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Scientific Reports Oct 2018Mutations in the progressive ankylosis protein (NP_473368, human ANKH) cause craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial...
Mutations in the progressive ankylosis protein (NP_473368, human ANKH) cause craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and widened metaphyses in long bones. The pathogenesis of CMD remains largely unknown, and treatment for CMD is limited to surgical intervention. We have reported that knock-in mice (Ank) carrying a F377del mutation in ANK (NM_020332, mouse ANK) replicate many features of CMD. Interestingly, ablation of the Ank gene in Ank mice also leads to several CMD-like phenotypes. Mutations causing CMD led to decreased steady-state levels of ANK/ANKH protein due to rapid degradation. While wild type (wt) ANK was mostly associated with plasma membranes, endoplasmic reticulum (ER), Golgi apparatus and lysosomes, CMD-linked mutant ANK was aberrantly localized in cytoplasm. Inhibitors of proteasomal degradation significantly restored levels of overexpressed mutant ANK, whereas endogenous CMD-mutant ANK/ANKH levels were more strongly increased by inhibitors of lysosomal degradation. However, these inhibitors do not correct the mislocalization of mutant ANK. Co-expressing wt and CMD-mutant ANK in cells showed that CMD-mutant ANK does not negatively affect wt ANK expression and localization, and vice versa. In conclusion, our finding that CMD mutant ANK/ANKH protein is short-lived and mislocalized in cells may be part of the CMD pathogenesis.
Topics: Animals; Bone Diseases, Developmental; Cells, Cultured; Craniofacial Abnormalities; Humans; Hyperostosis; Hypertelorism; Mice; Mutation; Phosphate Transport Proteins; Proteasome Endopeptidase Complex; Protein Stability; Rats; Saccharomyces cerevisiae; Ubiquitination
PubMed: 30356088
DOI: 10.1038/s41598-018-34157-5 -
Medicine Aug 2018X-linked dominant hypophosphatemia rickets (XLH, OMIM 307800) is the most common hereditary hypophosphatemic rickets and characterized by growth retardation, skeletal...
RATIONALE
X-linked dominant hypophosphatemia rickets (XLH, OMIM 307800) is the most common hereditary hypophosphatemic rickets and characterized by growth retardation, skeletal malformations, dental dysplasia, spontaneous fractures and osteomalacia. PHEX gene was identified for XLH and novel mutations were consistent with loss of function.
PATIENT CONCERNS
Case1: the proband 1 III3 in family 1 was a fourteen-year-old boy with bowing of bilateral legs, obviously enlarged joints, tooth absence and difficulty in walking; X-rays showed bilateral femoral multiple fractures with sclerosis at the fracture edge. Case 2: the proband 2 III2, a five-year-old boy in family 2, showed growth retardation, dental dysplasia, gingiva abscess and bilateral legs malformations; X-rays showed low bone density, delayed bone age, bowing of legs, frayed and widened metaphyses of the distal femurs and proximal tibias. Both of their mothers suffered from skeletal malformations, tooth absence and were performed with osteotomy due to fractures of lower limb. Their biochemical parameters showed hypophosphatemia, elevated alkaline phosphatase.
DIAGNOSES
X-linked dominant hypophosphatemia rickets (XLH).
INTERVENTIONS AND OUTCOMES
Treatment with high doses of phosphate and 1,25-dihydroxyvitamin D3, the height of proband 2 increased 10 cm and femoral Multiple fracture of proband1 almost healed after treatment for 6 months and the patients's PHEX gene was investigated.
LESSONS
Two novel pathogenic PHEX mutations were found: c.497delG in family 1 and c.388G> T in family 2, both of which caused early termination of translation and produced truncated protein. Serum FGF23 concentration in our XLH patients were obviously higher than the normal and may be related to age to some extent. Early initiation of treatment produces better effect.
Topics: Adolescent; Adult; Child, Preschool; Familial Hypophosphatemic Rickets; Female; Fibroblast Growth Factor-23; Humans; Male; Mutation; PHEX Phosphate Regulating Neutral Endopeptidase; Pedigree
PubMed: 30075510
DOI: 10.1097/MD.0000000000011453 -
Orthopaedic Surgery Aug 2018There are several types of metaphyseal chondrodysplasia and various clinical types have been differentiated. The Schmid type of metaphyseal chondrodysplasia is the most...
OBJECTIVES
There are several types of metaphyseal chondrodysplasia and various clinical types have been differentiated. The Schmid type of metaphyseal chondrodysplasia is the most common. Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. The Schmid type of metaphyseal dysostosis is characterized by failure of normal mineralization of the zone of provisional calcification, leading to widened physes and enlarged knobby metaphyses, effectively causing shortening of the tubular bones, splaying of the metaphyses, coxa vara, and bow legs. Orthopaedic interventions were primarily performed on the lower extremities.
METHODS
Twelve children (seven girls and five boys) aged 7-10 years were enrolled in this study. Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities. A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara. Hemiepiphysiodesis was performed to re-align the genu varum in three children.
RESULTS
Other forms of metaphyseal dysostosis were ruled based on full clinical and radiographic phenotypes, with confirmation through molecular pathology. Mutations in the COL10A1 gene located on chromosome 6q21-q22.3 were confirmed. Re-alignment was accomplished in our group of patients.
CONCLUSION
The most striking clinical features of Schmid metaphyseal chondrodysplasia which appear within the first 2-3 years of life are: moderate short limbs and short stature, a waddling gait, and increasing shortness of stature with age. The Schmid type of metaphyseal chondrodysplasia is a disorder that arises from defective type X collagen, which is typically found in the hypertrophic zone of the physes. Moderate short stature and a waddling gait associated with pain are the most common clinical presentations. Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases.
Topics: Child; Child, Preschool; Collagen Type X; Female; Femur; Genu Varum; Humans; Male; Mutation; Osteochondrodysplasias; Osteotomy; Phenotype; Radiography
PubMed: 30027601
DOI: 10.1111/os.12382 -
Annali Di Stomatologia 2017Craniometaphyseal dysplasia is a rare hereditary bone disease presenting metaphyseal widening of the tubular bones, sclerosis of craniofacial bones and bony overgrowth...
INTRODUCTION
Craniometaphyseal dysplasia is a rare hereditary bone disease presenting metaphyseal widening of the tubular bones, sclerosis of craniofacial bones and bony overgrowth of the facial and skull bones. Craniometaphyseal dysplasia occurs in an autosomal dominant (AD) and an autosomal recessive (AR) form.
CASE REPORT
We present a 32-year-old patient arrived at our unit in May 2009. His main discomfort was a major limitation of the mouth opening, in the context of a craniofacial deformity. Relying on patient's medical history and the performed diagnostic tests, the diagnosis of craniometaphyseal dysplasia was made.
CONCLUSION
After careful evaluation of the clinical case, in accordance with the requirements of the patient, we opted for a surgical treatment aimed at correction of functional limitation of temporomandibular joint and aesthetic improvement of the facial bones. The stability of the clinical results led us to suggest and to undertake the surgical path, also due to the lack of safe and consolidated non-surgical treatments for the specific case.
PubMed: 29299192
DOI: 10.11138/ads/2017.8.2.045 -
Academic Forensic Pathology Jun 2017Rickets was a common metabolic disease of bone a century ago in Europe, North America, and East Asia (mainly due to vitamin D deficiency) but was largely eradicated in... (Review)
Review
Rickets was a common metabolic disease of bone a century ago in Europe, North America, and East Asia (mainly due to vitamin D deficiency) but was largely eradicated in growing children by use of cod liver oil and the introduction of vitamin D fortification of milk in the 1930s in the United States. Vitamin D deficiency (VDD) remains the most common form of metabolic bone disease that is entirely preventable and treatable. Historically, rickets has appeared in sporadic epidemics and, despite the introduction of numerous preventive strategies, VDD has remained a global health problem amongst children. Moreover, developed countries such as Canada, Australia, the United Kingdom, and the United States have not been exempt from this. The radiological and histological features of rickets are both distinctive and characteristic and they reflect the underlying pathophysiological issue of decreased mineralization of bone as a result of VDD. The radiological features include 1) metaphyseal cupping and fraying, 2) poor mineralization of epiphyseal centers, 3) irregular and widened epiphyseal plates, 4) increased distance between the end of shaft and epiphyseal center, 5) cortical spurs at right angles to the metaphysis, 6) coarse trabeculation, and 7) periosteal reactions. Fractures may also be evident. The histological features of rickets reflect the failure of cartilage to mineralize and undergo resorption. This results in 1) disordered proliferation of chondrocytes in the hypertrophic zone secondary to a lack of apoptosis, 2) loss of the columnar arrangement of chondrocytes that results in thickening and disorganization of the hypertrophic zone, 3) tongue-like projections of cartilage that extend into the spongiosa, 4) irregularity of the limit between the proliferative and hypertrophic zones, and 5) penetration of blood vessels into the hypertrophic zone. The case of a premature 3-month-old female infant, born in the winter months in the arctic region of Canada who died from a lobar pneumonia with an incidental finding of radiological and pathological evidence of rickets, is presented. The case is used to review the entity of rickets from historical, pathophysiological, radiological, and histological perspectives.
PubMed: 31239976
DOI: 10.23907/2017.024 -
Annals of Pediatric Endocrinology &... Sep 2016Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A) is an autosomal recessively-inherited disorder caused by mutations in encoding the 1α-hydroxylase enzyme. We...
Vitamin D hydroxylation-deficient rickets type 1A (VDDR1A) is an autosomal recessively-inherited disorder caused by mutations in encoding the 1α-hydroxylase enzyme. We report on a female patient with VDDR1A who presented with hypocalcemic seizure at the age of 13 months. The typical clinical and biochemical features of VDDR1A were found, such as hypocalcemia, increased alkaline phosphatase, secondary hyperparathyroidism and normal 25-hydroxyvitamin D3 (25(OH)D). Radiographic images of the wrist showed metaphyseal widening with cupping and fraying of the ulna and distal radius, suggesting rickets. A mutation analysis of the gene identified a homozygous mutation of c.589+1G>A in the splice donor site in intron 3, which was known to be pathogenic. Since that time, the patient has been under calcitriol and calcium treatment, with normal growth and development. During the follow-up period, she did not develop genu valgum, scoliosis, or nephrocalcinosis.
PubMed: 27777911
DOI: 10.6065/apem.2016.21.3.169 -
Child's Nervous System : ChNS :... Jul 2016Metaphyseal dysplasia (Pyle disease) is a rare autosomal recessive disease with impressive and characteristic radiological findings but relatively mild clinical...
INTRODUCTION
Metaphyseal dysplasia (Pyle disease) is a rare autosomal recessive disease with impressive and characteristic radiological findings but relatively mild clinical features. It is usually incidentally diagnosed, despite the impressive radiological findings of gross metaphyseal widening and thinning of cortical bone.
CASE REPORT
Herein, we report an exceptionally unusual case of metaphyseal dysplasia in association with chronic facial nerve palsy.
DISCUSSION
Chronic facial nerve palsy due to compression of the facial nerve in a patient with Pyle disease represents an unusual novelty. Furthermore, this case delineates the clinical spectrum and phenotype of such a rare clinical entity. To the best of our knowledge, this is the first time that such an association is being described.
Topics: Bone Diseases, Developmental; Child; Chronic Disease; Facial Nerve; Facial Paralysis; Female; Humans; Osteochondrodysplasias
PubMed: 26847543
DOI: 10.1007/s00381-016-3021-6 -
Indian Journal of Orthopaedics 2015The anterior cruciate ligament (ACL) is one of the major stabilizing factor of the knee that resist anterior translation, valgus and varus forces. ACL is the most...
BACKGROUND
The anterior cruciate ligament (ACL) is one of the major stabilizing factor of the knee that resist anterior translation, valgus and varus forces. ACL is the most commonly ruptured ligament of the knee. The graft fixation to bone is considered to be the weakest link of the reconstruction. According to the parallel forces to the tibial drill hole and the quality of tibial metaphyseal bone is inferior to femoral bone stock, graft fixation to the tibia is more difficult to secure. AperFix system (Cayenne Medical, Inc., Scottsdale, Arizona, USA) which consists femoral and tibial component that includes bioinert polymer polyetheretherketone (PEEK) is one of the new choice for ACL reconstruction surgery. aim of this study was to assess the clinical outcomes and fixation durability of the AperFix (Cayenne Madical, Inc., Scottsdale, Arizona, USA) system and to determine the effect of patient's age in arthroscopic reconstruction of the anterior cruciate ligament.
MATERIALS AND METHODS
Patients with symptomatic anterior cruciate ligament rupture underwent arthroscopic reconstruction. Patients were evaluated in terms of range of motion (ROM) values; Lysholm, Cincinati and Tegner activity scales; laxity testing and complications. Femoral tunnel widening was assessed by computer tomography scans. Early postoperative and last followup radiographs were compared.
RESULTS
Fifty one patients were evaluated with mean followup of 29 months (range 25-34 months). Mean age at the surgery was 26.5 ± 7.2 years. Lysholm, Cincinati and Tegner activity scales were significantly higher from preoperative scores (Lysholm scores: Preoperative: 51.4 ± 17.2, postoperative: 88.6 ± 7.7 [P < 0.001]; Tegner activity scores: Preoperative 3.3 ± 1.38, postoperative: 5.3 ± 1.6 [P < 0.001]; Cincinati scores: Preoperative: 44.3 ± 17, postoperative: 81.3 ± 13.9 [P < 0.001]). The mean femoral tunnel diameter increased significantly from 9.94 ± 0.79 mm postoperatively to 10.79 ± 0.95 mm (P < 0.05). The mean ROM deficit (involved vs. contra knee) was -7.2 ± 16 (P < 0.001). There was no significant difference for knee score, ROM deficits (<30 years: -7.3 ± 15 and >30 years -7.06 ± 19) and femoral tunnel enlargement (<30 years: 0.83 ± 0.52 and >30 years 0.87 ± 0.43) of the patients with below and above 30 year. There was no significant difference for knee scores and femoral tunnel enlargement between patients with meniscal injuries and don't have meniscus lesions.
CONCLUSION
The AperFix system gives satisfactory clinical and radiological results with low complication rate. However, long term clinical and radiological results are needed to decide the ideal anterior cruciate ligament reconstruction method.
PubMed: 26015602
DOI: 10.4103/0019-5413.152436 -
American Journal of Medical Genetics.... Oct 2014Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structure that alters its interactions with collagens II and V, resulting in...
Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structure that alters its interactions with collagens II and V, resulting in abnormalities in cartilage and ocular vitreous. The most common type XI collagenopathies are dominantly inherited Stickler or Marshall syndromes, while severe recessive skeletal dysplasias, such as fibrochondrogenesis, occur less frequently. We describe a family with a severe skeletal dysplasia caused by a novel dominantly inherited COL11A1 mutation. The siblings each presented with severe myopia, hearing loss, micromelia, metaphyseal widening of the long bones, micrognathia, and airway compromise requiring tracheostomy. The first child lived for over 2 years, while the second succumbed at 5 months of age. Their mother has mild rhizomelic shortening of the limbs, brachydactyly, and severe myopia. Sequencing of COL11A1 revealed a novel deleterious heterozygous mutation in COL11A1 involving the triple helical domain in both siblings, and a mosaic mutation in their mother, indicating germline mosaicism with subsequent dominant inheritance. These are the first reported individuals with a dominantly inherited mutation in COL11A1 associated with a severe skeletal dysplasia. The skeletal involvement is similar to, yet milder than fibrochondrogenesis and allowed for survival beyond the perinatal period. These cases highlight both a novel dominant COL11A1 mutation causing a significant skeletal dysplasia and the phenotypic heterogeneity of collagenopathies.
Topics: Bone Diseases, Developmental; Collagen Type XI; Female; Hearing Loss; Humans; Musculoskeletal Abnormalities; Mutation; Myopia; Pedigree
PubMed: 25091507
DOI: 10.1002/ajmg.a.36688