Infantile Hypophosphatasia Research Articles

12472 Clinical Features Of Adult Hypophosphatasia And Correlation Between Laboratory Findings And Patient’s Symptomatology: A Retrospective Review At The Penn Bone Center

Abstract Disclosure: J. Ocampo Mascaro: None. R. Tran: None. S. Kallish: Consulting Fee; Self; Sanofi, Amicus. Research Investigator; Self; Ipsen, Sanofi, Incyte, Idorsia. Speaker; Self; Sanofi, Amicus. J. Berman: None. M. Al Mukaddam: Grant Recipient; Self; Ipsen, Incyte Research Funding. Hypophosphatasia (HPP) is an inborn error of metabolism resulting in low activity of the enzyme tissue non-specific alkaline phosphatase (ALP). It primarily involves bone and teeth mineralization. HPP has a wide clinical spectrum. It may present with rickets, fractures, failure to thrive, weakness, respiratory complications, and seizures in its more severe perinatal/infantile forms. Childhood forms tend to be milder but may have substantial musculoskeletal complications and early teeth loss. The clinical picture in adults is extremely variable too. It is usually mild with stress fractures and/or teeth loss in most individuals but can be debilitating in others due to musculoskeletal pain and recurrent fractures. This retrospective study describes the characteristics of 35 adult patients (ages 22-74 years) with HPP based on clinical presentation +/- molecular testing at the Penn Bone Center, located at a US-based large academic hospital. Out of 35 patients, 26 had an ALPL variant in genetic testing (12 pathogenic, 5 likely pathogenic, and 9 of uncertain significance), 3 were negative, and 6 did not undergo testing yet. ALP values ranged from 11 to 39 U/L (N: 38-126). Serum fasting vitamin B6 levels (off supplements) ranged from normal range to 18 times the upper limit of normal. Main symptoms reported were fractures (74%), arthralgias/myalgias (51%), diffuse bone pain (29%), atraumatic teeth loss (20%), muscle weakness (14%), and nephrolithiasis (9%). We found no significant negative correlation between ALP levels and number of symptoms (rs -0.026) or age of first symptom occurrence (rs 0.205). We also found no significant positive correlation between B6 elevation and number of symptoms (rs 0.236) or age of first symptom occurrence (rs -0.175). Six patients within our cohort had previous or current treatment with asfotase alfa. This is an FDA-approved therapy for the treatment of perinatal, infantile, and childhood HPP and has been used in adult patients if one of the presenting symptoms was before age 18 years. Response to therapy in our patient cohort was mixed. Three out of six patients discontinued treatment due to lack of clinical benefit. Continued research of the clinical characteristics of adult HPP is needed to better understand its natural history, markers of severity of disease, and how to determine who may potentially benefit from asfostase alfa therapy. Presentation: 6/1/2024

Tissue nonspecific alkaline phosphatase deficiency impairs Purkinje cell development and survival in a mouse model of infantile hypophosphatasia

Loss-of-function mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene can result in hypophosphatasia (HPP), an inherited multi-systemic metabolic disorder that is well-known for skeletal and dental hypomineralization. However, emerging evidence shows that both adult and pediatric patients with HPP suffer from cognitive deficits, higher measures of depression and anxiety, and impaired sensorimotor skills. The cerebellum plays an important role in sensorimotor coordination, cognition, and emotion. To date, the impact of TNAP mutation on the cerebellar circuitry development and function remains poorly understood. The main objective of this study was to investigate the roles of TNAP in cerebellar development and function, with a particular focus on Purkinje cells, in a mouse model of infantile HPP. Male and female wild type (WT) and TNAP knockout (KO) mice underwent behavioral testing on postnatal day 13–14 and were euthanized after completion of behavioral tests. Cerebellar tissues were harvested for gene expression and immunohistochemistry analyses. We found that TNAP mutation resulted in significantly reduced body weight, shorter body length, and impaired sensorimotor functions in both male and female KO mice. These developmental and behavioral deficits were accompanied by abnormal Purkinje cell morphology and dysregulation of genes that regulates synaptic transmission, cellular growth, proliferation, and death. In conclusion, inactivation of TNAP via gene deletion causes developmental delays, sensorimotor impairment, and Purkinje cell maldevelopment. These results shed light on a new perspective of cerebellar dysfunction in HPP.

Enzyme replacement therapy for hypophosphatasia-The current paradigm.

Hypophosphatasia (HPP) is a rare, inherited, and systemic disorder characterized by impaired skeletal mineralization and low tissue nonspecific serum alkaline phosphatase (TNSALP) activity. It is caused by either autosomal recessive or dominant-negative mutations in the gene that encodes TNSALP. The phenotype of HPP is very broad including abnormal bone mineralization, disturbances of calcium and phosphate metabolism, pain, recurrent fracture, short stature, respiratory impairment, developmental delay, tooth loss, seizures, and premature death. Other than supportive care, there has been no disease-specific treatment available for those with HPP. Asfotase alfa is a fully humanized, recombinant enzyme replacement therapy for the management of HPP. It is available in several countries for the treatment of the more severe forms of HPP, namely perinatal and infantile HPP. This review will summarize the preclinical data on asfotase alfa and highlight the data from clinical trials and case reports. These data show the transformative nature of asfotase alfa when administered as part of an interdisciplinary treatment model.

A case of infantile hypophosphatasia: Phenotypic findings of a compound heterozygous inheritance with a novel mutation

We report the case of a 9-month infant who presented with failure to thrive and bony deformities, mimicking a ricket-like picture. Biochemical parameters showed hypercalcemia, low serum alkaline phosphatase, normal serum phosphorus, magnesium, and parathormone levels. Ultrasound revealed nephrocalcinosis. Clinical exome sequencing revealed infantile hypophophatasia with two compound heterozygous mutations in exon 6 (mutation being novel) and 12. To the best of our knowledge, compound heterozygous mutations in exon 9 and exon 12 have presented with pyridoxine responsive seizure (PRS) along with hypophosphatasia (HPP). This is the third case of infantile HPP reported from India, but with a novel mutation who had not yet manifested with PRS.

Gene Therapy Using Recombinant AAV Type 8 Vector Encoding TNAP-D10 Improves the Skeletal Phenotypes in Murine Models of Osteomalacia.

Hypophosphatasia (HPP), caused by loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNAP), is characterized by skeletal and dental hypomineralization that can vary in severity from life-threatening to milder manifestations only in adulthood. PHOSPHO1 deficiency leads to early-onset scoliosis, osteomalacia, and fractures that mimic pseudo-HPP. Asfotase alfa, a life-saving enzyme replacement therapy approved for pediatric-onset HPP, requires subcutaneous injections 3 to 6times per week. We recently showed that a single injection of an adeno-associated virus vector serotype 8 harboring TNAP-D10 (AAV8-TNAP-D10) effectively prevented skeletal disease and prolonged life in Alpl -/- mice phenocopying infantile HPP. Here, we aimed to determine the efficacy of AAV8-TNAP-D10 in improving the skeletal and dental phenotype in the Alpl Prx1/Prx1 and Phospho1 -/- mouse models of late-onset (adult) HPP and pseudo-HPP, respectively. A single dose of 3 × 1011 vector genomes per body (vg/b) was injected intramuscularly into 8-week-old Alpl Prx1/Prx1 and wild-type (WT) littermates, or into 3-day-old Phospho1 -/- and WT mice, and treatment efficacy was evaluated after 60 days for late-onset HPP mice and after 90 days for Phospho1 -/- mice. Biochemical analysis showed sustained serum alkaline phosphatase activity and reduced plasma PPi levels, and radiographic images, micro-computed tomography (micro-CT) analysis, and hematoxylin and eosin (H&E) staining showed improvements in the long bones in the late-onset HPP mice and corrected scoliosis in the Phospho1 -/- mice. Micro-CT analysis of the dentoalveolar complex did not reveal significant changes in the phenotype of late-onset HPP and pseudo-HPP models. Moreover, alizarin red staining analysis showed that AAV8-TNAP-D10 treatment did not promote ectopic calcification of soft organs in adult HPP mice after 60 days of treatment, even after inducing chronic kidney disease. Overall, the AAV8-TNAP-D10 treatment improved the skeletal phenotype in both the adult HPP and pseudo-HPP mouse models. This preclinical study will contribute to the advancement of gene therapy for the improvement of skeletal disease in patients with heritable forms of osteomalacia. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Effects of Infantile Hypophosphatasia on Human Dental Tissue

Hypophosphatasia (HPP) is an inherited, systemic disorder, caused by loss-of-function variants of the ALPL gene encoding the enzyme tissue non-specific alkaline phosphatase (TNSALP). HPP is characterized by low serum TNSALP concentrations associated with defective bone mineralization and increased fracture risk. Dental manifestations have been reported as the exclusive feature (odontohypophosphatasia) and in combination with skeletal complications. Enzyme replacement therapy (asfotase alfa) has been shown to improve respiratory insufficiency and skeletal complications in HPP patients, while its effects on dental status have been understudied to date. In this study, quantitative backscattered electron imaging (qBEI) and histological analysis were performed on teeth from two patients with infantile HPP before and during asfotase alfa treatment and compared to matched healthy control teeth. qBEI and histological methods revealed varying mineralization patterns in cementum and dentin with lower mineralization in HPP. Furthermore, a significantly higher repair cementum thickness was observed in HPP compared to control teeth. Comparison before and during treatment showed minor improvements in mineralization and histological parameters in the patient when normalized to matched control teeth. HPP induces heterogeneous effects on mineralization and morphology of the dental status. Short treatment with asfotase alfa slightly affects mineralization in cementum and dentin. Despite HPP being a rare disease, its mild form occurs at higher prevalence. This study is of high clinical relevance as it expands our knowledge of HPP and dental involvement. Furthermore, it contributes to the understanding of dental tissue treatment, which has hardly been studied so far.

Clinical and Genetic Characteristics of Pediatric Patients with Hypophosphatasia in the Russian Population.

(1) Hypophosphatasia (HPP) is a rare inherited disease caused by mutations (pathogenic variants) in the ALPL gene which encodes tissue-nonspecific alkaline phosphatase (TNSALP). HPP is characterized by impaired bone mineral metabolism due to the low enzymatic activity of TNSALP. Knowledge about the structure of the gene and the features and functions of various ALPL gene variants, taking into account population specificity, gives an understanding of the hereditary nature of the disease, and contributes to the diagnosis, prevention, and treatment of the disease. The purpose of the study was to describe the spectrum and analyze the functional features of the ALPL gene variants, considering various HPP subtypes and clinical symptoms in Russian children. (2) From 2014-2021, the study included the blood samples obtained from 1612 patients with reduced alkaline phosphatase activity. The patients underwent an examination with an assessment of their clinical symptoms and biochemical levels of TNSALP. DNA was isolated from dried blood spots (DBSs) or blood from the patients to search for mutations in the exons of the ALPL gene using Sanger sequencing. The PCR products were sequenced using a reagent BigDye Terminator 3.1 kit (Applied Biosystems). Statistical analysis was performed using the GraphPad Prism 8.01 software. (3) The most common clinical symptoms in Russian patients with HPP and two of its variants (n = 22) were bone disorders (75%), hypomyotonia (50%), and respiratory failure (50%). The heterozygous carriage of the causal variants of the ALPL gene was detected in 225 patients. A total of 2 variants were found in 27 patients. In this group (n = 27), we identified 28 unique variants of the ALPL gene, of which 75.0% were missense, 17.9% were frameshift, 3.6% were splicing variants, and 3.6% were duplications. A total of 39.3% (11/28) of the variants were pathogenic, with two variants being probably pathogenic, and 15 variants had unknown clinical significance (VUS). Among the VUS group, 28.6% of the variants (7/28) were discovered by us for the first time. The most common variants were c.571G > A (p.Glu191Lys) and c.1171del (Arg391Valfs*12), with frequencies of 48.2% (13/28) and 11% (3/28), respectively. It was found that the frequency of nonsense variants of the ALPL gene was higher (p < 0.0001) in patients with the perinatal form compared to the infantile and childhood forms of HPP. Additionally, the number of homozygotes in patients with the perinatal form exceeded (p < 0.01) the frequencies of these genotypes in children with infantile and childhood forms of HPP. On the contrary, the frequencies of the compound-heterozygous and heterozygous genotypes were higher (p < 0.01) in patients with infantile childhood HPP than in perinatal HPP. In the perinatal form, residual TNSALP activity was lower (p < 0.0005) in comparison to the infantile and childhood (p < 0.05) forms of HPP. At the same time, patients with the heterozygous and compound-heterozygous genotypes (mainly missense variants) of the ALPL gene had greater residual activity (of the TNSALP protein) regarding those homozygous patients who were carriers of the nonsense variants (deletions and duplications) of the ALPL gene. Residual TNSALP activity was lower (p < 0.0001) in patients with pathogenic variants encoding the amino acids from the active site and the calcium and crown domains in comparison with the nonspecific region of the protein.

Dental outcomes for children receiving asfotase alfa for hypophosphatasia.

Hypophosphatasia, a genetic disease impeding development of teeth and bones, is associated with premature exfoliation of primary teeth. Hypophosphatasia is caused by mutations in the ALPL gene, which encodes the tissue non-specific form of alkaline phosphatase. Asfotase alfa (Strensiq®) is a human recombinant bone-targeted alkaline phosphatase. To review development and exfoliation patterns of primary/permanent teeth in a cohort of patients with hypophosphatasia enrolled in an open-label clinical trial of enzyme replacement therapy (ERT) with asfotase alfa. Data were collected from existing study files of a cohort of patients ≤5years of age with infantile hypophosphatasia. Children were recruited at the Winnipeg site of a global clinical trial and were treated with ERT. Dental information, including the exfoliation/eruption patterns, were recorded at each visit. Eleven children (7 females, 4 males) participated. Participants enrolled as infants (5 infants; mean age 3.0±2.3months) prematurely lost significantly fewer teeth to hypophosphatasia than patients recruited as preschoolers (6 preschoolers; mean age 52.5±11.3months), who started on asfotase alfa at a later age. Conclusion The oral health of children with early onset infantile hypophosphatasia may be improved with early and continued administration of ERT, compared to institution of therapy later in childhood.

Prenatal enzyme replacement therapy for Akp2 -/- mice with lethal hypophosphatasia.

Hypophosphatasia (HPP) is a congenital skeletal disease. Impairment of bone mineralization and seizures are due to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP). Enzyme replacement therapy (ERT) is available as a highly successful treatment for pediatric-onset HPP. However, the potential for prenatal ERT has not been fully investigated to date. In this study, we assessed outcomes and maternal safety using a combinational approach with prenatal and postnatal administration of recombinant TNAP in Akp2−/− mice as a model of infantile HPP. For the prenatal ERT, we administered subcutaneous injections of recombinant TNAP to pregnant mice from embryonic day 11.5–14.5 until delivery, and then sequentially to Akp2−/− pups from birth to day 18. For the postnatal ERT, we injected Akp2−/− pups from birth until day 18. Prenatal ERT did not cause any ectopic mineralization in heterozygous maternal mice. Both prenatal and postnatal ERT preserved growth, survival rate and improved bone calcification in Akp2−/− mice. However, the effects of additional prenatal treatment to newborn mice appeared to be minimal, and the difference between prenatal and postnatal ERT was subtle. Further improvement of the prenatal ERT schedule and long-term observation will be required. The present paper sets a standard for such future studies.

Hypophosphatasia as a rare cause of neonatal seizures

Severe forms of hypophosphatasia due to loss-of-function in the ALPL gene may present with diverse neurological problems including pyridoxine-responsive seizures. We present a short report of pyridoxine-responsive neonatal seizures. Due to severe osteopenia with unmeasurable levels of alkaline phosphatase, targeted genetic screening was performed and two pathogenic variants in the gene for the nonspecific alkaline phosphatase confirmed the diagnosis of hypophosphatasia. We would like to emphasize the importance of considering infantile hypophosphatasia in the differential diagnosis of pyridoxine-responsive seizures with concomitant low alkaline phosphatase level and bone pathology, especially with the new treatments becoming available in the future.

Hypophosphatasia Misdiagnosed as Osteoporosis in a Young Girl

Introduction: Hypophosphatasia (HPP) is a rare inherited disease of mineral metabolism characterized by low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNALP), which causes an inability to liberate inorganic phosphate for hydroxyapatite crystal propagation as well as toxic accumulation of inorganic pyrophosphate, pyridoxal-5’-phosphate and urinary phosphoethanolamine. It has a prevalence of 1/100,000 to 1/900,000, although milder forms have an estimated prevalence of 1/6,370. Variable mutations in TNALP cause clinical expressions ranging from a severe perinatal form, which is often fatal after birth from pulmonary complications, to an infantile form, which can cause vitamin B6-responsive seizures, to an asymptomatic adult form. Case: A 27-year-old, ventilator-dependent female with osteoporosis, hypothyroidism, cerebral palsy with previous spinal fusion, seizure disorder and nephrocalcinosis presented with surgical site infection from a right femur ORIF she underwent a month ago. She had a history of microfractures and low-impact fractures of both femurs requiring several surgeries. Osteoporosis was diagnosed at age 5 and she had been on Fosamax ever since. She did not meet any developmental milestones as a baby and never reached menarche. Various diagnoses by multiple specialists did not fully explain her clinical presentation. Her medications included alendronate 5 mg, calcium carbonate 600 mg, ergocalciferol 400 U and levothyroxine 50 mcg. Physical exam showed poor dentition, a misshapen skull and bowed legs with contractures of her extremities. Her labs revealed Ca 9.1 mg/dL (8.4–10.2 mg/dL), albumin 3.2 gm/dL (3.5–5.2 gm/dL), phosphorus 5.1 mg/dL (2.5–4.5 mg/dL), alkaline phosphatase 32 U/L (35–105 U/L), PTH 28 pg/mL (15–65 pg/mL), vitamin D 33.5 ng/mL (30–100 ng/mL), C-telopeptide 509 pg/mL (34–635 pg/mL). A right knee X-Ray reported diffusely gracile and demineralized bones with muscular atrophy. She recently transitioned care from a pediatric endocrinologist to an adult endocrinologist, who tested her positive for heterozygous ALPL pathogenic variant hypophosphatasia and was considering her for asfotase alfa enzyme replacement therapy. Discussion: Our patient had infantile HPP, but due to misdiagnosis as osteoporosis, she was inappropriately treated with a bisphosphate for over 20 years. Treatment of HPP had been supportive until the approval of asfotase alfa (Strensiq) in October 2015. It is a bone-targeted human recombinant enzyme replacement therapy approved for infantile- and juvenile-onset HPP and has been shown to decrease mortality from 73% to 16% at age 5. With improvement in life-sustaining technology, more HPP patients are able to survive into adulthood. Awareness of the complex and polymorphic presentation of HPP by adult endocrinologists is paramount for accurate diagnosis, thus avoiding inappropriate treatments.

Clinical follow-up and genetic analysis of six cases with hypophosphatasia

Objective: To analyze the clinical, genetic characteristics and follow-up data of Chinese patients with hypophosphatasia (HPP). Methods: A retrospective analysis was conducted on six children with HPP admitted to the Department of Endocrinology, Genetics and Metabolism in Beijing Children's Hospital from October 2010 to January 2019. Summarized the clinical and follow-up data of all six patients, as well as the pathogenic variants of five children. Results: The serum alkaline phosphatase levels of all six children (five males and one female) were significantly reduced (2-49 U/L). The 6 patients aged from 2 months to 6 years and 4 months, 4 infantile HPP, 1 childhood HIP and 1 odonto HPP. The four patients with infantile HPP presented with anorexia, slow weight gain and hypercalcemia, whereas the one patient with childhood HPP and the other patient with odonto HPP had tooth loss. The patient with childhood HPP also manifested with motor dysfunction. Genetic testing was conducted for five patients and 4 unrelated Chinese families and revealed 10 variations in ALPL gene, including 7 missense variation, 1 insertion variation, 1 frameshift variation, 1 deletion variation.Of which 3 were novel (p.Y28C, p.268, F>L, p.A176V).One of the infantile patients lost follow-up and the other three deceased. The clinical conditions were much improved with medical intervention for patients with childhood, orodonto HPP. Conclusions: While HPP patients with different ages of onset present with common features, the prognosis differ significantly. The prognosis is good for patients with childhood, orodonto HPP and poor for patients with infantile HPP. Genetic testing is the main method for definitive diagnosis.

Effects of Enzyme Replacement Therapy for Primary Teeth in a Patient with Infantile Hypophosphatasia

Hypophosphatasia (HPP) is a skeletal disorder characterized by hypomineralization of bone, with early exfoliation of primary teeth. Alkaline phosphatase enzyme replacement therapy (ERT) has been shown to improve bone hypomineralization for patients with HPP, although its dental effects are unknown. A 20-month-old Japanese boy diagnosed with infantile HPP was referred to our clinic because of early exfoliation of primary teeth. The patient had been followed by a pediatrician since the age of 3 months, due to slow weight gain. At the age of 12 months, primary incisors showed sudden exfoliation; at the age of 19 months, a diagnosis of HPP was made based on bone and dental manifestations. ERT was initiated at the age of 21 months. The patient demonstrated stable periodontal conditions of primary molars that erupted after initiation of ERT, due to improved alveolar bone and tooth mineralization. Thus, ERT may improve both dental and systemic conditions.

Characterization of tracheobronchomalacia in infants with hypophosphatasia

BackgroundPerinatal and infantile hypophosphatasia (HPP) are associated with respiratory failure and respiratory complications. Effective management of such complications is of key clinical importance. In some infants with HPP, severe tracheobronchomalacia (TBM) contributes to respiratory difficulties. The objective of this study is to characterize the clinical features, investigations and management in these patients.MethodsWe report a case series of five infants with perinatal HPP, with confirmed TBM, who were treated with asfotase alfa and observed for 3–7 years. Additionally, we reviewed respiratory function data in a subgroup of patients with perinatal and infantile HPP included in the clinical trials of asfotase alfa, who required high-pressure respiratory support (positive end-expiratory pressure [PEEP] ≥6 cm H2O and/or peak inspiratory pressure ≥18 cm H2O) during the studies.ResultsThe case series showed that TBM contributed significantly to respiratory morbidity, and prolonged respiratory support with high PEEP was required. However, TBM improved over time, allowing weaning of all patients from ventilator use. The review of clinical trial data included 20 patients and found a high degree of heterogeneity in PEEP requirements across the cohort; median PEEP was 8 cm H2O at any time and some patients presented with high PEEP (≥8 cm H2O) over periods of more than 6 months.ConclusionIn infants with HPP presenting with persistent respiratory complications, it is important to screen for TBM and initiate appropriate respiratory support and treatment with asfotase alfa at an early stage.Trial registrationClinicalTrials.gov numbers: NCT00744042, registered 27 August 2008; NCT01205152, registered 17 September 2010; NCT01176266, registered 29 July 2010.

MON-LB71 Adult Hypophosphatasia and Postmenopausal Osteoporosis: A Challenging Case

Introduction: Hypophosphatasia (HPP) is a rare disease that cause osteomalacia and premature tooth loss due to abnormal bone mineralization. The clinical presentation ranges from severe neonatal and infantile HPP with a high morbidity and mortalilty to mild Adult HPP. The ranging spectrum is possibly due to autosomal recessive versus autosomal dominant missense mutations at the gene that encodes TNSALP. The hallmark of the disease is a low serum total alkaline phosphatase level (ALP). It is important to diagnose adult HPP particularly to refrain from treating with bone antiresorptive medications. Low levels of alkaline phosphatase generally are undectected in the adult population even in patients with osteoporosis and fractures. We describe a case of a woman with postmenopausal osteoporosis without fractures diagnosed with adult HPP. The clinical course and management is described below. Case Description: A 62 y.o. women was referred for evaluation and treatment of osteoporosis. She had no fractures, including during childhood, no history of premature deciduous teeth loss, dental problems or nephrolithiasis. No family history of osteoporosis or fractures. Menopause at age 48 without hormone replacement therapy. Evaluation for secondary causes of osteoporosis was normal including serum TSH, calcium, phosphate, PTH, 24 hours urinary calcium and vitamin D-25. ALP ranged from 33-40 U/L (nl 37-126) before therapy. She was treated with raloxifene for 2 years. Therapy was switched to alendronate due to a decrease in bone density. She subsequently treated with alendronate for 5 years until 5/2012. Due to a decrease in bone density alendronate therapy was reinstituted between Jan 2013-Jan 2016 but in spite of therapy and a CTX level of 333 pg/ml bone density in the spine decreased significantly. In view of the low ALP and decreasing bone density while on bisphosphonate and a high B6 level (B6= 37 nl: -27) a genetic test for HPP and a compound heterozygote mutation in ALPL gene was detected. Her daughter was also found to have low ALP and carries the same mutation. Bone density has been stable since bisphosphonate therapy was stopped (spine T -3.2, LT femoral neck T -2.9) CTX 360 pg/ml. Recently therapy with raloxifene was initiated in view of the low bone density and high risk of fractures. Conclusion: The proper diagnosis and management of patients with adult HPP is challenging because the diagnosis may be missed in patients with borderline low ALP and on the other hand the proper managent of osteoporosis in these patients is not known.

SAT-381 Adjunct Benefit of Aquatic Therapy in Juvenile Hypophosphatasia Initiated in an Adult

Background: This is a case of improvement in visual analog scale pain rating and objective functional capacity in juvenile hypophosphatasia (HPP) following treatment with asfotase alfa and adjunct physical therapy (PT) performed in an aquatic environment. Clinical Case: A 45-year-old female with a history of psoriatic arthritis and osteoarthritis was referred for low serum alkaline phosphatase (ALKP) (<10 U/L). Her history of eight fractures over the preceding 25 years including bilateral femur nonunion repaired with rods eight years prior to presentation led to a diagnosis of juvenile HPP, and asfostase alfa was ordered. She is ambulatory only with a rolling walker from a deficit in dynamic standing balance and chronic pain. Referrals were made for both PT and pain management for these symptoms. The initial PT evaluation established reasonable goals to include the performance of in-home exercise, increase strength and range of motion, decrease pain, improve standing balance, and progress from walker to cane. Aquatic therapy was chosen in order to reduce patient’s effective weight. The right hip complex, lumbar spine, and left leg were chosen as areas of focus based on pain reports. A four-week follow-up evaluation by the therapist reported patient had been performing at home exercises. Pain scale reports of the lumbar spine, right hip, and left leg were within the moderate range and near or meeting the patient’s self-reported least pain experienced. Goniometric measurements of the right hip showed range of motion improvements averaging 9%. The lumbar spine’s range of motion increased an average of 18%. Discussion: HPP is capable of creating severe disability, and its rarity has led to a dearth of investigation into appropriate treatment. Recommendations have been made previously for PT in children and infants presenting with juvenile or infantile HPP; this case suggests these recommendations are applicable to adults as well. The mechanisms of these improvements remain unclear; however, evidence exists that weight-bearing exercise may result in increased levels of bone-specific isoforms of ALKP. This endogenous path to increased serum ALKP may play a role in potentiating the effects of asfostase alfa. 1. Shapiro JR, Lewiecki EM. Hypophosphatasia in Adults: Clinical Assessment and Treatment Considerations. Journal of Bone and Mineral Research 2017;32(10):1977–1980. 2. Phillips D, Case LE, Griffin D, Hamilton K, Lara SL, Leiro B, Monfreda J, Westlake E, Kishnani PS. Physical therapy management of infants and children with hypophosphatasia. Molecular Genetics and Metabolism 2016;119(1–2):14–19. 3. Rudberg A, Magnusson P, Larsson L, Joborn H. Serum Isoforms of Bone Alkaline Phosphatase Increase During Physical Exercise in Women. Calcified Tissue International 2000;66(5):342–347.

Infantile Hypophosphatasia: Clinical Case

Background . Hypophosphatasia is rare hereditary disease caused by deficiency of the tissue-nonspecific alkaline phosphatase isozyme. It manifests with bone and teeth mineralisation defects, electrolyte imbalance, respiratory disorders, convulsive syndrome, physical developmental delay, nephrocalcinosis. The rarity of this disease, clinical polymorphism, non-specificity of complains and signs are the major reasons of hypophosphatasia late diagnosis. The enzyme replacement therapy with recombinant alkaline phosphatase (asfotase alfa) can be used for treatment of severe forms of disease. Clinical Case Description . The girl (1 y 4 m) was routinely admitted with complains of physical developmental delay and psychomotor retardation, deformation of lower limbs, chest, gait abnormality, teeth loss and with diagnosis «protein-calorie malnutrition». Rickets-like changes in skeleton, myopathic syndrome, early normal teeth loss, hepatomegaly were revealed. Reduced activity of alkaline phosphatase in blood serum (33 u/l; reference range 156–369 u/l) was revealed. The infantile hypophosphatasia has been diagnosed. Due to molecular genetic testing of ALPL gene we revealed pathogenic variants c.526G>A (p.Ala176Thr) and c.1375G>A (p.Val459Met) in compound heterozygous state. The asphotase alpha therapy was initiated at the age of 1 y 10 m, the dose was 2 mg/kg subcutaneously 3 times a week. The results of 6 months of the therapy are the following: significant increase in the activity of alkaline phosphatase (maximum 4400 u/l), body weight (+ 2 kg), growth (+ 6 cm), reduction of bone deformation, normalisation of muscle tone and gait, exercise tolerance. The patient tolerated the drug administration well. Rarely there were hyperemia zones up to 4 cm in diameter with moderate induration at the injection site but they spontaneous disappeared in 2–3 days though. Conclusion. Patients with rickets-like diseases and low alkaline phosphatase activity requires performing of molecular genetic testing to confirm hypophosphatasia. Timely diagnosis and early initiation of enzyme replacement therapy can significantly improve the quality of life of children with hypophosphatasia.

Perinatal severe hypophosphatasia: a case report

Abstract Objectives Hypophosphatasia is a rare, inherited metabolic disorder characterized by low serum alkaline phosphatase activity. It is caused by mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP) [1], [2], [3]. The degree of skeletal malformation varies, but the severe form carries a very poor prognosis. Case presentation This study reports a male neonate diagnosed with infantile hypophosphatasia (HPP). Genetic analysis showed two heterozygous missense variants at nucleotides c.977G&gt;T (protein Gly326Val) and c.862+4A&gt;G (IVS8+4A&gt;G) (protein NA). The two mutations originated separately from the parents, consistent with autosomal recessive infantile HPP. The pathogenic variant was ALPL exon-9-heterozygous, and the other allele was ALPL IVS8-heterozygous, a variant of uncertain significance. Conclusions This case of infantile HPP was caused by two heterozygous mutations. One of those is a novel genetic mutation needed for further study. Genetic consultation is recommended for future offspring of affected parents.

Гипофосфатазия у детей. Три лица одной болезни

Hypophosphatasia (HPP) is a rare multisystem inherited metabolic disorder caused by mutations in ALPL gene that encodes tissue nonspecific alkaline phosphatase responsible for bone mineralization. HPP is characterized by impaired bone mineralization, skeletal abnormalities, and systemic manifestations which result in significant morbidity and mortality. Clinical presentations of HPP vary greatly. Early (perinatal and infantile) HPP is characterized by the most severe symptoms, i.e., respiratory and neurological disorders are of crucial importance being the leading causes of death. Progressive skeletal impairment, rickets-like deformities, reduced mobility, and severe disability are typical of childhood-onset HPP. The biochemical hallmark of HPP is low alkaline phosphatase (ALP) activity. HPP diagnosis is verified by clinical symptoms in combination with persistently low ALP activity (adjusted for age and sex). Molecular genetic test to identify ALPL gene mutation is performed as needed. Three case reports addresses authors’ experience with the diagnosis and treatment for HPP.Keywords: hypophosphatasia, case series, alkaline phosphatase, impaired bone mineralization, asfotase alfa.For citation: Boykov S.A., Chernyak I.Yu., Shatokhina N.S. et al. Hypophosphatasia in children. Three faces of one disease. Russian Journal of Woman and Child Health. 2020;3(2):136–141. DOI: 10.32364/2618-8430-2020-3-2-136-141.

Hypophosphatasia: Biological and Clinical Aspects, Avenues for Therapy.

Hypophosphatasia (HPP) is a rare inherited systemic metabolic disease caused by mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. TNSALP is expressed in the liver, kidney and bone, and its substrates include TNSALP inorganic pyrophosphate, pyridoxal-5'-phosphate (PLP)/vitamin B6 and phosphoethanolamine (PEA). Autosomal recessive and dominant forms of the disease result in a range of clinical entities. Major hallmarks are low alkaline phosphatase (ALP) and elevated PLP and PEA levels. Very severe infantile forms of HPP cause premature death as a result of respiratory insufficiency and also present with hypo-mineralisation leading to deformed limbs with, in some cases, the near-absence of bones and skull altogether. Respiratory failure, rib fractures and seizures due to vitamin B6 deficiency are indicative of a poor prognosis. Craniosynostosis is frequent. HPP leads to an unusual presentation of rickets with high levels of calcium and phosphorus, resulting in hypercalciuria, nephrocalcinosis and low ALP levels. Hypercalcaemic crisis, failure to thrive and growth retardation are concerns in infants. Fractures are common in both infantile and adult forms of the disease, concomitantly occurring with unexplained chronic pain and fatigue. Dental clinical presentations, which include the premature loss of teeth, are also commonly found in HPP and specifically manifest as odontohypophosphatasia. A novel enzyme therapy for human HPP, asfotase alfa, which is specifically targeted to mineralised tissues, has been developed in the past decades. While this treatment seems very promising, especially for infantile HPP, many questions regarding its long-term effects, the management of treatment, and any potential secondary adverse effects remain unresolved.