Skeletal Deformities Research Articles

Uncommon clinical features of juvenile primary hypothyroidism

This case study presents an 18-year-old boy with severe short stature and distinct physical features, including facial abnormalities, skeletal deformities, and intellectual impairment. Further investigations revealed hypothyroidism, autoimmune thyroiditis, and delayed bone age. Treatment with levothyroxine replacement therapy was initiated. The study highlights the importance of detection and management of hypothyroidism in individuals with short stature and associated features.

A study on transfusion-transmitted infections and other complications amongst children with beta-thalassaemia major attending a tertiary care institution in Kolkata

Abstract Background: Chronic blood disorders such as beta-thalassaemia major require continuous blood transfusions, which results in complications such as transfusion-transmitted infections (TTIs), iron overload, skeletal deformities, endocrinal and cardiac and hepatic disorders. This study aimed at assessing proportion of TTIs, other complications and factors associated with their occurrence amongst children with beta-thalassaemia major. Methods: This cross-sectional study was conducted amongst children with beta-thalassaemia majo attending a tertiary care institution in Kolkata One hundred and ninety two children were selected amongst participants who fulfilled the inclusion criteria. Parents of study participants were interviewed using pre-designed, pre-tested, semi-structured schedule. Results: TTIs were evident in 8.3% of the study participants. Amongst them, hepatitis C, malaria and hepatitis B were present amongst 3.6%, 2.6% and 2.1%, respectively. No cases of human immunodeficiency virus infection and syphilis were found. Elevated serum ferritin levels (53.6%), Chipmunk facies (5.2%), hypothyroidism (2.1%), cardiomyopathy and diabetes mellitus (0.5% each) were noted. A significant association was observed between iron chelation therapy and serum ferritin level amongst these children (P = 0.042). Conclusions: Various transfusion-related complications are still prevalent amongst children suffering from beta-thalassaemia major.

Skeletal Deformities in Cultured Striped Catfish Pangasianodon hypophthalmus (Sauvage, 1878) in the Mekong Delta, Vietnam

Skeletal deformities are a common issue that poses a challenge that hinders the production of cultured finfish worldwide. The present study aims to describe for the first time skeletal deformities in cultured striped catfish Pangasianodon hypophthalmus (Sauvage, 1878) from the Mekong Delta, Vietnam. A total of 68 striped catfish were collected from three nurseries in highly concentrated areas of Long An and Dong Thap provinces. These provinces are known for their numerous hatcheries and nursing farms of P. hypophthalmus in the country. The skeletal deformities recorded included saddleback syndrome, missing pectoral fins, lordosis and kyphosis, unilateral deformities of the opercular complex bones, branchiostegal ray and lower jaw deformities. Abnormalities in bone morphotypes between normal and deformed fish were analysed using X-ray scanning and double staining (alizarin red and alcian blue) methods. The morphological abnormalities, in general, can reduce the fillet yield of fish, thereby affecting their market value. Since P. hypophthalmus is the most important freshwater fish exported from the Mekong Delta, a regular monitoring program of skeletal deformities can contribute to identifying improved rearing protocols and enhance the product quality available in the markets.

A recurrent homozygous LMNA missense variant p.Thr528Met causes atypical progeroid syndrome characterized by mandibuloacral dysostosis, severe muscular dystrophy, and skeletal deformities.

Atypical progeroid syndromes (APS) are premature aging syndromes caused by pathogenic LMNA missense variants, associated with unaltered expression levels of lamins A and C, without accumulation of wild-type or deleted prelamin A isoforms, as observed in Hutchinson-Gilford progeria syndrome (HGPS) or HGPS-like syndromes. A specific LMNA missense variant, (p.Thr528Met), was previously identified in a compound heterozygous state in patients affected by APS and severe familial partial lipodystrophy, whereas heterozygosity was recently identified in patients affected by Type 2 familial partial lipodystrophy. Here, we report four unrelated boys harboring homozygosity for the p.Thr528Met, variant who presented with strikingly homogeneous APS clinical features, including osteolysis of mandibles, distal clavicles and phalanges, congenital muscular dystrophy with elevated creatine kinase levels, and major skeletal deformities. Immunofluorescence analyses of patient-derived primary fibroblasts showed a high percentage of dysmorphic nuclei with nuclear blebs and typical honeycomb patterns devoid of lamin B1. Interestingly, in some protrusions emerin or LAP2α formed aberrant aggregates, suggesting pathophysiology-associated clues. These four cases further confirm that a specific LMNA variant can lead to the development of strikingly homogeneous clinical phenotypes, in these particular cases a premature aging phenotype with major musculoskeletal involvement linked to the homozygous p.Thr528Met variant.

Atypical Cardiac Compression Technique on a Seriously Skeletal Deformity Child.

Atypical Cardiac Compression Technique on a Seriously Skeletal Deformity Child.

Absence of TRIC-B from type XIV Osteogenesis Imperfecta osteoblasts alters cell adhesion and mitochondrial function – A multi-omics study

Osteogenesis Imperfecta (OI) is a heritable collagen-related bone dysplasia characterized by bone fractures, growth deficiency and skeletal deformity. Type XIV OI is a recessive OI form caused by null mutations in TMEM38B, which encodes the ER membrane intracellular cation channel TRIC-B. Previously, we showed that absence of TMEM38B alters calcium flux in the ER of OI patient osteoblasts and fibroblasts, which further disrupts collagen synthesis and secretion. How the absence of TMEM38B affects osteoblast function is still poorly understood. Here we further investigated the role of TMEM38B in human osteoblast differentiation and mineralization. TMEM38B-null osteoblasts showed altered expression of osteoblast marker genes and decreased mineralization. RNA-Seq analysis revealed that cell-cell adhesion was one of the most downregulated pathways in TMEM38B-null osteoblasts, with further validation by real-time PCR and Western blot. Gap and tight junction proteins were also decreased by TRIC-B absence, both in patient osteoblasts and in calvarial osteoblasts of Tmem38b-null mice. Disrupted cell adhesion decreased mutant cell proliferation and cell cycle progression. An important novel finding was that TMEM38B-null osteoblasts had elongated mitochondria with altered fusion and fission markers, MFN2 and DRP1. In addition, TMEM38B-null osteoblasts exhibited a significant increase in superoxide production in mitochondria, further supporting mitochondrial dysfunction. Together these results emphasize the novel role of TMEM38B/TRIC-B in osteoblast differentiation, affecting cell-cell adhesion processes, gap and tight junction, proliferation, cell cycle, and mitochondrial function.

The NAD salvage pathway in mesenchymal cells is indispensable for skeletal development in mice

NAD is an essential co-factor for cellular energy metabolism and multiple other processes. Systemic NAD+ deficiency has been implicated in skeletal deformities during development in both humans and mice. NAD levels are maintained by multiple synthetic pathways but which ones are important in bone forming cells is unknown. Here, we generate mice with deletion of Nicotinamide Phosphoribosyltransferase (Nampt), a critical enzyme in the NAD salvage pathway, in all mesenchymal lineage cells of the limbs. At birth, NamptΔPrx1 exhibit dramatic limb shortening due to death of growth plate chondrocytes. Administration of the NAD precursor nicotinamide riboside during pregnancy prevents the majority of in utero defects. Depletion of NAD post-birth also promotes chondrocyte death, preventing further endochondral ossification and joint development. In contrast, osteoblast formation still occurs in knockout mice, in line with distinctly different microenvironments and reliance on redox reactions between chondrocytes and osteoblasts. These findings define a critical role for cell-autonomous NAD homeostasis during endochondral bone formation.

The role of DNA methylation on gene expression in the vertebrae of ancestrally benzo[a]pyrene exposed F1 and F3 male medaka

ABSTRACT Benzo[a]pyrene (BaP) is ubiquitously present in the aquatic environment and has been identified as a bone toxicant. Previous studies have demonstrated that ancestral BaP exposure can cause transgenerational bone deformities in fish. Transgenerational effects are thought to be caused by heritable epigenetic changes, such as DNA methylation, histone modification, and non-coding RNAs. To investigate the role of DNA methylation in BaP-induced transgenerational skeletal deformities and the related transcriptomic changes in deformed vertebrae, we examined the vertebrae of male F1 and F3 medaka fish using high-throughput RNA sequencing (RNA-seq) and whole-genome bisulphite sequencing (WGBS). The histological results revealed that osteoblast numbers at the vertebral bone decreased in the BaP-derived F1 and F3 adult males in comparison with the control group. Differentially methylated genes (DMGs) associated with osteoblastogenesis (F1 and F3), chondrogenesis (F1 and F3), and osteoclastogenesis (F3) were identified. However, RNA-seq data did not support the role of DNA methylation in the regulation of genes involved in skeletogenesis since there was very little correlation between the level of differential methylation and gene expression profiles related to skeletogenesis. Although DNA methylation plays a major role in the epigenetic regulation of gene expression, the dysregulation of vertebral gene expression patterns observed in the current study is most likely to be mediated by histone modification and miRNAs. Notably, RNA-seq and WGBS data indicated that genes related to nervous system development are more sensitive to ancestral BaP exposure, indicating a more complex transgenerational phenotype in response to ancestral BaP exposure.

Merosin-deficient congenital muscular dystrophy type 1a: detection of LAMA2 variants in Vietnamese patients.

Background: Merosin-deficient congenital muscular dystrophy type 1A (MDC1A), also known as laminin-α2 chain-deficient congenital muscular dystrophy (LAMA2-MD), is an autosomal recessive disease caused by biallelic variants in the LAMA2 gene. In MDC1A, laminin- α2 chain expression is absent or significantly reduced, leading to some early-onset clinical symptoms including severe hypotonia, muscle weakness, skeletal deformity, non-ambulation, and respiratory insufficiency. Methods: Six patients from five unrelated Vietnamese families presenting with congenital muscular dystrophy were investigated. Targeted sequencing was performed in the five probands. Sanger sequencing was carried out in their families. Multiplex ligation-dependent probe amplification was performed in one family to examine an exon deletion. Results: Seven variants of the LAMA2 (NM_000426) gene were identified and classified as pathogenic/likely pathogenic variants using American College of Medical Genetics and Genomics criteria. Two of these variants were not reported in the literature, including c.7156-5_7157delinsT and c.8974_8975insTGAT. Sanger sequencing indicated their parents as carriers. The mothers of family 4 and family 5 were pregnant and a prenatal testing was performed. The results showed that the fetus of the family 4 only carries c.4717 + 5G>A in the heterozygous form, while the fetus of the family 5 carries compound heterozygous variants, including a deletion of exon 3 and c.4644C>A. Conclusion: Our findings not only identified the underlying genetic etiology for the patients, but also provided genetic counseling for the parents whenever they have an offspring.

X-linked hypophosphatemic rickets: from diagnosis to management.

X-linked hypophosphatemia (XLH), the most common cause of hypophosphatemic rickets, affects one in every 20,000 people. Although conventional therapy for XLH was introduced approximately 4 decades ago, the temporary replacement of oral phosphate salts and activated vitamin D cannot completely control chronic hypophosphatemia, leaving patients with incomplete healing and residual skeletal deformity as well as at risk of endocrine abnormalities and adverse drug reactions. However, understanding the pathophysiology has led to the development of a targeted therapy, burosumab, a fibroblast growth factor-23 inhibitor that was recently approved in Korea for the treatment of XLH. This review provides insight into the diagnosis, evaluation, treatment, and recommended follow-up for a typical case of XLH and reviews its pathophysiology.

Elevated Carbon Dioxide and Its Impact on Growth, Blood Properties, and Vertebral Column of Freshwater Fish Mahseer, Tor tambroides Juveniles

The level of carbon dioxide, which resembles water acidification, is critical to the success of juvenile fish production. The growth, skeletal deformities, and blood parameters of the economically important freshwater fish mahseer, Tor tambroides, were assessed in different concentrations of pCO2 (400, 700, and 1000 µatm pCO2). The highest growth properties (survival rate, body weight gain (BWG), specific growth rate (SGR)) in mahseer were observed at 400 µatm, whereas the lowest growth indices were found in the treatment of 1000 µatm pCO2. The lowest pCO2 concentration was found to be within the optimum healthy blood parameter range. The fish exposed to acidic conditions (700 and 1000 µatm) exhibited considerably higher levels of haemoglobin and haematocrit compared to the control fish. Glucose levels were significantly lower in the acidic conditions, while total cholesterol levels in mahseer fish exposed to acidic conditions were higher. The fish displayed skeleton malformations as the concentration of pCO2 was elevated. The findings from this research could be set as a standard technique in the juvenile rearing of mahseer fish under acidified conditions.

Co-occurrence of Spondyloepiphyseal Dysplasia and X-Linked Hypophosphatemia in a Three-Generation Chinese Family.

Rare genetic skeletal disorders (GSDs) remain the major problem in orthopedics and result in significant morbidity in patients, but the causes are highly diverse. Precise molecular diagnosis will benefit management and genetic counseling. This study aims to share the diagnostic experience on a three-generation Chinese family with co-occurrence of spondyloepiphyseal dysplasia (SED) and X-linked hypophosphatemia (XLH), and evaluate the therapeutic effects of two third-generation siblings. The proband, his younger brother, and mother presented with short stature, skeletal problems, and hypophosphatemia. His father, paternal grandfather, and aunt also manifested short stature and skeletal deformities. Whole exome sequencing (WES) of proband-brother-parents initially only found the proband and his younger brother had a pathogenic c.2833G>A(p.G945S) variant in the COL2A1 gene inherited from their father. Re-analysis of WES uncovered the proband and his younger brother also harbored a pathogenic ex.12 del variant in the PHEX gene transmitted from their mother. Sanger sequencing, agarose gel electrophoresis, and quantitative polymerase chain reaction proved these results. The proband and his younger brother were confirmed to have a paternally inherited SED and a maternally inherited XLH. During a 2.8-year follow-up, these two siblings remained short stature and hypophosphatemia, but their radiographic signs and serum bone alkaline phosphatase levels were improved with treatment of oral phosphate and calcitriol. Our study presents the first report of co-occurrence of SED and XLH, shows the possibility that two different rare GSDs co-exist in a single patient, and alerts clinicians and geneticists to be cautious about this condition. Our study also suggests that next-generation sequencing has limit in detecting exon-level large deletions.

Clinical Characteristics and Factors associated with Bone Erosion in Gout Patients with Tophi

Background: A large number of urate crystals are deposited in the joint cavity for a long time, causing bone erosion and gradually forming joint skeletal muscle necrosis and joint deformity.

In Transfusion-Dependent Thalassemia Children, Increased Iron Overload is Associated with Lower Serum Alpha-Klotho, Which is Strongly Associated with Lower Total and Ionized Calcium Concentrations.

Patients with transfusion-dependent thalassemia (TDT) show disorders in calcium metabolism. The α-Klotho protein is predominantly expressed in tissues that are involved in calcium homeostasis, and lowered levels are associated with bone disease. The aim of the study is to examine the associations between low α-Klotho status and calcium metabolism in relation to iron status in children with TDT. Calcium, α-Klotho, parathyroid hormone (PTH), calcyphosin, vitamin D3, phosphorous, fibroblast growth factor receptor 2 (FGFR2), as well as iron and erythron biomarkers were measured in 60 children with TDT and 30 healthy control children. A meaningful part of TDT patients showed lowered α-Klotho levels, and those children also showed low serum total and ionized calcium concentrations. TDT patients showed increased PTH, FGFR2, and calcyphosin and lowered vitamin D3 as compared with healthy children. The α-Klotho levels were significantly correlated with total and ionized calcium (positively) and with iron overload and transfusions biomarkers (inversely). Partial Least Squares path analysis showed that 40.1% of the variance in serum total calcium could be explained by the regression on α-Klotho, vitamin D3 (both positively), and calcyphosin (inversely) and that the effects of the latter are mediated by iron overload and the number of blood transfusions. In conclusion, the iron overload in TDT and its consequences may induce lowered levels of α-Klotho which in turn may lead to lower calcium thereby explaining at least in part the effects of TDT on bone metabolism including spontaneous pathological fractures, osteoporosis, osteopenia, and skeletal deformities.

Effects of n-3 HUFA-enriched Artemia on growth, biochemical response, skeletal morphology and stress resistance of Asian sea bass (Lates calcarifer) larvae reared at high temperature

Improving the growth and health status of marine fish larvae to adapt to climate change, is crucial for commercial hatchery production in tropical regions. This study evaluated the effects of dietary essential fatty acids used for Artemia enrichment on growth, biochemical responses, skeletal morphology, and stress resistance of Asian sea bass larvae, reared at high temperatures of 30 °C and 34 °C. Starting 11 days after hatch, Asian sea bass larvae, were fed Artemia, enriched with a commercial emulsion of n-3 HUFA for 14 days, at four concentrations (0, 100, 300, and 500 ppm), at two rearing temperatures (30 °C and 34 °C). The results showed that enriching Artemia with n-3 HUFA significantly improved the final weight and specific growth rate of the larvae fed n-3 HUFA enrichment at 300 ppm, at 34 °C (P < 0.05). Moreover, n-3 HUFA enriched Artemia significantly increased the essential fatty acids of the larvae in parallel with the dose of enrichment. Fish fed unenriched HUFA Artemia resulted in significantly higher ratio of skeletal deformities and lower survival rate following an air exposure test than the larvae fed the n-3 HUFA enriched diets. Overall, the findings showed that n-3 HUFA-enriched Artemia diets had benefits on body weight, specific growth rate, and stress tolerance in Asian sea bass fed HUFA enriched diets, even at high temperatures.

Etiology Understanding Is the Core of Skeletal Diagnosis

Background: The term idiopathic is a non-specific disease label, which fails account for proper etiological understanding. The frequent usage of the term idiopathic may indicate clinical incompetence. We describe a number of patients from our practice with a history of complex bone disorders who were falsely given the term idiopathic by other Institutes. The sole tool used by other Institutes to conclude osteoporosis as a diagnosis is the bone mineral density. Material and Methods: Two Austrian families and one unrelated adult female patient (total number of 12 subjects) have been referred to our department with referral letters confirming the diagnosis of idiopathic osteoporosis. All patients manifested a diverse constellation of skeletal deformities. In all these patients, regular courses of anti-resorptive treatment plus calcium and vitamin D supplements. These have been excessively prescribed. Results: Our diagnostic process which is based heavily on detailed clinical and radiological phenotypic characterizations, we refuted the diagnosis of idiopathic osteoporosis for all patients because of the clear-cut clinical features. For the first family, we suggested the diagnosis of a novel type of mucopolysaccharidosis (the genetic results confirmed the diagnosis of a novel subtype of mucopolysaccharidosis (through the identification of arylsulfatase K ARSK). For the second family which has been subjected to a lengthy useless investigation for almost more than a decade, we refuted the diagnosis of idiopathic osteoporosis and the whole exome sequencing was consistent with the phenotypic diagnosis Nasu-Hakola disease (heterozygous missense mutations in TYROBP gene). The other unrelated 42-year-old- female patient was correctly diagnosed with Nasu-Hakola disease. Conclusion: The objective of this study is to minimize and suppress the usage of the term idiopathic. It has been imperative to understand the sequence of pathological events that occurred in these families. The core for diagnosis is the etiological understanding, which stemmed from professional conscientiousness. Patients underwent misdiagnosis of idiopathic osteoporosis and were treated extensively with anti-resorptive agents, calcium supplements and vitamin D. Strikingly, these medications resulted in a combination of serious cranial and cerebral lesions because of massive pathological calcifications. Imaging analysis via conventional radiographs, MRI and CT scan showed massive calcifications of the cranial sutures, inter-clinoid ligaments and hyper-calcification of the skull base. Sadly speaking, early onset dementia emerged in connection with sclerosing leukoencephalopathy. We believe that the exogenous toxic effects of the huge amounts of bone supplements consumed by these patients enhanced the pre-existing metabolic bone and cerebral disorders. Our findings can ameliorate the etiological understanding of early onset dementia and other correlated cranial and skeletal lesions.

Management of temporomandibular joint arthritis in children and adolescents: An introduction for orthodontists.

Juvenile idiopathic arthritis (JIA) is the most common inflammatory rheumatic disease of childhood. JIA can affect any joint and the temporomandibular joint (TMJ) is one of the joints most frequently involved. TMJ arthritis impacts mandibular growth and development and can result in skeletal deformity (convex profile and facial asymmetry), and malocclusion. Furthermore, when TMJs are affected, patients may present with pain at joint and masticatory muscles and dysfunction with crepitus and limited jaw movement. This review aims to describe the role of orthodontists in the management of patients with JIA and TMJ involvement. This article is an overview of evidence for the diagnosis and treatment of patients with JIA and TMJ involvement. Screening for the orofacial manifestation of JIA is important for orthodontists to identify TMJ involvement and related dentofacial deformity. The treatment protocol of JIA with TMJ involvement requires an interdisciplinary collaboration including orthopaedic/orthodontic treatment and surgical interventions for the management of growth disturbances. Orthodontists are also involved in the management of orofacial signs and symptoms; behavioural therapy, physiotherapy and occlusal splints are the suggested treatments. Patients with TMJ arthritis require specific expertise from an interdisciplinary team with members knowledgeable in JIA care. Since disorders of mandibular growth often appear during childhood, the orthodontist could be the first clinician to see the patient and can play a crucial role in the diagnosis and management of JIA patients with TMJ involvement.

Whole-Body Metabolism and the Musculoskeletal Impacts of Targeting Activin A and Myostatin in Severe Osteogenesis Imperfecta.

Mutations in the COL1A1 and COL1A2 genes, which encode type I collagen, are present in around 85%-90% of osteogenesis imperfecta (OI) patients. Because type I collagen is the principal protein composition of bones, any changes in its gene sequences or synthesis can severely affect bone structure. As a result, skeletal deformity and bone frailty are defining characteristics of OI. Homozygous oim/oim mice are utilized as models of severe progressive type III OI. Bone adapts to external forces by altering its mass and architecture. Previous attempts to leverage the relationship between muscle and bone involved using a soluble activin receptor type IIB-mFc (sActRIIB-mFc) fusion protein to lower circulating concentrations of activin A and myostatin. These two proteins are part of the TGF-β superfamily that regulate muscle and bone function. While this approach resulted in increased muscle masses and enhanced bone properties, adverse effects emerged due to ligand promiscuity, limiting clinical efficacy and obscuring the precise contributions of myostatin and activin A. In this study, we investigated the musculoskeletal and whole-body metabolism effect of treating 5-week-old wildtype (Wt) and oim/oim mice for 11 weeks with either control antibody (Ctrl-Ab) or monoclonal anti-activin A antibody (ActA-Ab), anti-myostatin antibody (Mstn-Ab), or a combination of ActA-Ab and Mstn-Ab (Combo). We demonstrated that ActA-Ab treatment minimally impacts muscle mass in oim/oim mice, whereas Mstn-Ab and Combo treatments substantially increased muscle mass and overall lean mass regardless of genotype and sex. Further, while no improvements in cortical bone microarchitecture were observed with all treatments, minimal improvements in trabecular bone microarchitecture were observed with the Combo treatment in oim/oim mice. Our findings suggest that individual or combinatorial inhibition of myostatin and activin A alone is insufficient to robustly improve femoral biomechanical and microarchitectural properties in severely affected OI mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Clinical Characteristics and Treatment Outcomes of Children with Primary Osteoporosis.

Primary osteoporosis is a rare and essential problem in childhood that can cause severe skeletal deformities. We aimed to reveal the spectrum of primary osteoporosis and assess the effectiveness and safety of bisphosphonates in increasing bone mineral density and reducing fractures. Patients with primary osteoporosis who received at least one course of pamidronate or zoledronic acid were included in the study. Patients were divided into 2 groups, osteogenesis imperfecta and non-osteogenesis imperfecta subjects. We evaluated bone densitometer parameters, activation scores, pain status, deformity status, and the number of fractures per year in all patients. Of the 31 patients, 21 with osteogenesis imperfect, 3 patients with spondyloocular syndromes, 2 with Bruck Syndrome, and 5 with idiopathic juvenile osteoporosis were included. A total of 21 patients had received pamidronate treatment, while only 4 received zoledronic acid, and 6 of them switched from pamidronate to zoledronic acid. At the end of the treatment, the mean bone mineral density height-adjusted Z-score increased from -3.39 ± 1.30 to -0.95 ± 1.34. The number of fractures per year decreased from 2.28 ± 2.67 to 0.29 ± 0.69. The activation score increased from 2.81 ± 1.47 to 3.16 ± 1.48. The pain decreased significantly. There was no difference in bone mineral density increase in patients treated with pamidronate or zoledronic acid. Those with osteogenesis imperfecta were diagnosed at an earlier age with severe deformity and fractures. Pamidronate and zoledronic acid increased bone mineral density in all types of primary osteoporosis.

Abstract #1412436: Nonclassical Presentation of Hypophosphatasia

Hypophosphatasia (HPP) is a rare genetic disorder characterized by impaired mineralization (calcification of bones and teeth). The signs and symptoms of HPP vary widely and can appear from birth to adulthood. We report a case of delayed bone fracture healing in the setting of hypophosphatasia. A 48-year-old male patient with a past medical history of vitamin D deficiency was seen in the outpatient clinic for low ALP levels. He had delayed wound healing involving the left clavicular and multiple rib fractures after a motor vehicle accident that occurred in 2012, which ultimately needed multiple surgeries requiring 1.5 years to fully heal/fuse. This involved placing and removing multiple plates and screws as well as bone grafts. He denied other fractures, skeletal deformities, or dental problems. He does have normal development and does not have short stature. He has a history of vitamin D deficiency and is on vitamin D 2000 units daily. He was found to have a family history remarkable with two sons with low ALP and vitamin D beginning in childhood. The older son was noted to have lost his teeth early at age 3-4 years, with no history of fractures. Musculoskeletal examination: no swelling noted, and no tenderness was noted but the patient did have a bone spur on the elbow, knee, and heel. He is able to ambulate without assistance and was found to have no other skeletal deformity. Laboratory findings: ALP 31 U/L (Normal 34-122). Bone-specific alkaline phosphatase: 5.6 ug/L (Normal 6.5-20.1). Vitamin D 25 OH level: 84 (on replacement therapy). Calcium: 9.2 mg/dl, phosphorus 3.5 mg/dl, iPTH levels 23 pg/ml. DXA scan: shows T values on the lumbar spine of -1.8, right hip of -1.4, and right neck of -1.9, consistent with osteopenia. We checked vitamin B6 level: 1087.7 nmol/L, consistent with hypophosphatasia. The patient then underwent genetic testing and is positive for ALPL gene mutation (heterozygous). Both his 2 sons are positive for ALPL gene mutation. We present a case of hypophosphatasia with nonclassical presentations, his mild symptoms likely from incomplete penetration. HPP causes pathogenic variants in ALPL gene. This gene provides instruction for making an enzyme called tissue non-specific alkaline phosphatase (TNSALP) which plays an essential role in the mineralization of the skeleton and teeth. Mutation in the ALP gene leads to the production of an abnormal version of TNSALP that cannot participate effectively in the mineralization process. There is currently no cure for hypophosphatasia, however human recombinant enzyme replacement therapy called asfotase alfa is now available.