Epiphyseal Abnormalities Research Articles

A Collagen10a1 mutation disrupts cell polarity in a medaka model for metaphyseal chondrodysplasia type Schmid

Heterozygous mutations in COL10A1 lead to metaphyseal chondrodysplasia type Schmid (MCDS), a skeletal disorder characterized by epiphyseal abnormalities. Prior analysis revealed impaired trimerization and intracellular retention of mutant collagen type X alpha 1 chains as cause for elevated endoplasmic reticulum (ER) stress. However, how ER stress translates into structural defects remained unclear. We generated a medaka (Oryzias latipes) MCDS model harboring a 5 base pair deletion in col10a1, which led to a frameshift and disruption of 11 amino acids in the conserved trimerization domain. col10a1Δ633a heterozygotes recapitulated key features of MCDS and revealed early cell polarity defects as cause for dysregulated matrix secretion and deformed skeletal structures. Carbamazepine, an ER stress-reducing drug, rescued this polarity impairment and alleviated skeletal defects in col10a1Δ633a heterozygotes. Our data imply cell polarity dysregulation as a potential contributor to MCDS and suggest the col10a1Δ633a medaka mutant as an attractive MCDS animal model for drug screening.

Spondylo-meta-epiphyseal dysplasia (SMED), short limb-hand abnormal calcification type: Further expanding the mutational spectrum and dental findings of three new patients

Genetic skeletal disorders are clinically and genetically heterogeneous group of disorders that affect the normal development, growth, and maintenance of the human skeleton. Spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type (SMED-SL/AC; MIM# 271665) is a rare autosomal recessive genetic skeletal disorder characterized by distinctive facial features, disproportionate short stature, vertebral, metaphyseal, and epiphyseal abnormalities. This unique phenotype is caused by biallelic loss-of-function variants in Discoidin domain receptor 2 gene (DDR2, MIM# 191311). To date, only 10 pathogenic variants (six missense, two nonsense, one deletion, and one splice site) in DDR2 have been reported in patients with SMED-SL/AC. Dental anomalies related to skeletal dysplasia can include various abnormalities in the number, shape, and position of teeth in the jaw, as well as enamel hypoplasia and dentinogenesis imperfecta. Although abnormal dentition has previously been reported, orodental findings were described in only six patients with SMED-SL/AC. This study aimed to define the clinical, dental, radiological, and molecular findings of three new SMED-SL/AC patients from three unrelated families. Three DDR2 variants, two of which were novel, were detected with the aid of Sanger sequencing. Interestingly, one of the patients was diagnosed with Wilson's disease (WD) during the follow-up, a co-occurrence that has never been reported in patients with SMED-SL/AC so far.

Novel COL2A1 variants in Japanese patients with spondyloepiphyseal dysplasia congenita

Spondyloepiphyseal dysplasia congenita (SEDC) is a multisystemic skeletal disorder caused by pathogenic variants in COL2A1. Here, we report the genotype-phenotype correlations in five Japanese patients with SEDC based on their clinical and radiological findings. All five patients had novel missense variants resulting in glycine substitutions (G474V, G543E, G567S, G594R, and G1170R). Genetic testing is important for early intervention for the extraskeletal complications of SEDC. Spondyloepiphyseal dysplasia congenita (SEDC) (OMIM#183900) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses, flattened vertebral bodies (skeletal abnormalities), and extraskeletal features, including myopia, retinal degeneration with retinal detachment, and cleft palate. SEDC is caused by a heterozygous variant in the collagen II alpha 1 (COL2A1) gene.

Discovery of sensorineural hearing loss and ossicle deformity in a Chinese Li nationality family with spondyloepiphyseal dysplasia congenita caused by p.G504S mutation of COL2A1

BackgroundSpondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses, and flattened vertebral bodies. COL2A1 has been confirmed as the pathogenic gene. Hearing loss represents an infrequent manifestation for 25–30% of patients with SEDC. The characteristics of the hearing impairment were rarely documented.MethodsAudiological, ophthalmic, imaging examinations were conducted on the family members. The whole exome sequencing (WES) was performed to detect the candidate gene, and the Sanger sequencing was used to confirm the causative variation.ResultsCOL2A1 c.1510G>A (p.G504S), a hot spot variation, was identified as the disease-causing mutation of the Chinese Li nationality family with SEDC. This variation was co-segregated with the SEDC phenotype in the family and was absent in the 1000 Genomes Project, ESP and ExAC. Clinically, several manifestations were first demonstrated in SEDC patients caused by p.G504S, including sensorineural hearing loss, auditory ossicles deformity, retinal detachment, sacrum cracked and elbow and wrist joints deformity. Other classical SEDC manifestations such as bones and joints pain, midfacial dysplasia, disproportionate short stature, spinal deformity, thoracocyllosis, coxa arthropathy, myopia and waddling gait were also showed in the family patients.ConclusionWe first identified the mutation p.G504S in COL2A1 gene as the pathogenesis in a Chinese Li nationality family and reported the correlation between p.G504S and atypical clinical phenotypes including sensorineural hearing loss, auditory ossicles deformity, retinal detachment, sacrum cracked and elbow and wrist joints deformity. Our findings would extend the phenotypic spectrum of SEDC and deepen clinicians' understanding of genotype–phenotype correlation of the disease.

A novel p.A191D matrilin-3 variant in a Vietnamese family with multiple epiphyseal dysplasia: a case report

BackgroundMultiple epiphyseal dysplasia (MED) is a common skeletal dysplasia that is characterized by variable degrees of epiphyseal abnormality primarily involving the hip and knee joints. Mutations in a gene encoding matrilin-3 (MATN3) have been reported as disease causing of autosomal dominant MED. The current study identified a novel c.572 C > A variant (p.A191D) in exon 2 of MATN3 in a Vietnamese family with MED.Case presentationA standard clinical tests and radiological examination were performed in an 8-year-old Vietnamese girl patient. The clinical examination showed that patient height was under average, with bent lower limbs, limited mobility and dislocation of the joints at both knees. Radiological documentation revealed abnormal cartilage development at the epiphysis of the femur and patella. The patient has a varus deformity of the lower limbs. The patient was diagnosed with autosomal dominant MED using molecular testing in the order of the coding sequences and flanking sequences of five genes: COMP (exons 8–19), MATN3 (exon 2), COL9A2 (exon 3), COL9A3 (exon 3), COL9A1 (exon 8) by Sanger sequencing. A novel heterozygous missense variant (c.572 C > A, p.A191D) in MATN3 was identified in this family, which were not inherited from parents. The p.A191D was predicted and classified as a pathogenic variant. When the two predicted structures of the wild type and mutant matrilin-3 were compared, the p.A191D substitution caused conformational changes near the substitution site, resulting in deformity of the β-sheet of the single A domain of matrilin- 3.ConclusionsThis is the first Vietnamese MED family attributed to p.A191D matrilin-3 variant, and our clinical, radiological and molecular data suggest that the novel de novo missense variant in MATN3 contributed to MED.

Analysis of Causes for Congenital Ulnar Deviated Thumbs at the Distal Phalanx Level in 157 Thumbs

To investigate anatomic abnormalities causing a congenital ulnarly deviated thumb at the distal phalanx. A total of 122 children with 157 congenital ulnarly deviated thumbs at the distal phalanges were reviewed, including those with isolated deformity or polydactyly. We analyzed the incidence and characteristics of the underlying anatomic abnormalities as well as the differential diagnoses. Three main causes of an ulnarly deviated thumb were observed. Abnormal hypertrophic epiphyses were found in 96 thumbs. An extra phalanx lying between the normal proximal and distal phalanges was found in 59 thumbs. A previously undescribed cause was found in 2 thumbs with Wassell IV polydactyly, in which an obliquely angled articular surface of the proximal phalanx manifested with ulnar deviation at the interphalangeal joint. Radiographic analysis showed that in cases with abnormal epiphyses, the epiphysis was in good apposition and good alignment with its relevant distal phalanx; the distance from the abnormal epiphysis to the phalanx was usually less than 1 mm. In contrast, in cases of extra phalanges, the distance from the epiphysis to the phalanx averaged more than 2 mm and there was poor apposition between the distal phalanx and the extra bone. Abnormal hypertrophic epiphysis and triphalangeal thumb are the 2 main causes of a congenital ulnarly deviated thumb. A distance of more than 2 mm between the abnormal bone and the distal phalanx suggests a triphalangeal thumb. Therapeutic IV.

Dysplasies spondylo-épiphysaires

Spondyloepiphyseal dysplasias is a term used to designate more than 20 genetic disorders of the skeleton, all defined by the combination of vertebral and epiphyseal abnormalities. They represent a hererogenous group of disorders with distinct modes of inheritance, presenting symptoms and radiological abnormalities. In most cases, the diagnosis is made in childhood but in some moderate presentations the diagnosis may be missed in childhood and is sometimes only suspected in teenage or adult patients, or in parents of a newly diagnosed child. In an adult, a genetic disorder can be suspected in front of the following symptoms: severe or extensive osteoarthritis in a young patient, combined with inconstant short stature or extraskeletal features such as facial dysmorphism, deafness, ocular involvement, and/or a familial history of similar symptoms. In these cases, advice from a Competence or Reference Center for Rare Skeletal Dysplasias can be useful to recommend genetic tests and therapeutic management. This article describes the main causes of spondyloepiphyseal dysplasia.

Skeletal impairment in Pierson syndrome: Is there a role for lamininβ2 in bone physiology?

IntroductionPierson syndrome is caused by a mutation of LAMB2, encoding for laminin β2. Clinical phenotype is variable but usually associates congenital nephrotic syndrome (CNS) and ocular abnormalities. Neuromuscular impairment has also been described. MethodsWe report on a 15-year old girl, suffering from Pierson Syndrome, who developed severe bone deformations during puberty.This patient initially displayed CNS and microcoria, leading to the clinical diagnosis of Pierson syndrome. Genetic analysis revealed a truncating mutation and a splice site mutation of LAMB2. The patient received a renal transplantation (R-Tx) at the age of 3. After R-Tx, renal evolution was simple, the patient receiving low-dose corticosteroids, tacrolimus and mycophenolate mofetil. At the age of 12, bone deformations progressively appeared. At the time of bone impairment, renal function was subnormal (glomerular filtration rate using iohexol clearance 50mL/min per 1.73m2), and parameters of calcium/phosphate metabolism were normal (calcium 2.45mmol/L, phosphorus 1.30mmol/L, PTH 81ng/L, ALP 334U/L, 25OH-D 73nmol/L). Radiographs showed major deformations such as scoliosis, genu varum and diffuse epiphyseal abnormalities. A high resolution scanner (HR-pQCT) was performed, demonstrating a bone of “normal low” quantity and quality; major radial and cubital deformations were observed. Stainings of laminin β2 were performed on bone and renal samples from the patient and healthy controls: as expected, laminin β2 was expressed in the control kidney but not in the patient's renal tissue, and a similar pattern was observed in bone. ConclusionThis is the first case of skeletal impairment ever described in Pierson syndrome. Integrin α3β1, receptor for laminin β2, are found in podocytes and osteoblasts, and the observation of both the presence of laminin β2 staining in healthy bone and its absence in the patient's bone raises the question of a potential role of laminin β2 in bone physiology.

Characterization of Normal Murine Carpal Bone Development Prompts Re-Evaluation of Pathologic Osteolysis as the Cause of Human Carpal-Tarsal Osteolysis Disorders

Multicentric carpal-tarsal osteolysis; multicentric osteolysis, nodulosis, and arthropathy; and Winchester syndromes, skeletal dysplasias characterized by carpal/tarsal and epiphyseal abnormalities, are caused by mutations in v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B (MAFB), matrix metalloproteinase (MMP) 2, and MMP14, respectively; however, the underlying pathophysiology is unclear. Osteoclast-mediated osteolysis has been regarded as the main mechanism, but does not explain the skeletal distribution. We hypothesized that MAFB, MMP-2, and MMP-14 have integral roles in carpal/tarsal and epiphyseal bone development. Normal neonatal mouse forepaws were imaged by micro-computed tomography and examined histologically. Murine forepaw ossification occurred sequentially. Subarticular regions of endochondral ossification showed morphologic and calcification patterns that were distinct from archetypical physeal endochondral ossification. This suggests that two different forms of endochondral ossification occur. The skeletal sites showing the greatest abnormality in the carpal-tarsal osteolysis syndromes are regions of subarticular ossification. Thus, abnormal bone formation in areas of subarticular ossification may explain the site-specific distribution of the carpal-tarsal osteolysis phenotype. MafB, Mmp-2, and Mmp-14 were expressed widely, and tartrate-resistant acid phosphatase staining notably was absent in the subarticular regions of the cartilage anlagen and entheses at a time point most relevant to the human osteolysis syndromes. Thus, abnormal peri-articular skeletal development and modeling, rather than excessive bone resorption, may be the underlying pathophysiology of these skeletal syndromes.

A long term follow-up study of the development of hip disease in Mucopolysaccharidosis type VI.

Hip problems in Mucopolysaccharidosis type VI (MPS VI) lead to severe disability. Lack of data on the course of hip disease in MPS VI make decisions regarding necessity, timing and type of surgical intervention difficult. We therefore studied the development of hip pathology in MPS VI patients over time. Data were collected as part of a prospective follow-up study. Standardized supine AP pelvis and frog leg lateral radiographs of both hips were performed yearly or every 2years. Image assessment was performed quantitatively (angle measurements) and qualitatively (hip morphology). Clinical burden of hip disease was evaluated by physical examination, six minute walking test (6MWT) and a questionnaire assessing pain, wheelchair-dependency and walking distance. A total of 157 pelvic radiographs of 14 ERT treated MPS VI patients were evaluated. Age at first image ranged from 2.0 to 21.1years. Median follow up duration was 6.8years. In all patients, even in the youngest, the acetabulum and os ilium were dysplastic. Coverage of the femoral head by the acetabulum improved over time, but remained insufficient. While the femoral head appeared normal in the radiographs at young age, the ossification pattern became abnormal in all patients over time. In all patients the distance covered in the 6MWT was reduced (median Z scores -3.3). Twelve patients had a waddling gait. Four patients were partially wheelchair-dependent and ten patients had limitations in their maximum walking distance. In conclusion, clinically significant hip abnormalities develop in all MPS VI patients from very early in life, starting with deformities of the os ilium and acetabulum. Femoral head abnormalities occur later, most likely due to altered mechanical forces in combination with epiphyseal abnormalities due to glycosaminoglycan storage. The final shape and angle of the femoral head differs significantly between individual MPS VI patients and is difficult to predict.

Rickets, BeriBeri, and Iron Deficiency: micronutrient deficiencies in children

Some “forgotten” micronutrient deficiencies continue to be common in children. Deficiencies of vitamin D and/or calcium can cause rickets, a crippling condition related to poor mineralization of growing bones. Rickets is diagnosed by identifying skeletal deformities, elevation of alkaline phosphatase levels, and abnormal epiphyses on x-ray. Treatment is with vitamin D and calcium. Prevention hinges on improving the daily intake of calcium, regular sun exposure, or dietary supplementation. Beriberi is due to thiamine deficiency. Infants with beriberi present in heart failure while older children present with neurological abnormalities. Treatment is with thiamine, and prevention requires alterations to improve dietary thiamine intake – by supplementing mothers of breastfed babies, increasing legume and unpolished rice intake, and diversifying diets. Iron deficiency continues to be a problem for nearly half of the world’s children. Bhutan has made strides to eliminate this problem through active de-worming programs and iron supplementation programs.

Classification and surgical treatment of the angled thumb

In type 1 separate ossicle, variable surgical procedures for the delta phalanx can be applied, however, excision and tightening of collateral ligament is recommended in most cases. In type 2 and 3 abnormal ossification centers, the treatment can depend on the age of the patient. If the angular deformity is seen before the age of one year and the abnormal ossification center is not clearly visible, close observation and periodic follow-up is reasonable. When the abnormal epiphysis is confirmed on radiography, usually between the age of 1 and 2 years, either partial excision of the epiphysis or intra-epiphyseal osteotomy can be done. When the patient is seen late and the remodeling of the joint is not likely to occur, intraepiphyseal osteotomy is recommended with careful attention to the physis and articular cartilage, because it addresses the anatomic deformity and produce better correction regardless of the IP position.

Correction of Lower Extremity Angular Deformities in Skeletal Dysplasia With Hemiepiphysiodesis

Lower extremity angular deformities are common in children with skeletal dysplasia and can be treated with various surgical options. Both acute correction by osteotomy with internal fixation and gradual correction by external fixation have been used with acceptable results. Recently, the Guided Growth concept using temporary hemiepiphysiodesis for correction of angular deformities in the growing child has been proposed. This study presents the results of temporary hemiepiphysiodesis using eight-Plates and medial malleolus transphyseal screws in children with skeletal dysplasia with lower extremity angular deformities. Twenty-nine patients (50 lower extremities) with skeletal dysplasia of different types were treated for varus or valgus deformities at 2 centers. The mean age at the time of hemiepiphysiodesis was 10±2.9 years. A total of 66 eight-Plates and 12 medial malleolus screws were used. The average follow-up time between the index surgery and the latest follow-up with the eight-Plate in was 25±13.4 months. Erect long-standing anteroposterior and lateral view radiographs were obtained for deformity planning before the procedure. Angular deformities on radiograph were evaluated by mechanical axis deviation, mechanical lateral distal femoral angle, medial proximal tibial angle, and lateral distal tibial angle. Mechanical axis deviation was also expressed as a percentage to one half of the width of the tibial plateau, and the magnitude of the deformity was classified by determining the zones through which the mechanical axis of the lower extremity passed. Four zones were determined on both the medial and lateral side of the knee and the zones were labeled 1, 2, 3, and 4, corresponding to the severity of the deformity. A positive value was assigned for valgus alignment and a negative for varus alignment. Patients were analyzed in valgus and varus groups. There was correction in 34 of 38 valgus legs and 7 of 12 varus legs. In the valgus group, the mean preoperative and postoperative mechanical lateral distal femoral angles were 82.1±3.7 and 91.1±4.9 degrees, respectively (P<0.001). The mean preoperative and postoperative medial proximal tibial angles were 98.5±8 and 87.8±7.1 degrees, respectively (P<0.001). Six patients with bilateral ankle valgus deformities (12 ankles) underwent single-screw medial malleolus hemiepiphysiodesis. The mean preoperative and postoperative lateral distal tibial angles were 73.9±8.7 and 86.1±6.8 degrees, respectively (P<0.001). The numbers of plates in each anatomic location were not enough to make statistical conclusions in varus legs. Four patients in the valgus group and 3 patients in the varus group did not benefit from the procedure. Mechanical axes were in zone 2 or over in 94% of the legs preoperatively, whereas postoperatively, only 23% of the legs had mechanical axes in zone 2 or over in varus and valgus groups. Growth modulation with an eight-Plate is a relatively simple surgery and has low risk of mechanical failure or physeal damage. It can be performed in very young patients, which is an important advantage in skeletal dysplasia. Screw purchase is reliable even in the abnormal epiphysis and metaphysis. Our results show that Guided Growth using eight-Plates in skeletal dysplasia is safe and effective. Level IV.

The value of X-ray graphy in the diagnosis of the rhiozomelic chondrodysplasia punctata: a case report

Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by typical facial appearances, contracture, proximal shortening of the extremities, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities, clefts of the vertebral bodies and mental retardation. Diagnosis is usually made based on clinical and radiological criteria. Peroxisome functions, such as the red blood cell concentration of plasmalogenes and the plasma concentrations of phytanic acid and very long chain fatty acids are biochemical indicators of RCDP. In this article, we present a case of the rare disorder RCDP manifested as proximal limb shortening, punctuate calcifications of the cartilage, vertebral clefts, cataracts and hypotonia. In conclusion, case with dysmorphic facial appearances, proximal shortening of the extremities, and contractures should be considered RCDP. Furthermore, direct X-Ray findings can contribute to diagnosis.

Novel and recurrent COL2A1 mutations in Chinese patients with spondyloepiphyseal dysplasia

Spondyloepiphyseal dysplasia (SED) is an autosomal dominant skeletal dysplasia characterized by short stature, abnormal epiphyses and flattened vertebral bodies. SED is mainly caused by mutations in the gene encoding the type II procollagen α-1 chain (COL2A1). We looked for mutations in COL2A1 in three unrelated Chinese families with SED. Putative mutations were confirmed by RFLP analysis. We identified three missense mutations (p.G504S, p.G801S and p.G1176V) located in the triple-helical domain; p.G801S and p.G1176V are novel mutations. The p.G504S mutation has been associated with diverse phenotypes in previous studies. Our study extends the mutation spectrum of SED and confirms a relationship between mutations in the COL2A1 gene and clinical findings of SED.

Revisit of multiple epiphyseal dysplasia: Ethnic difference in genotypes and comparison of radiographic features linked to the COMP and MATN3 genes

Multiple epiphyseal dysplasia (MED) is a genetically heterogeneous group of diseases characterized by variable degrees of epiphyseal abnormality primarily involving the hip and knee joints. The purpose of this study was to investigate the frequency of mutations in individuals with a clinical and radiographic diagnosis of MED and to test the hypothesis that characteristic radiological findings may be helpful in predicting the gene responsible. The radiographs of 74 Korean patients were evaluated by a panel of skeletal dysplasia experts. Six genes known to be associated with MED (COMP, MATN3, COL9A1, COL9A2, COL9A3, and DTDST) were screened by sequencing. Mutations were found in 55 of the 63 patients (87%). MATN3 mutations were found in 30 patients (55%), followed by COMP mutations in 23 (41%), and COL9A2 and DTDST mutations in one patient (2%) each. Comparisons of radiographic findings in patients with COMP and MATN3 mutations showed that albeit marked abnormalities in hip and knee joints were observed in both groups, the degree of involvement and the morphology of dysplastic epiphyses differed markedly. The contour of the pelvic acetabulum, the presence of metaphyseal vertical striations, and/or the brachydactyly of the hand were also found to be highly correlated with the genotypes. The study confirms that MATN3 and COMP are the genes most frequently responsible for MED and that subtle radiographic signs may give precious indications on which gene(s) should be prioritized for mutational screening in a given individual.

Identification of three novel mutations in the COL2A1 gene in four unrelated Chinese families with spondyloepiphyseal dysplasia congenita

IntroductionSpondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant skeletal dysplasia characterized by short stature, abnormal epiphyses, and flattened vertebral bodies. The condition occurs through a mutation in the COL2A1 gene that encodes the type II procollagen alpha1 chain (proalpha1 (II)). Method and ResultsWe investigated nine affected individuals from four unrelated Chinese families with SEDC. We screened for COL2A1 gene mutations, and identified found four missense mutations (G447A, G456A, R789C and G1152D). The G447A, G456A and G1152D mutations are novel and the R789C mutation has been reported previously in several other studies with a strikingly similar phenotype. ConclusionsOur study extends the mutation spectrum of SEDC and is helpful in early molecular diagnoses of SEDC.

Molecular prenatal diagnosis in 2 pregnancies at risk for spondyloepiphyseal dysplasia congenita

BackgroundSpondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant skeletal dysplasia characterized by short stature, abnormal epiphyses, and flattened vertebral bodies. Secondary prevention of SEDC can be achieved by prenatal diagnosis. Reports of antenatally-diagnosed SEDC fetuses have been very rare and molecular prenatal diagnosis even rarer. We previously reported a familial G504S mutation in the type II collagen (COL2A1) gene resulting in SEDC. In this study, molecular prenatal diagnosis was performed to 2 couples in this family with pregnancies at risk for SEDC. MethodsAmniotic fluid was sampled by amniocentesis under ultrasound guidance at 19+3 and 18+6 weeks' gestation, respectively. Karyotype and molecular genetic analysis were performed on cultured amniotic fluid cells. Maternal cell contamination was excluded by short tandem repeat (STR) analysis. Direct DNA sequencing and DHPLC were conducted to detect the potential mutation in exon 23 of COL2A1 gene. Both women underwent serial sonograms because they insisted that the molecular diagnosis should be confirmed by another method, although they had been informed that mutation analysis is predictive of the disease. ResultsKaryotype of both fetuses was normal and molecular genetic analysis revealed that fetus 1 carried a G504S mutation in exon 23, while fetus 2 was normal. In case 1, femur length of the fetus was markedly below the 5th centile at 23 weeks' gestation, which confirms the accuracy of molecular diagnosis. A medical termination was carried out at 27+5 weeks' gestation and a male fetus with a relatively large head and short limbs was delivered. The fetal radiograph demonstrated a number of features, including generalised platyspondyly, absent ossification of the vertebral bodies in the cervical region and significant shortening of the long bones. The diagnosis of SEDC was thus confirmed clinically. Ultrasound monitoring of fetus 2 showed that its femur length was normal for gestational age at repeated scans, which was consistent with the molecular diagnosis. ConclusionsMolecular analysis allows early and accurate prenatal diagnosis for SEDC once mutation is known in a family. However, considering the poor genotype/phenotype correlation in many cases of SEDC, the combination of ultrasound as well as molecular genetic approach might be needed.

Treatment of First Metatarsal Longitudinal Epiphyseal Bracket by Excision Before Closure

The longitudinal metatarsal epiphyseal bracket is a rare ossification abnormality of tubular bones in which an abnormal epiphysis brackets the diaphysis of a phalanx, metacarpal, or metatarsal. This leads to progressive shortening and angular deformity of the involved bone. When it affects the first metatarsal, the longitudinal metatarsal epiphyseal bracket leads to a short, trapezoidal metatarsal. We present the case of a 6-year-old patient with an ossified longitudinal epiphyseal bracket along the medial side of the first metatarsal. The abnormality was surgically treated by bracket excision before physeal closure. At 6 years' follow-up, the patient displayed a normally aligned hallux of appropriate size in proportion to the other toes. Surgical correction resulted in alteration of the first metatarsophalangeal angle, which went from a preoperative value of 13 degrees of hallux varus to a postoperative value of 9 degrees of hallux valgus; the first metatarsal intraosseous angulation went from a preoperative value of 30 degrees to a postoperative value of 5 degrees , and the metadiaphyseal length index went from a preoperative value of 0.39 to a postoperative value of 0.92. This case study demonstrates that early resection of an ossified abnormal bracket before physeal closure, a relatively simple procedure, can restore longitudinal growth and correct angular deformity.

The Radiographic Morphology of Foot Deformities in Patients with Fibrodysplasia Ossificans Progressiva

The most consistent deformities that allow early diagnosis of fibrodysplasia ossificans progressiva are the presence of bilateral short first rays and hallux valgus. The purpose of this study was to describe the radiographic features observed in the feet of patients with fibrodysplasia ossificans progressiva. The radiographs of 26 feet (15 patients with fibrodysplasia ossificans progressiva) were reviewed to evaluate the radiographic changes that occur in the first ray. Variables analyzed were the hallux valgus (HV) angle, the distal metatarsal articular (DMA) angle, the proximal phalangeal articular (PPA) angle, the intermetatarsal (IM) angle, ratio of the lengths of the first and second metatarsal lengths (MT1:MT2), and the first and second ray length ratio. The length ratios were then subtracted from similar ratios in radiographs of age- and gender-matched normal patients previously reported. The proximal phalanx was consistently shortened but morphologically dissimilar from subject to subject. Asymmetry was noted in some patients with bilateral radiographs. The mean HV angle was 28 degrees, and the mean IM angle was 10 degrees. The mean DMA angle was 33 degrees, and the mean PPA angle was 14 degrees. The MT1:MT2 ratio was 0.89, and the mean first ray to second ray length ratio was 0.87. The mean of the differences in the MT1:MT2 and first and second ray length ratios in patients with fibrodysplasia ossificans progressiva compared to the normal controls were 0.05 and 0.01, respectively. Fusion occurred between the abnormal tibial epiphysis of the proximal phalanx and metatarsal head with advancing age, and 68% of the metatarsal heads were fused with the abnormal proximal phalangeal epiphysis. Foot pathology in patients with fibrodysplasia ossificans progressiva is variable but consistently involves an abnormality of the tibial aspect of the proximal phalangeal epiphysis of the hallux. This results in the clinical observation of hallux valgus in these patients. The first metatarsal is consistently shortened, and fusion between the epiphysis of the abnormal proximal phalanx and the shortened first metatarsal head occurs with advancing age.