transient hypophosphatasemia. 75 out of 122 patients with unresolved hypophosphatasemia could be reanalyzed for sALP, of whom PLP and PEA measurements were required in 37 due to persistent hypophosphatasemia. Both PEA and PLP were elevated in 4 patients, and ALPL gene analysis showed heterozygous mutations in 3 patients and homozygous in 1 patient. Elevated PEA with normal PLP were detected in 3 patients, and one had a heterozygous ALPL mutation. Anemia was the most common diagnosis, and upper respiratory tract infections and chronic diseases were more common in transient and unresolved hypophosphatasemia, respectively. In conclusion, reflected persistent hypophosphatasemia frequency was 1/1552 (0.06%) in this large pediatric cohort and, ALPL gene mutations were detected in 13.5% (5/37) of the studied cases. Although biochemical hypophosphatasemia is not uncommon, clinically significant HPP is rare.