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

<p>Abstract</p> <p>Introduction</p> <p>A 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.</p> <p>Case presentation</p> <p>A 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.</p> <p>Conclusion</p> <p>Enchondromas 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.</p

Progressive non-infectious anterior vertebral fusion, split cord malformation and situs inversus visceralis

BACKGROUND: Progressive non-infectious anterior vertebral fusion is a unique spinal disorder with distinctive radiological features. Early radiographic findings consist of narrowing of the anterior aspect of the intervertebral disk with adjacent end plate erosions. There is a specific pattern of progression. The management needs a multi-disciplinary approach with major input from the orthopaedic surgeon. CASE REPORT: We report a 12-year-old-female with progressive anterior vertebral fusion. This occurred at three vertebral levels. In the cervical spine there was progressive fusion of the lateral masses of the Axis with C3. Secondly, at the cervico-thoracic level, a severe, progressive, anterior thoracic vertebral fusion (C7-T5) and (T6-T7) resulted in the development of a thick anterior bony ridge and massive sclerosis and thirdly; progressive anterior fusion at L5-S1. Whereas at the level of the upper lumbar spines (L1) a split cord malformation was encountered. Situs inversus visceralis was an additional malformation. The role of the CT scan in detecting the details of the vertebral malformations was important. To our knowledge, neither this malformation complex and nor the role of the CT scan in evaluating these patients, have previously been described. CONCLUSION: The constellations of the skeletal abnormalities in our patient do not resemble any previously reported conditions with progressive anterior vertebral fusion. We also emphasise the important role of computerized tomography in the investigation of these patients in order to improve our understanding of the underlying pathology, and to comprehend the various stages of the progressive fusion process. 3D-CT scan was performed to improve assessment of the spinal changes and to further evaluate the catastrophic complications if fracture of the ankylosed vertebrae does occur. We believe that prompt management cannot be accomplished, unless the nature of these bony malformations is clarified

Ellis-Van Creveld syndrome

Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal dysplasia characterized by short ribs, polydactyly, growth retardation, and ectodermal and heart defects. It is a rare disease with approximately 150 cases reported worldwide. The exact prevalence is unknown, but the syndrome seems more common among the Amish community. Prenatal abnormalities (that may be detected by ultrasound examination) include narrow thorax, shortening of long bones, hexadactyly and cardiac defects. After birth, cardinal features are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth. Heart defects, especially abnormalities of atrial septation, occur in about 60% of cases. Cognitive and motor development is normal. This rare condition is inherited as an autosomal recessive trait with variable expression. Mutations of the EVC1 and EVC2 genes, located in a head to head configuration on chromosome 4p16, have been identified as causative. EVC belongs to the short rib-polydactyly group (SRP) and these SRPs, especially type III (Verma-Naumoff syndrome), are discussed in the prenatal differential diagnosis. Postnatally, the essential differential diagnoses include Jeune dystrophy, McKusick-Kaufman syndrome and Weyers syndrome. The management of EVC is multidisciplinary. Management during the neonatal period is mostly symptomatic, involving treatment of the respiratory distress due to narrow chest and heart failure. Orthopedic follow-up is required to manage the bones deformities. Professional dental care should be considered for management of the oral manifestations. Prognosis is linked to the respiratory difficulties in the first months of life due to thoracic narrowness and possible heart defects. Prognosis of the final body height is difficult to predict

Mucopolysaccharidosis VI

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 μg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 μg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme®), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided

Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene

Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders

Osteopetrosis

Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy

Identification of Novel α-Synuclein Isoforms in Human Brain Tissue by using an Online NanoLC-ESI-FTICR-MS Method

Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn1–140) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn1–139 and Ac-α-syn1–103) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA)

Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome

Acute increase of alpha-synuclein inhibits synaptic vesicle recycling evoked during intense stimulation

This work was supported by grants from the NIH/National Institute of Neurological Disorder and Stroke RO1 NS078165 (to J.R.M.), the Morton Cure Paralysis Fund (to J.R.M.), and the Branfman Family Foundation (to J.M.G.) and by a Dorothea Bennett graduate fellowship (to D.J.B.)

The N-Terminal residues 43 to 60 form the interface for dopamine mediated α-synuclein dimerisation

α-synuclein (α-syn) is a major component of the intracellular inclusions called Lewy bodies, which are a key pathological feature in the brains of Parkinson's disease patients. The neurotransmitter dopamine (DA) inhibits the fibrillisation of α-syn into amyloid, and promotes α-syn aggregation into SDS-stable soluble oligomers. While this inhibition of amyloid formation requires the oxidation of both DA and the methionines in α-syn, the molecular basis for these processes is still unclear. This study sought to define the protein sequences required for the generation of oligomers. We tested N- (α-syn residues 43-140) and C-terminally (1-95) truncated α-syn, and found that similar to full-length protein both truncated species formed soluble DA: α-syn oligomers, albeit 1-95 had a different profile. Using nuclear magnetic resonance (NMR), and the N-terminally truncated α-syn 43-140 protein, we analysed the structural characteristics of the DA:α-syn 43-140 dimer and α-syn 43-140 monomer and found the dimerisation interface encompassed residues 43 to 60. Narrowing the interface to this small region will help define the mechanism by which DA mediates the formation of SDS-stable soluble DA:α-syn oligomers