Metaphyseal Changes Research Articles

Then and now: Past Opitz winners discuss the influence of the award on their careers

Then and now: Past Opitz winners discuss the influence of the award on their careers

TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families

BackgroundThe TRPV4 gene encodes a calcium-permeable ion-channel that is widely expressed, responds to many different stimuli and participates in an extraordinarily wide range of physiologic processes. Autosomal dominant brachyolmia, spondylometaphyseal dysplasia Kozlowski type (SMDK) and metatropic dysplasia (MD) are currently considered three distinct skeletal dysplasias with some shared clinical features, including short stature, platyspondyly, and progressive scoliosis. Recently, TRPV4 mutations have been found in patients diagnosed with these skeletal phenotypes.Methods and ResultsWe critically analysed the clinical and radiographic data on 26 subjects from 21 families, all of whom had a clinical diagnosis of one of the conditions described above: 15 with MD; 9 with SMDK; and 2 with brachyolmia. We sequenced TRPV4 and identified 9 different mutations in 22 patients, 4 previously described, and 5 novel. There were 4 mutation-negative cases: one with MD and one with SMDK, both displaying atypical clinical and radiographic features for these diagnoses; and two with brachyolmia, who had isolated spine changes and no metaphyseal involvement.ConclusionsOur data suggest the TRPV4 skeletal dysplasias represent a continuum of severity with areas of phenotypic overlap, even within the same family. We propose that AD brachyolmia lies at the mildest end of this spectrum and, since all cases described with this diagnosis and TRPV4 mutations display metaphyseal changes, we suggest that it is not a distinct entity but represents the mildest phenotypic expression of SMDK.

Early congenital syphilis in a premature baby

In the UK, diagnosis of syphilis among women of child-bearing age has more than doubled between 1999 and 2007, and each year, around ten cases of congenital syphilis have been reported. Doctors should, therefore, be aware of the potential presentation of congenital syphilis, a deadly disease yet curable when managed correctly. We present a rare case of a premature neonate of 29 weeks displaying manifold clinical signs of congenital syphilis acutely after delivery, including coagulopathy, hepatosplenomegaly, intraventricular ischaemic lesions and metaphyseal bone changes, not previously described in the literature at this age in the UK.

Skeletal imaging effects of pamidronate therapy in osteosarcoma patients

After observing metaphyseal changes in pediatric and young adult patients with osteosarcoma who were treated with pamidronate, we initiated a retrospective study to identify bone findings on computed radiography of the chest and extremities, chest CT, extremity MRI, and radionuclide bone scans in this population. To review the generalized skeletal imaging findings on computed radiography, CT, and MR examinations in patients with osteosarcoma (OS) receiving pamidronate. A retrospective review of 40 patients with newly diagnosed OS (mean age, 16.5 years) receiving pamidronate with chemotherapy were identified at one institution. Computed radiography, CT, MR, and bone scans on 36 patients were reviewed for osseous changes. Dense metaphyseal bands at the growth plates in long bones, epiphyseal ossification centers, anterior rib ends, sternum and spine were observed. Osseous changes occurred on CT in 69% of patients, and on computed chest radiography in 53%. Bone-within-bone appearance in the spine and ossification centers was identified on computed radiography in 36%. OS patients treated with pamidronate can develop metaphyseal sclerotic bands as well as epiphyseal and vertebral endplate sclerosis progressing to a bone-within-bone appearance. Findings occur more frequently in younger patients with open epiphyses.

Case Report A novel COMP mutation in an Inuit patient with pseudoachondroplasia and severe short stature

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia, generally identified clinically at two years of age due to decreased linear growth and a waddling gait. Radiographic features include small and irregular epiphyses, with metaphyseal changes of the long bones and characteristic vertebral changes. Mutations in the COMP gene cause PSACH and some cases of multiple epiphyseal dysplasia. Mutations generally cluster in the calmodulin-like repeat regions of the gene. Mutations in exon 13 (encoding the seventh calmodulin-like repeat) have been associated with severe short stature (-6 SD) in PSACH. We examined an Inuit boy with PSACH and severe short stature. Height essentially remained at -1 SD on the PSACH growth curve (-7.5 SD on a normal growth curve at 10.5 years). Analysis of COMP in our patient revealed a previously undescribed heterozygous A>T substitution in exon 8, at nucleotide 812. This change in the sequence resulted in replacement of a highly conserved and negatively charged aspartic acid with an uncharged, hydrophobic valine at amino acid position 271. Both unaffected parents were negative for this genetic change. This exon encodes the first calmodulin-like repeat, which has not been previously implicated in severe short stature. We propose that this novel missense substitution is responsible for the phenotype of this patient.

Chronic Recurrent Multifocal Osteomyelitis Mimicked in Childhood Hypophosphatasia

Hypophosphatasia (HPP) is the inborn error of metabolism characterized by low serum alkaline phosphatase (ALP) activity caused by inactivating mutations within TNSALP, the gene that encodes the "tissue-nonspecific" isoenzyme of ALP (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate, a TNSALP substrate, inhibits hydroxyapatite crystal growth leading to rickets or osteomalacia. Chronic recurrent multifocal osteomyelitis (CRMO) is the pediatric syndrome of periarticular pain and radiographic changes resembling infectious osteomyelitis but without lesional pathogens. Some consider CRMO to be an autoinflammatory disease. An unrelated boy and girl with the childhood form of HPP suffered chronic, multifocal, periarticular pain, and soft tissue swelling. To investigate this unusual complication, we evaluated their cumulative clinical, biochemical, radiological, and histopathological findings and performed mutation analysis of their TNSALP alleles. The earliest radiographic disturbances were typical of childhood HPP. Subsequently, changes consistent with CRMO developed at sites where there was pain, including lucencies, osteosclerosis, and marked expansion of the underlying metaphyses. Bone marrow edema was shown by MRI. Biopsies of affected bone showed nonspecific histopathological findings and no pathogens. The boy was heterozygous (c.1133A>T, p.D378V) and the girl compound heterozygous (c.350A>G, p.Y117C, c.400_401AC>CA, p.T134H) for different TNSALP missense mutations. Nonsteroidal anti-inflammatory drugs diminished their pain, which improved or resolved at maturity. HPP should be considered when CRMO is a diagnostic possibility. Metaphyseal radiographic changes and marrow edema associated with periarticular bone pain and soft tissue swelling suggestive of osteomyelitis can complicate childhood HPP.

Copper histidine therapy started in a boy at the age of three years – Treatment option for a mild form of Menkes's disease

Aims: Menkes's disease is a rare X-chromosomal-linked disorder of copper metabolism caused by mutations in the ATPA7 gene. Copper deficiency and defective intestinal absorption lead to reduced levels in serum, brain and liver tissue. Main clinical features of Menkes's disease are neurological symptoms in combination with pili torti, metaphyseal changes and alterations of connective tissue. A spectrum of a severe neonatal form to a mild variant and occipital Horn disease are described. A causal therapy does not exist. Therefore a symptomatic multimodal individual therapy is required. Copper histidine therapy has been known since the 1970s. Controversial neurological effects have been reported.

Achondroplasia manifesting as enchondromatosis and ossification of the spinal ligaments: a case report

IntroductionA girl presented with achondroplasia manifested as mild knee pain associated with stiffness of her back. A skeletal survey showed enchondroma-like metaphyseal dysplasia and ossification of the spinal ligaments. Magnetic resonance imaging of the spine further clarified the pathological composites.Case presentationA 7-year-old girl presented with the classical phenotypic features of achondroplasia. Radiographic documentation showed the co-existence of metaphyseal enchondromatosis and development of spinal bony ankylosis. Magnetic resonance imaging showed extensive ossification of the anterior and posterior spinal ligaments. Additional features revealed by magnetic resonance imaging included calcification of the peripheral vertebral bodies associated with anterior end-plate irregularities.ConclusionEnchondromas are metabolically active and may continue to grow and evolve throughout the patient's lifetime; thus, progressive calcification over a period of years is not unusual. Ossification of the spinal ligaments has a specific site of predilection and often occurs in combination with senile ankylosing vertebral hyperostosis. Nevertheless, ossification of the spinal ligaments has been encountered in children with syndromic malformation complex. It is a multifactorial disease in which complex genetic and environmental factors interact, potentially leading to chronic pressure on the spinal cord and nerve roots with subsequent development of myeloradiculopathy. Our patient presented with a combination of achondroplasia, enchondroma-like metaphyseal dysplasia and calcification of the spinal ligaments. We suggest that the development of heterotopic bone formation along the spinal ligaments had occurred through an abnormal ossified enchondral mechanism. We postulate that ossification of the spinal ligaments and metaphyseal enchondromatous changes are related to each other and represent impaired terminal differentiation of chondrocytes in this particular case. Standard radiographic examination showed spinal bony ankylosis only. The pathological composites of the vertebrae have been clarified using scanning technology. Extensive spinal ligament ossification associated with calcification of the peripheral vertebral bodies and anterior end-plate irregularities were notable. We report what may be a novel spinal and extraspinal malformation complex in a girl with achondroplasia.

A multiplex family with possible metaphyseal Spahr‐type dysplasia and exclusion of RMRP and COL10A1 as candidate genes

We report a consanguineous Lebanese family where six individuals had disproportionate short stature, short limbs, and bilateral genu varum that were apparent after 2 years of age. Major radiographic features in infancy included flared, cupped, and ragged metaphyses of all long bones, delayed maturation of the scaphoid, trapezoid, and trapezium bones, wide and slightly irregular ribs, short femoral necks, flat femoral heads, and irregularity of the iliac crest. Radiographs of an affected adult showed diminished metaphyseal changes and slightly short femoral necks, when compared to the younger patients. We suggest that this family is affected with the Spahr type of metaphyseal chondrodysplasia. Sequencing of RMRP, and a haplotype analysis using highly informative markers around the COL10A1 excluded both genes from being pathogenic in this family. We are aware of only two previous reports of families with clinical features similar to the Spahr type of metaphyseal chondrodysplasia.

Correlation of Radiographic Changes With Disease Severity and Demographic Variables in Children With Stable Slipped Capital Femoral Epiphysis

The duration of symptoms in children with stable slipped capital femoral epiphysis (SCFE) varies widely, and radiographic metaphyseal changes develop at some point. It was the purpose of this study to investigate if metaphyseal changes correlate with symptom duration and other demographic parameters. A retrospective review of 97 children with idiopathic stable SCFE between 1998 and 2005 was performed. The child's sex, age, weight, height, body mass index (BMI) at diagnosis, and symptom duration were recorded. Anteroposterior and frog-lateral radiographs were reviewed to measure SCFE severity, the occurrence of adaptive changes, and the status of Klein line. Standard bivariate and logistic regression statistical analyses were used. A P < 0.05 was considered statistically significant. The average age was 12.4 +/- 1.7 years, symptom duration, 5.7 +/- 5.9 months; BMI, 28.3 +/- 4.3 kg/m; and SCFE angle, 28 degrees +/- 18 degrees. There was a correlation between SCFE severity and symptom duration (P = 0.002) but significant variability (r = 0.09). Metaphyseal changes were seen superiorly in 76%, inferiorly in 56%, anteriorly in 80%, and posteriorly in 84%. Symptom duration was not predictive of an abnormal Klein line. Those with more metaphyseal changer were older, had a longer duration of symptoms, had higher BMI, and had more severe SCFEs. Although SCFE severity generally increased with longer symptoms, some had prolonged symptoms with a mild SCFE, whereas others had short symptoms with a severe SCFE; perhaps the SCFE remains silent for varying periods of time before symptoms occur. Those children with more metaphyseal changes had higher BMIs; perhaps the larger body mass per unit of height translates into more bony adaptation following Wolf law.

Pulsed electromagnetic fields induced femoral metaphyseal bone thickness changes in the rat

The effect of 1 Hz, 30 mT pulsed magnetic fields on young adult rat femoral metaphyseal bone thickness was assessed. Ten same litter, female Wistar rats were studied; five of them underwent 30 min magnetic stimulation sessions for 20 consecutive days. The anterior and posterior cortical, as well as trabecular bone transverse thicknesses were measured. The results obtained under clear field microscopy in stimulated and control histological cuts were (in microm) 398 +/- 32 versus 260 +/- 22 (P = 0.002), 380 +/- 68 versus 252 +/- 21 (P = 0.03), and 168 +/- 11 versus 112 +/- 11 (P = 0.002), respectively. The transcranial magnetic stimulation system, approved for human therapy, generates pulsed electromagnetic fields, which induce a significant thickness increase in cortical and trabecular in vivo stimulated bone tissues. This is the first time this effect in healthy animals is shown.

Clinical and radiographic delineation of odontochondrodysplasia

The association of dentinogenesis imperfecta (DI) with a distinct form of chondrodysplasia in a boy was reported by Goldblatt et al. [1991; Am J Med Genet 39:170-172] and has been given the name of Goldblatt syndrome or odontochondrodysplasia (ODCD; OMIM#184260). Since the original description, only four further individuals have been reported (one sib pair and two unrelated cases). We report on an additional six individuals, including a second sib pair (brother and sister), with clinical and radiographic features that cluster and thus confirm the nosologic status of this entity. The main radiographic features are congenital platyspondyly with coronal clefts, severe metaphyseal changes particularly of the hands, wrists, and knees, mesomelic limb shortening, and coxa valga. The main physical signs are short stature, joint laxity, narrow chest, scoliosis, and DI. This combination of clinical and radiographic findings allows clear recognition of this syndrome in early childhood. Of note, the signs that are present in the newborn period are not entirely specific and the differential diagnosis includes spondylometaphyseal dysplasia (SMD) Sedaghatian type or platyspondylic lethal dysplasia (PSLD) Torrance type. The occurrence of two sib pairs in a group of only 11 patients suggests an autosomal recessive inheritance pattern. Overmodification of cartilage-extracted collagen 2 has been reported in two sibs, but mutation analysis of COL2A1 as well as of COMP, FGFR3, RMRP, and SBDS in one or more patients have given negative results, and the molecular etiology is as yet unknown.

Efficacy of Gadolinium Enhanced MR Imaging for the Diagnosis of Legg-Calve-Perthes Disease

Purpose: The purpose of this study was to evaluate the efficacy of gadolinium enhanced MR imaging for making the diagnosis of Legg-Calve-Perthes (LCP) disease. Materials and Methods: We studied the gadolinium enhanced MR images of 14 hips in 12 children who had the diagnosis of LCP disease. We retrospectively analyzed the extent of necrosis, the epiphyseal revascularization pathways and the metaphyseal changes. Results: The absence of enhancement on gadolinium enhanced MRI was noted in all cases of LCP disease. Diffuse absence of enhancement was observed in 9 femoral epiphyses. Two of them showed normal bone marrow signal intensity on the T1 and T2-weighted images. Focal absence of enhancement was observed in 5 femoral epiphyses. Enhanced MRI showed better epiphyseal revascularization in the lateral column (five cases), in the lateral and medial columns (four cases) and in the transphyseal pathway (three cases). Metaphyseal change was observed in two cases. Conclusion: Gadolinium enhanced MRI allows detection of LCP disease and an accurate analysis of the different revascularization patterns, and this helpful for predicting the prognosis.

A Case of Shwachman-Diamond Syndrome Confirmed with Genetic Analysis in a Korean Child

Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disorder, consisting of exocrine pancreatic insufficiency, chronic neutropenia, neutrophil chemotaxis defects, metaphyseal dysostosis, short stature, dental caries, and multiple organ involvements. Although SDS is the second most common hereditary abnormality of exocrine pancreas following cystic fibrosis in the Western countries, it has rarely been reported in Asia. We diagnosed a case of SDS in a 42-month-old girl, and genetic analysis including the relatives of the patient confirmed the diagnosis for the first time in Korea. She had short stature, steatorrhea, dental caries, and recurrent prulent otitis media and pneumonias. Laboratory studies revealed cyclic neutropenia, and serum levels of trypsin, amylase, and lipase were decreased. Simple radiography revealed metaphyseal sclerotic changes at the distal femur. A CT scan demonstrated a fatty infiltration and atrophy of the pancreas. On direct sequencing analysis of Shwachman-Bodian-Diamond Syndrome gene exon 2 region, the patient was homozygous for the c.258+2T>C mutation and heterozygous for the c.183_184TA>CT mutation and c.201A>G single nucleotide polymorphism. Treatment with pancreatic enzyme replacement, multivitamin supplementation, and regular to high fat diet improved her weight gain and steatorrhea.

Phenotypic Characteristics of Bone in Carbonic Anhydrase II-Deficient Mice

Carbonic anhydrase II (CAII)-deficient mice were created to study the syndrome of CAII deficiency in humans including osteopetrosis, renal tubular acidosis, and cerebral calcification. Although CAII mice have renal tubular acidosis, studies that analyzed only cortical bones found no changes characteristic of osteopetrosis. Consistent with previous studies, the tibiae of CAII-deficient mice were significantly smaller than those of wild-type (WT) mice (28.7 +/- 0.9 vs. 43.6 +/- 3.7 mg; p < 0.005), and the normalized cortical bone volume of CAII-deficient mice (79.3 +/- 2.2%) was within 5% of that of WT mice (82.7 +/- 2.3%; p < 0.05), however, metaphyseal widening of the tibial plateau was noted in CAII-deficient mice, consistent with osteopetrosis. In contrast to cortical bone, trabecular bone volume demonstrated a nearly 50% increase in CAII-deficient mice (22.9 +/- 3.5% in CAII, compared to 15.3 +/- 1.6% in WT; p < 0.001). In addition, histomorphometry demonstrated that bone formation rate was decreased by 68% in cortical bone (4.77 +/- 1.65 microm3/microm2/day in WT vs. 2.07 +/- 1.71 microm3/microm2/day in CAII mice; p < 0.05) and 55% in trabecular bone (0.617 +/- 0.230 microm3/microm2/day in WT vs. 0.272 +/- 0.114 microm3/microm2/day in CAII mice; p < 0.05) in CAII-deficient mice. The number of osteoclasts was significantly increased (67%) in CAII-deficient mice, while osteoblast number was not different from that in WT mice. The metaphyseal widening and changes in the trabecular bone are consistent with osteopetrosis, making the CAII-deficient mouse a valuable model of human disease.

Persistent upper airway obstruction is a diagnostic feature of spondyloepimetaphyseal dysplasia with multiple dislocations (Hall type) with further evidence for dominant inheritance

The spondyloepimetaphyseal dysplasias (SEMD) are a group of skeletal dysplasias of variable severity with a heterogeneous genetic aetiology. SEMD with multiple dislocations (Hall type) is a recently identified disorder (OMIM 603546) which is characterized by striking epiphyseal and metaphyseal changes of the long bones and joint laxity with multiple dislocations of the large joints. We report on persistent inspiratory stridor in a child with this type of SEMD in the second reported family with dominant transmission of this disorder. Microlaryngoscopy showed laryngeal stenosis due to failure of abduction of the vocal cords and a tracheostomy was required to provide a satisfactory airway. Since airway compromise has been reported previously in a small series of patients (total of five out of 13 cases so far), the evidence to date supports the association of upper airway obstruction in early childhood with the Hall type of SEMD. We therefore suggest that this is a clinically important diagnostic feature of this disorder.

Achondroplasia and enchondromatosis: report of three boys

We report on three boys suffering from achondroplasia concurrent with enchondromatosis-like metaphyseal changes. Two boys who were examined by molecular analysis harbored a mutation of FGFR3, which occurs in most achondroplastic individuals. Given the prevalence of achondroplasia and enchondromatosis, the metaphyseal changes in these patients are less likely to represent the coincidence of both disorders, but rather to result from a rare consequence of the FGFR3 mutation. Impaired FGFs/FGFR3 signaling pathway in achondroplasia inhibits chondrocytic proliferation, which accounts for most characteristics of achondroplasia. On the other hand, it causes conflicting biological consequences that can suppress or stimulate chondrocytic maturation. In a small subset of achondroplastic individuals, the suppression of chondrocytic maturation may outweigh the stimulation, which leads to cartilaginous overgrowth into the metaphysis, eventually causing the metaphyseal dysplasia found in the present patients.

Head-at-risk signs in Legg-Calvé-Perthes disease: Poor inter- and intra-observer reliability

Background The head-at-risk signs are used as prognostic indicators in Legg-Calvé-Perthes disease. These signs have been assessed only once regarding inter-observer reliability, however. Intra-observer reliability seems not to have been studied to date.Method 76 anteroposterior pelvic radiographs of unilateral Legg-Calvé-Perthes disease were assessed by 5 observers on 2 occasions, in order to assess the inter- and intra-observer reliability in identifying head-at-risk signs. The observers included 1 consultant pediatric orthopaedic surgeon, 1 consultant radiologist, 2 specialist registrars and 1 senior house officer. Inter- and intra-observer reliabilities were assessed using the kappa coefficient.Results The intra-observer reliability was good for lateral subluxation and metaphyseal cystic changes, moderate for lateral calcification, and fair for Gage's sign and horizontal growth plate. The inter-observer reliability was moderate for lateral subluxation, fair for lateral calcification and metaphyseal cystic changes, and slight for Gage's sign and horizontal growth plate.Interpretation There was considerable variation in the diagnosis of the head-at-risk signs between observers. This makes the classification difficult to use in clinical practice.

Schmid type of metaphyseal chondrodysplasia and COL10A1 mutations—findings in 10 patients

The Schmid type of metaphyseal chondrodyplasia (MCDS) is characterized by short stature, widened growth plates, and bowing of the long bones. It results from autosomal dominant mutations of COL10A1, the gene which encodes alpha1(X) chains of type X collagen. We report the clinical and radiographic findings in 10 patients with MCDS and COL10A1 mutations. Six patients had lower limb deformities, which necessitated orthopedic surgeries in all of them. One patient demonstrated no deformities and normal stature at age 11 years (height -1.2 SDS) while the others manifested severe short stature (<-3.5 SDS). Radiographs showed metaphyseal changes which were most pronounced at the hips and knees. Five of the identified 10 mutations in COL10A1 were novel. Six mutations resulted in truncation of the NC1 domain while four mutations were single amino-acid substitutions. Our findings suggest that COL10A1 mutations result in a uniform pattern of growth plate abnormalities. However, the clinical variability in severity among affected individuals is greater than previously thought.

Gadolinium-enhanced MR imaging of epiphyseal and metaphyseal marrow in normal piglets

The purpose of this study is to define the appearance of normal epiphyseal and metaphyseal marrow and normal changes of marrow due to fatty conversion on Gadolinium (Gd)-enhanced MR Imaging. Unenhanced and enhanced T1-weighted MR imaging were performed in proximal and distal femoral ends of 8 healthy piglets at the ages of 2, 4, 6 and 8 weeks, respectively. The changes with age in signal intensity and enhancement ratio of the epiphyseal and metaphyseal marrow with age were examined. The correlation of MRI characteristics with histological findings was studied. Our study showed that marrow of the metaphysis and of periphery of the 2nd ossification center were well vascularized hematopoietic marrow and had great enhancements. The enhancement ratio of metaphysis was greater than that of epiphyseal marrow and both enhancement ratios degraded gradually with age. The central regions of the epiphyseal ossification center and of the diaphysis were of fatty marrow and had little enhancement. It is concluded that on Gd-enhanced MR imaging the hematopoietic marrow of metaphysis and of periphery of the 2nd ossification center had greater enhancement than that of fatty marrow of central region of the 2nd ossification center. All of their enhancements decreased gradually with age.