Tomographic Study of the Malformation Complex in Correlation With the Genotype in Patients With Robinow Syndrome: Review Article.

We aimed to understand the etiology behind the abnormal craniofacial contour and other clinical presentations in a number of children with Robinow syndrome. Seven children with Robinow syndrome were enrolled in this study (autosomal recessive caused by homozygous mutations in the ROR2 gene on chromosome 9q22, and the autosomal dominant caused by heterozygous mutation in the WNT5A gene on chromosome 3p14). In the autosomal recessive (AR) group, the main clinical presentations were intellectual, disability, poor schooling achievement, episodes of headache/migraine, and poor fine motor coordinative skills, in addition to massive restrictions of the spine biomechanics causing effectively the development of kyposcoliosis and frequent bouts of respiratory infections. Three-dimensional reconstruction computed tomography scan revealed early closure of the metopic and the squamosal sutures of skull bones. Massive spinal malsegmentation and unsegmented spinal bar were noted in the AR group. In addition to severe mesomelia and camptodactyly, in the autosomal dominant (AD) group, no craniosynostosis but few Wormian bones and the spine showed limited malsegemetation, and no mesomelia or camptodactyly have been noted. We wish to stress that little information is available in the literature regarding the exact pathology of the cranial bones, axial, and appendicular malformations in correlation with the variable clinical presentations in patients with the 2 types of Robinow syndrome.

Massive Axial and Appendicular Skeletal Deformities in Connection with Gorham-Stout Syndrome.

: Background: Etiological understanding is the corner stone in the management of skeletal deformities. Methods: Multi-centre study of patients with deformities in connection with diverse etiological backgrounds. We aimed to study four patients (one boy and three girls) with variable axial and appendicular deformities in connection with a vanishing bone disorder. Results: Axial deformities such as scoliosis, kyphoscoliosis, compressed fused vertebrae, appendicular fractures, dislocations, and vicious disorganization deformities of the joints were in connection with the vanishing bone disorder, namely Gorham-Stout syndrome. Conclusions: It is mandatory to establish proper clinical and radiological phenotypic characterization in children and adults presented with unusual skeletal deformities. Identifying the reason behind these deformities is the key factor to draw a comprehensive management plan.

Turning the backbone into an ankylosed concrete-like structure: Case report.

RATIONALE: Progressive restriction of the spinal bio-mechanics is not-uncommon deformity encountered in spine clinics. Congenital spinal fusion as seen in Klippel-Feil-anomaly, progressive non-infectious anterior vertebral fusion, and progressive spinal hyperostosis secondary to ossification of the anterior longitudinal spinal ligament are well delineated and recognized. PATIENT CONCERNS: A 24-year-old girl has history of osteoporosis since her early childhood, associated with multiple axial and appendicular fractures and scoliosis. Recently she presented with episodes of severe back pain, spinal rigidity/stiffness with total loss of spine biomechanics. DIAGNOSES: She was provisionally diagnosed as having osteogenesis imperfecta and was investigated for COL1A1/A2 mutations which have been proven to be negative. Autosomal recessive type of osteogenesis imperfecta was proposed as well, no mutations have been encountered. A homozygous for CTSA gene mutation, the gene associated with Galactosialidosis was identified via whole exome sequencing (Next-Generation Sequencing projects) has been identified. INTERVENTIONS: Early in her life she had a history of frequent fractures of the long bones since she was 4 years which was followed by vertebral fractures at the age of 12 years. She manifested lower serum 25OH-D levels and were associated with lower LS-aBMD Z-scores with higher urinary bone turnover indexes (urinary NTX/Cr). OUTCOMES: Lysosomal storage diseases (LSD) have a strong correlation with the development of osteoporosis. LSD causes skeletal abnormalities results from a lack of skeletal remodeling and ossification abnormalities owing to abnormal deposition of GAGs (impaired degradation of glycosaminoglycans ) in bone and cartilage. 3D reconstruction CT scan of the spine showed diffuse hyperostosis of almost the entire spine (begins at the level of T4- extending downwards to involve the whole thoraco-lumbar and upper part of the sacrum) with total diffuse fusion of the pedicles, the transverse and articular processes, the laminae and the spinous processes. LESSONS: This is the first clinical report of adult patient with a history of osteoporosis and fractures with the late diagnosis of Galactosialidosis. Osteogenesis imperfecta (autosomal dominant and recessive) were the first given diagnoses which proven negative. The pathophysiology of the spine ankylosis in our current patient and its correlation with LSD, antiresorptive medications, vitamin D3 and supplemental calcium is not fully understood. Therefore, further studies are needed to elucidate this sort of correlation.

Spine malformation complex in 3 diverse syndromic entities: Case reports.

RATIONALE: Clinical and radiographic phenotypic characterizations were the base line tool of diagnosis in 3 syndromic disorders in which congenital cervico-thoracic kyphosis was the major deformity. PATIENTS CONCERNS: Directing maximal care toward the radiographic analysis is not only the axial malformation but also toward the appendicular abnormalities was our main concern. We fully documented the diversity of the spine phenotypic malformation complex via the clinical and radiographic phenotypes. DIAGNOSES: We established the diagnosis via phenotypic/genotypic confirmation in 3 diverse syndromic entities namely acampomelic campomelic dysplasia, Larsen syndrome and Morquio syndrome type A (mucopolysaccharidosis type IV A). INTERVENTIONS: Surgical interventions have been carried out in the Larsen syndrome and Morquio syndrome type A, resepectively. OUTCOMES: The earliest the diagnosis is, the better the results are. The necessity to diagnose children in their first year of life has many folds, firstly the management would be in favor of the child's growth and development and secondly, the prognosis could be clearer to the family and the medical staff as well. Our current paper is to sensitize paediatricians, physicians and orthopedic surgeons regarding the necessity to detect the aetiological understanding in every child who manifests a constellation of malformation complex. LESONS: Scoliosis and kyphosis/kyphoscoliosis are not a diagnosis in themselves. Such deformities are mostly a symptom complex correlated to dozens of types of syndromic associations. The rate curve progression and the final severity of congenital spine tilting are related to 3 factors: (a) the type of vertebral malformation present, (b) the patient's phenotype, and

The constellation of skeletal deformities in a family with mixed types of mucopolysaccharidoses: Case report.

INTRODUCTION: A 13-year-old child was clinically diagnosed with mucopolysaccharidosis type VI-Maroteaux-Lamy syndrome (MPS VI) at the age of 5 years, and the diagnosis was confirmed biochemically and genetically (homozygous mutation in ARSB gene). At that time, his older brother manifested with increasing severe mental retardation. His urinary glycosaminoglycan excretion in urine was elevated, but there was only 1 mutation in the ARSB gene defining him as a healthy carrier of MPS VI. The 15-year-old boy was born with dysmorphic facial features, cleft lip and palate, and multiple contractures associated with profound skeletal deformities manifested, severe mental retardation, and seizures, leading to the diagnosis of cerebral palsy from birth on.Clinical and radiographic phenotypic characterization was the baseline tool to document the older sibling, parents, and relatives, all of them examined at the Orthopaedic Hospital of Speising, Vienna, Austria. The family history (from maternal and paternal sides) showed >10 subjects with variable clinical histories of hyperactivity and attention deficit disorder, depression, and a diversity of skeletal abnormalities, such as dysplastic spondylolisthesis, discovertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age). METHODS: Eleven patients in a family with interrelated marriages (two male siblings of 15 and 13-year-old), parents and relatives over three generations were enrolled. One of the siblings was diagnosed with Maroteaux-Lamy syndrome at the age of five-years and mutation of the ARBS gene has been encountered. The older sibling manifested at birth craniofacial abnormalities associated with multiple contracture and seizures. Cerebral palsy was the suggested diagnosis. Clinical and radiographic phenotypes were the baseline tool to document the older sibling, parents and relatives at the orthopaedic Hospital of Speising, Vienna, Austria. These were followed by whole Exome sequencing in three family subjects. RESULTS: A series of genetic studies in the older sibling showed homozygous mutation in GNS gene compatible with MPS IIID. Both parents are first related and were found to be heterozygous for N-acetylglucosamine-6-sulfatase GNS gene. Family history showed more than 10 subjects with variable clinical presentations such as dysplastic spondylolisthesis, disco-vertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age). CONCLUSION: Owing to the multiple systemic involvements, a genetic cause was suspected and a molecular genetic investigation by using whole-exome-sequencing method in 3 family subjects (trios) was performed: the 15-year-old boy and his parents. A homozygous splice-site-mutation in the GNS gene could be found, compatible with mucopolysaccharidosis-Sanfillipo syndrome (type IIID). Both parents are first related and were now found also to be heterozygous for the GNS gene mutation found in their older son. Therefore, both parents are heterozygous carriers for the ARSB gene mutation but also the GNS gene mutation. In the son with MPS VI, no mutation in the GNS gene was found, but the brother with MPS IIID was heterozygous for the ARSB gene mutation.We presume that the intrafamilial variability of clinical signs in different family members could be the result of various mutations in the ARSB/GNS genes in the carriers or potential modulating effects of other genes or differences in genetic backgrounds.

Distinctive Skeletal Abnormalities With No Microdeletions or Microduplications on Array-CGH in a Boy With Mohr Syndrome (Oro-Facial-Digital Type II).

We describe a constellation of distinctive skeletal abnormalities in an 8-year-old boy who presented with the full clinical criteria of oro-facial-digital (OFD) type II (Mohr syndrome): bony changes of obtuse mandibular angle, bimanual hexadactyly and unilateral synostosis of the metacarpo-phalanges of 3-4, bilateral coxa valga associated with moderate hip subluxation, over-tubulation of the long bones, vertical talus of the left foot and talipes equinovarus of the right foot respectively. Interestingly, we encountered variable minor malformations in his parents, confirming the autosomal recessive pattern of inheritance. There were no microdeletions or microduplications after performing array-CGH-analysis. We report what might be a constellation of unreported skeletal abnormalities in a child with OFD type II (Mohr syndrome).

Extended phenotypes in a boy and his mother with oto-palato-digital-syndrome type II.

We describe additional phenotypic features in a boy and his mother. Both manifested the phenotypic/genotypic correlation of oto-palato-digital syndrome type II. The mother's radiographs showed wormian bones of the skull, and paranasal bossing, her feet showed bilateral fusion of the cuboid with the lateral cuneiform bone with subsequent development of metatarsus varus associated with dysplastic distal phalanges.

Treatment of varus deformities of the lower limbs in patients with achondroplasia and hypochondroplasia.

Angular deformities of the lower limbs are a common clinical problem encountered in pediatric orthopaedic practices particularly in patients with osteochondrodysplasias. The varus deformity is more common than the valgus deformity in achondroplasia and hypochondroplasia patients because of the unusual growth of the fibulae than that of the tibiae. We retrospectively reviewed six patients (four patients with achondroplasia and two patients with hypochondroplsia) with relevant limb deformities due to the above-mentioned entities. All patients manifested significant varus deformity of the lower limbs. Detailed phenotypic characterization, radiologic and genetic testing was carried out as baseline diagnostic tool. We described the re-alignment procedures, which have been applied accordingly. Therefore, bilateral multi-level procedures, multi-apical planning and limb lengthening have been successfully applied. While recognition of the underlying syndromic association in patients who are manifesting angular deformities is the baseline for proper orthopaedic management, this paper demonstrates how to evaluate and treat these complex patients.

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.

3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.

Severe skew foot deformity in a patient with freeman-sheldon syndrome.

UNLABELLED: We report on a 3-year-old boy with the full phenotypic features of Freeman Sheldon syndrome (FSS). Severe skew foot deformity has been recognized as additional skeletal abnormality. Parents were first degree cousins, raising the possibility of autosomal recessive pattern of inheritance. To the best of our knowledge this is the first report of severe skew foot deformity in a patient with (FSS). KEYWORDS: Freeman-Sheldon syndrome; Skew foot deformity; Metatarsus adductus.

Mid-diaphyseal Endosteal Thickening With Subsequent Medullary Narrowing in a Patient With Hallermann-Streiff Syndrome.

UNLABELLED: We report on a 5-year-old girl who presented with the full clinical criteria of Hallermann-Streiff syndrome (HSS). Classically, overtubulation (thin and gracile) bones are the characteristic and constant features in HSS. Interestingly, our present patient manifested unusual mid-diaphyseal endosteal thickening with subsequent medullary narrowing (defective endosteal resorption). To the best of our knowledge no previous reports described such unusual feature in a patient with HSS. KEYWORDS: Hallermann-Streiff syndrome; Mid-diaphyseal thickening; Radiology.

Tomographic assessment of the spine in children with spondylocostal dysotosis syndrome.

OBJECTIVE: The aim of this study was to perform a detailed tomographic analysis of the skull base, craniocervical junction, and the entire spine in seven patients with spondylocostal dysostosis syndrome. METHOD: Detailed scanning images have been organized in accordance with the most prominent clinical pathology. The reasons behind plagiocephaly, torticollis, short immobile neck, scoliosis and rigid back have been detected. Radiographic documentation was insufficient modality. RESULTS: Detailed computed tomography scans provided excellent delineation of the osseous abnormality pattern in our patients. CONCLUSION: This article throws light on the most serious osseous manifestations of spondylocostal dysostosissyndrome.

Tomographic assessment of the spine in children with spondylocostal dysotosis syndrome

OBJECTIVE: The aim of this study was to perform a detailed tomographic analysis of the skull base, craniocervical junction, and the entire spine in seven patients with spondylocostal dysostosis syndrome. METHOD: Detailed scanning images have been organized in accordance with the most prominent clinical pathology. The reasons behind plagiocephaly, torticollis, short immobile neck, scoliosis and rigid back have been detected. Radiographic documentation was insufficient modality. RESULTS: Detailed computed tomography scans provided excellent delineation of the osseous abnormality pattern in our patients. CONCLUSION: This article throws light on the most serious osseous manifestations of spondylocostal dysostosissyndrome.