Catalyzing precision: unraveling the diagnostic conundrum of tunisian familial hypophosphatasia case through integrative clinical and molecular approaches.

Familial Hypophosphatasia presents a complex diagnostic challenge due to its wide-ranging clinical manifestations and genetic heterogeneity. This study aims to elucidate the molecular underpinnings of familial Hypophosphatasia within a Tunisian family harboring a rare c.896 T > C mutation in the ALPL gene, offering insights into genotype-phenotype correlations and potential therapeutic avenues. The study employs a comprehensive approach, integrating biochemical examination, genetic analysis, structural modeling, and functional insights to unravel the impact of this rare mutation. Genetic investigation revealed the presence of the p.Leu299Pro mutation within the ALPL gene in affected family members. This mutation is strategically positioned in proximity to both the catalytic site and the metal-binding domain, suggesting potential functional consequences. Homology modeling techniques were employed to predict the 3D structure of TNSALP, providing insights into the structural context of the mutation. Our findings suggest that the mutation may induce conformational changes in the vicinity of the catalytic site and metal-binding domain, potentially affecting substrate recognition and catalytic efficiency. Molecular dynamics simulations were instrumental in elucidating the dynamic behavior of the tissue-nonspecific alkaline phosphatase isozyme (TNSALP) in the presence of the p.Leu299Pro mutation. The simulations indicated alterations in structural flexibility near the mutation site, with potential ramifications for the enzyme's overall stability and function. These dynamic changes may influence the catalytic efficiency of TNSALP, shedding light on the molecular underpinnings of the observed clinical manifestations within the Tunisian family. The clinical presentation of affected individuals highlighted significant phenotypic heterogeneity, underscoring the complex genotype-phenotype correlations in familial Hypophosphatasia. Variability in age of onset, severity of symptoms, and radiographic features was observed, emphasizing the need for a nuanced understanding of the clinical spectrum associated with the p.Leu299Pro mutation. This study advances our understanding of familial Hypophosphatasia by delineating the molecular consequences of the p.Leu299Pro mutation in the ALPL gene. By integrating genetic, structural, and clinical analyses, we provide insights into disease pathogenesis and lay the groundwork for personalized therapeutic strategies tailored to specific genetic profiles. Our findings underscore the importance of comprehensive genetic and clinical evaluation in guiding precision medicine approaches for familial Hypophosphatasia.

Hypophosphatasia diagnosis: current state of the art and proposed diagnostic criteria for children and adults.

BACKGROUND: This manuscript provides a summary of the current evidence to support the criteria for diagnosing a child or adult with hypophosphatasia (HPP). The diagnosis of HPP is made on the basis of integrating clinical features, laboratory profile, radiographic features of the condition, and DNA analysis identifying the presence of a pathogenic variant of the tissue nonspecific alkaline phosphatase gene (ALPL). Often, the diagnosis of HPP is significantly delayed in both adults and children, and updated diagnostic criteria are required to keep pace with our evolving understanding regarding the relationship between ALPL genotype and associated HPP clinical features. METHODS: An International Working Group (IWG) on HPP was formed, comprised of a multidisciplinary team of experts from Europe and North America with expertise in the diagnosis and management of patients with HPP. Methodologists (Romina Brignardello-Petersen and Gordon Guyatt) and their team supported the IWG and conducted systematic reviews following the GRADE methodology, and this provided the basis for the recommendations. RESULTS: The IWG completed systematic reviews of the literature, including case reports and expert opinion papers describing the phenotype of patients with HPP. The published data are largely retrospective and include a relatively small number of patients with this rare condition. It is anticipated that further knowledge will lead to improvement in the quality of genotype-phenotype reporting in this condition. CONCLUSION: Following consensus meetings, agreement was reached regarding the major and minor criteria that can assist in establishing a clinical diagnosis of HPP in adults and children.

Proposed diagnostic criteria for the diagnosis of hypophosphatasia in children and adolescents: results from the HPP International Working Group.

Hypophosphatasia (HPP) is a rare inborn error of metabolism that presents variably in both age of onset and severity. HPP is caused by pathogenic variants in the ALPL gene, resulting in low activity of tissue nonspecific alkaline phosphatase (TNSALP). Patients with HPP tend have a similar pattern of elevation of natural substrates that can be used to aid in diagnosis. No formal diagnostic guidelines currently exist for the diagnosis of this condition in children, adolescents, or adults. The International HPP Working Group is a comprised of a multidisciplinary team of experts from Europe and North America who have expertise in the diagnosis and management of patients with HPP. This group reviewed 93 papers through a Medline, Medline In-Process, and Embase search for the terms "HPP" and "hypophosphatasia" between 2005 and 2020 and that explicitly address either the diagnosis of HPP in children, clinical manifestations of HPP in children, or both. Two reviewers independently evaluated each full-text publication for eligibility and studies were included if they were narrative reviews or case series/reports that concerned diagnosis of pediatric HPP or included clinical aspects of patients diagnosed with HPP. This review focused on 15 initial clinical manifestations that were selected by a group of clinical experts.The highest agreement in included literature was for pathogenic or likely pathogenic ALPL variant, elevation of natural substrates, and early loss of primary teeth. The highest prevalence was similar, including these same three parameters and including decreased bone mineral density. Additional parameters had less agreement and were less prevalent. These were organized into three major and six minor criteria, with diagnosis of HPP being made when two major or one major and two minor criteria are present.

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.

The diagnosis of hypophosphatasia in children as a multidisciplinary effort: an expert opinion.

Hypophosphatasia (HPP) is a rare genetic disorder in which pathogenic variants of the ALPL gene lead to a marked decrease of tissue non-specific alkaline phosphatase (TNSALP) activity. Although HPP is a systemic disorder, its clinical manifestations are more evident on bones, teeth, muscle and central nervous system. The clinical spectrum ranges from severe forms with extreme skeletal deformities, respiratory impairment, seizures, to very mild forms with onset in late adulthood and few clinical signs. The diagnosis can be suspected by measurement of TNSALP activity, but the insufficient awareness among health professionals and the lack of official guidelines are responsible for delayed diagnosis in children with HPP. The purpose of the current document is to provide an expert opinion directed at optimizing the diagnostic pathway of pediatric HPP. From April to December 2022, a multidisciplinary working group of 6 experts including two pediatric endocrinologists, a pediatric neurologist, a pediatric odontologist, a clinical geneticist, and a molecular biologist gathered in a series of periodic meetings to discuss the main issues related to the diagnosis of HPP in children and formalize an Expert Opinion statement. The experts agreed on a diagnostic trail that begins with the recognition of specific clinical signs, leading to biochemical analyses of TNSALP activity and vitamin B6 serum concentration. Very important are the neurological and dental manifestation of the disease that should be thoroughly investigated. The evaluation of TNSALP activity must consider sex and age variability and low activity must be persistent. Repeated blood measurements are thus necessary. The molecular analysis is then mandatory to confirm the diagnosis and for genetic counseling.

A Delphi panel to build consensus on assessing disease severity and disease progression in adult patients with hypophosphatasia in the United States.

BACKGROUND: Hypophosphatasia (HPP) is an inborn error of metabolism with a variable presentation. We conducted a modified Delphi panel to obtain expert consensus on knowledge gaps regarding disease severity and progression in adult patients with HPP. METHODS: Healthcare professionals (HCPs) with experience managing adult patients with HPP were recruited to participate in a 3-round Delphi panel (round 1: paper survey and 1:1 interview; rounds 2-3: email survey). Panelists rated the extent of their agreement with statements about disease severity and progression in adult patients with HPP. Consensus was defined as ≥ 80% agreement. RESULTS: Ten HCPs completed round 1; nine completed rounds 2 and 3. Consensus was reached on 46/120 statements derived from steering committee input. Disease severity markers in adult patients with HPP can be bone-related (recurrent/poorly healing fractures, pseudo-fractures, metatarsal fractures, osteomalacia) or involve dentition or physiologic/functional manifestations (use of mobility devices/home modifications, abnormal gait, pain). Disease progression markers can include recurrent/poorly healing low-trauma fractures, development of ectopic calcifications, and/or impairment of functional activity. Panelists supported the development of a tool to help assess disease severity in the clinic and track changes in severity over time. Panelists also highlighted the role of a multidisciplinary team, centers with expertise, and the need to refer patients when disease severity is not clear. CONCLUSIONS: These statements regarding disease severity, progression, and assessment methods address some knowledge gaps in adult patients with HPP and may be helpful for treating HCPs, although the small sample size affects the ability to generalize the healthcare provider experience.

Reducing diagnostic delay in hypophosphatasia: a case series of 14 patients presenting to general rheumatology.

OBJECTIVES: Hypophosphatasia (HPP) is a rare genetic metabolic bone disease that can cause chronic pain and fractures. Its hallmark is a persistently low serum ALP. HPP is now recognised by many osteoporosis specialists, but other specialists, such as rheumatologists and primary care physicians, may be less aware of this condition, causing diagnostic delay and possible harm to these patients. Our objective was to highlight features that can reduce this delay. METHODS: We retrospectively analysed 14 patients that presented with musculoskeletal pain to general rheumatology clinic at St. George's Hospital and were subsequently diagnosed with HPP. RESULTS: Median diagnostic delay was 13 years. All patients had an ALP below reference range for age and gender, with lowest mean ALP of 16 IU/L. All but one patient were women with median age of 51 years. Most common presentation was peripheral joint pain in 85.7% of patients. This was due to early-onset CPPD (calcium pyrophosphate deposition disease) in 71.4% of patients, osteoarthritis in 50%, or bursitis in 50%. Axial pain was reported in 64% of patients due to osteoarthritis or spinal stenosis. Fifty percent of patients had a history of long bone pain. Fifty percent had previous fracture(s). A total of 28.6% of patients had psoriatic arthritis, of which 1 patient had spondyloarthropathy, and 4 patients also had enthesitis. CONCLUSION: Patients with HPP can present to rheumatology with musculoskeletal pain, and if a persistently low ALP is confirmed, this may reduce the diagnostic delay of this rare disease. Similar to other rheumatologic patients, musculoskeletal pain in HPP was noted in peripheral joints and in the spine with almost a third of patients having psoriatic arthritis. Pain was also noted in the long bones, a feature consistent with metabolic bone disease. The diagnosis of HPP was also more likely in those patients with a personal or family history of dental disease or arthritis.

A low serum alkaline phosphatase may signal hypophosphatasia in osteoporosis clinic patients.

Low serum alkaline phosphatase (ALP) was found in 9% of patients attending an osteoporosis clinic, 0.6% of hospital patients, and 2/22 with an atypical femoral fracture. Hypophosphatasia was diagnosed in 3% of osteoporosis clinic patients with low ALP. Low ALP is a screening tool for hypophosphatasia, a condition potentially aggravated by antiresorptive therapy. INTRODUCTION: Hypophosphatasia (HPP) is an inherited disorder associated with impaired primary mineralisation of osteoid (osteomalacia). HPP may be misdiagnosed as osteoporosis, a reduction in the volume of normally mineralized bone. Both illnesses may result in fragility fractures, although stress and atypical fractures are more common in HPP. Antiresorptive therapy, first-line treatment for osteoporosis, is relatively contraindicated in HPP. Misdiagnosis and mistreatment can be avoided by recognising a low serum alkaline phosphatase (ALP). Our aim was to determine the prevalence of a low ALP (< 30 IU/L) in patients attending an osteoporosis clinic, in a hospital-wide setting, and in a group of patients with atypical femoral fractures (AFF). METHODS: This was a retrospective study of patients attending an osteoporosis clinic at a tertiary hospital during 8 years (2012-2020). Patients were categorised into those with a transiently low ALP, those with low ALP on ≥ 2 occasions but not the majority of measurements, and those with a persistently low ALP. ALP levels were also assessed in hospital-wide records and a group of patients with AFF. RESULTS: Of 1839 patients attending an osteoporosis clinic, 168 (9%) had ≥ 1 low ALP, 50 (2.7%) had low ALP for ≥ 2 months, and seven (0.4%) had persistently low ALP levels. HPP was diagnosed in five patients, four of whom had persistently low ALP levels. The prevalence of HPP was 0.3% in the osteoporosis clinic and 3% in patients with ≥ 1 low ALP. Low ALP occurred in 0.6% of all hospital patients and 2/22 with AFF. CONCLUSION: Persistently low ALP in osteoporosis clinic attendees is easy to identify and signals the possibility of hypophosphatasia, a condition that may be mistaken for osteoporosis and incorrectly treated with antiresorptive therapy.

Musculoskeletal pain and muscular weakness as the main symptoms of adult hypophosphatasia in a Spanish cohort: clinical characterization and identification of a new ALPL gene variant.

INTRODUCTION: Hypophosphatasia (HPP) is a rare inherited disorder, caused by mutations in the alkaline phosphatase (ALPL) gene, which encodes for the tissue non-specific alkaline phosphatase (TNSALP) isoform of alkaline phosphatase (ALP). Adult HPP is one of the mild forms that presents with unspecific signs such as osteopenia, osteomalacia and muscle involvement. Our purpose was to identify and characterize possibly misdiagnosed adult HPP patients at a clinical and biochemical level. MATERIAL AND METHODS: At the laboratory of Miguel Servet University Hospital we retrospectively reviewed serum ALP levels in adults over a 48-month period. The clinical records of individuals with consistently low ALP levels were reviewed to exclude secondary causes. Those with persistent hypophosphatasemia were screened for symptoms of HPP. The study participants were evaluated at biochemical and genetic levels. RESULTS: We identified 705 ALP determinations (out of 384,000 processed) in 589 patients below the reference range (30 U/l). Only 21 patients with clinical signs and symptoms of HPP were selected for genetic testing. Finally, only 12 patients participated in the study, 83.3% of whom (10/12) harbored a pathogenic or likely pathogenic variant in a heterozygous state. The major symptoms of our cohort were the presence of musculoskeletal pain (100% of patients) and muscular weakness (83.3% patients). CONCLUSION: Mild HPP patients presenting with diffuse symptoms such as musculoskeletal pain may be undiagnosed or misdiagnosed as osteoporosis patients by routine diagnosis. It is important to identify these individuals, to avoid inappropriate treatment with antiresorptive drugs.

Proposing a clinical algorithm for better diagnosis of hypophosphatasia in resource-limiting situations.

Early diagnosis of hypophosphatasia (HPP) is challenging. Here, we propose to broaden the diagnostic criteria of HPP by reviewing published data on BMD and fractures in HPP patients. Non-osteoporotic fractures and higher than normal lumbar BMD were recurrent in HPP patients and could be included as diagnostic criteria. HPP is a genetic disorder caused by autosomal recessive or dominant loss-of-function mutations in the ALPL gene that encodes for tissue-nonspecific alkaline phosphatase (TNSALP). Expressive genetic heterogeneity and varying severity of TNSALP deficiency lead to a wide-ranging presentation of skeletal diseases at different ages that coupled with HPP's rarity and limitation of biochemical and mutational studies present serious hurdles to early diagnosis and management of HPP. To widen the scope of HPP diagnosis, we assessed the possibility of areal bone mineral density (BMD) as an additional clinical feature of this disease. PubMed, Web of Science, and ScienceDirect were searched with the following keywords: ("Hypophosphatasia OR HPP") AND ("Bone Mineral Density OR BMD") AND "Human". Studies and case reports of subjects with age ≥ 18 years and having BMD data were included. We pooled data from 25 publications comprising 356 subjects (90 males, 266 females). Only four studies had a control group. Biochemical hallmarks, pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA), were reported in fifteen and six studies, respectively. Twenty studies reported genetic data, nineteen studies reported non-vertebral fractures, all studies reported lumbar spine (LS) BMD, and nineteen reported non-vertebral BMD. Higher than normal and normal BMD at LS were reported in three and two studies, respectively. There was marked heterogeneity in BMD at the non-vertebral sites. Higher than normal or normal LS BMD in an adult with minimal or insufficient fractures, pseudofractures, non-healing fractures, fragility fractures, and stress fractures may be included in the diagnostic protocol of HPP. However, genetic testing is recommended for a definitive diagnosis.

Massive calcification around large joints in a patient subsequently diagnosed with adult-onset hypophosphatasia.

We report a 64-year-old Japanese woman with a history of progressive loss of motor function and painful swelling of large joints. At the age of 54, profound calcification appeared around the shoulder and hip joints, which did not heal after repeated surgical resections. Iliac bone biopsy revealed osteomalacic changes. Laboratory data showed low serum alkaline phosphatase (ALP) activity and a high urine phosphoethanolamine (PEA) concentration with normal serum calcium, phosphate, and fibroblast growth factor 23 (FGF23) levels. Subsequent genetic analysis of the ALPL gene confirmed the diagnosis of hypophosphatasia (HPP) with the identification of a heterozygous single nucleotide deletion, c.1559delT (p.Leu520ArgfsX86). We started a mineral-targeted enzyme replacement therapy, asfotase alfa (AA), to treat the patient's musculoskeletal symptoms. A follow-up bone biopsy after 12 months of AA treatment showed improvement of osteomalacia. Calcified deposits around the large joints were unchanged radiographically. To our knowledge, this is the first report of a patient with an adult-onset HPP who presented with profound calcification around multiple joints. Nonspecific clinical signs and symptoms in patients with adult-onset HPP often result in delayed diagnosis or misdiagnosis. We propose that bone biopsy and genetic analysis should be considered along with laboratory analysis for all patients with ectopic calcification around joints of unknown etiology for accurate diagnosis and better treatment.

[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.

Utility of genetic testing for prenatal presentations of hypophosphatasia.

Hypophosphatasia (HPP) is a rare inherited disease affecting bone and dental mineralization due to loss-of-function mutations in the ALPL gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). Prenatal benign HPP (PB HPP) is a rare form of HPP characterized by in utero skeletal manifestations that progressively improve during pregnancy but often still leave symptoms after birth. Because the prenatal context limits the diagnostic tools, the main difficulty for clinicians is to distinguish PB HPP from perinatal lethal HPP, the most severe form of HPP. We previously attempted to improve genotype phenotype correlation with the help of a new classification of variants based on functional testing. Among 46 perinatal cases detected in utero or in the neonatal period for whose ALPL variants could be classified, imaging alone was thought to clearly diagnose severe lethal HPP in 35 cases, while in 11 cases, imaging abnormalities could not distinguish between perinatal lethal and BP HPP. We show here that our classification of ALPL variants may improve the ability to distinguish between perinatal lethal and PB HPP in utero.

Predictive modeling of hypophosphatasia based on a case series of adult patients with persistent hypophosphatasemia.

Approximately half of individuals with hypophosphatasemia (low levels of serum alkaline phosphatase) have hypophosphatasia, a rare genetic disease in which patients may have stress fractures, bone and joint pain, or premature tooth loss. We developed a predictive model based on specific biomarkers of this disease to better diagnose this condition. INTRODUCTION: Hypophosphatasemia is a condition in which low levels of alkaline phosphatase (ALP) are detected in the serum. Some individuals presenting with this condition may have a rare genetic disease called hypophosphatasia (HPP), which involves mineralization of the bone and teeth. Lack of awareness of HPP and its nonspecific symptoms make this genetic disease difficult to diagnose. We developed a predictive model based on biomarkers of HPP such as ALP and pyridoxal 5'-phosphate (PLP), because clinical manifestations sometimes are not recognized as symptoms of HPP. METHODS: We assessed 325,000 ALP results between 2010 and 2015 to identify individuals suspected of having HPP. We performed univariate and multivariate analyses to characterize the relationship between hypophosphatasemia and HPP. Using several machine learning algorithms, we developed several models based on biomarkers and compared their performance to determine the best model. RESULTS: The final cohort included 45 patients who underwent a genetic test. Half (23 patients) showed a mutation of the ALPL gene that encodes the tissue-nonspecific ALP enzyme. ALP (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.3-0.8, p = 0.01) and PLP (OR 1.06, 95% CI 1.01-1.15, p = 0.04) were the only variables significantly associated with the presence of HPP. Support vector machines and logistic regression were the machine learning algorithms that provided the best predictive models in terms of classification (area under the curve 0.936 and 0.844, respectively). CONCLUSIONS: Given the high probability of a misdiagnosis, its nonspecific symptoms, and a lack of awareness of serum ALP levels, it is difficult to make a clinical diagnosis of HPP. Predictive models based on biomarkers are necessary to achieve a proper diagnosis. Our proposed machine learning approaches achieved reasonable performance compared to traditional statistical methods used in biomedicine, increasing the likelihood of properly diagnosing such a rare disease as HPP.

Hypophosphatasia: is it an underdiagnosed disease even by expert physicians?

INTRODUCTION: Hypophosphatasia (HPP) is caused by mutations in the ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (ALP). Clinical manifestations range from extreme life-threatening lethal forms to no signs or symptoms at all. MATERIALS AND METHODS: Consecutive 30,000 outpatients and inpatients with ALP data were screened retrospectively, out of which 1000 patients were found to have low levels of ALP more than once. Then, patients were evaluated for the symptoms and signs of HPP with further biochemical and genetic analyses. RESULTS: Thirty-seven patients who had severe musculoskeletal pain, recurrent fractures, and tooth anomalies were then screened with substrate and DNA sequencing analyses for HPP. It was determined that eight patients had variants in the ALPL gene. A total of eight different ALPL variants were identified in eight patients. The variants, namely c.244G > C (p.Gly82Arg), c.1444C > T (p.His482Tyr), c.1487A > G (p.Asn493Ser), and c.675_676insCA (p.Met226GlnfsTer52), had not been previously reported. DISCUSSION: Considering the wide spectrum of clinical signs and symptoms, HPP should be among the differential lists of bone, muscle, and tooth abnormalities at any age.

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.

[Rare bone disorders and respective treatments]. / Seltene osteologische Erkrankungen und ihre Therapie.

Delineating the genetic background and the underlying pathophysiology of rare skeletal dysplasias enables a broader understanding of these disorders as well as novel perspectives regarding differential diagnosis and targeted development of therapeutic approaches. Hypophosphatasia (HPP) due to genetically determined Alkaline Phosphatase deficiency exemplifies this development. While an enzyme replacement therapy could be established for severe HPP with the prevailing bone manifestation, the clinical impact of not immediately bone-related manifestations just being successively understood. Correspondingly, the elucidation of the pathophysiology underlying renal phosphate wasting expanded our knowledge regarding phosphate metabolism and bone health and facilitated the development of an anti-FGF-23 Antibody for targeted treatment of X­linked Hypophosphatemia (XLH). Evolutions regarding the nosology of osteogenesis imperfecta (OI) along with the identification of further causative genes also detected in the context of genetically determined osteoporosis illustrate the pathophysiologic interrelation between monogenetic bone dysplasias and multifactorial osteoporosis. While current therapeutic strategies for OI follow osteoporosis treatment, the expanding knowledge about OI forms the fundament for establishing improved treatment strategies-for both OI and osteoporosis. Similar developments are emerging regarding rare skeletal disorders like Achondroplasia, Fibrodysplasia ossificans progressive and Morbus Morquio (Mukopolysaccharidosis Type IV).

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).

Hypophosphatasia in Japan: ALPL Mutation Analysis in 98 Unrelated Patients.

Hypophosphatasia (HPP) is highly variable in clinical expression and is generally classified into six subtypes. Although it would be beneficial to be able to predict the clinical course from the ALPL genotype, studies on this issue are limited. Here, we aimed to clarify the features of Japanese HPP and the relationships between genotype and clinical manifestations. We analyzed 98 unrelated Japanese patients to investigate the percentage of each clinical form, frequently detected mutations, and the relationship between the genotype and phenotype. Some of the identified mutants were characterized by transfection experiments. Perinatal severe form was the most frequent (45.9%), followed by perinatal benign form (22.4%). Among the 196 alleles, p.Leu520ArgfsX86 (c.1559delT) was detected in 89 alleles, and p.Phe327Leu (c.979T>C) was identified in 23 alleles. All of the homozygotes for p.Leu520ArgfsX86 were classified into perinatal severe form, and patients carrying p.Phe327Leu in one of the alleles were classified into perinatal benign or odonto HPP. Twenty of the 22 patients with perinatal benign HPP were compound heterozygous for p.Phe327Leu and another mutation. Most patients with odonto HPP were found to be monoallelic heterozygotes for dominant-negative mutations or compound heterozygotes with mutants having residual activity. The high prevalence of p.Leu520ArgfsX86 and p.Phe327Leu mutations might underlie the high rate of perinatal severe and perinatal benign forms, respectively, in Japanese HPP. Although ALPL genotyping would be beneficial for predicting the clinical course to an extent, the observed phenotypical variability among patients sharing the same genotypes suggests the presence of modifiers.