Torticollis in Connection with Spine Phenotype.

PURPOSE: Torticollis is not of uncommon occurrence in orthopaedic departments. Various theories and studies concerning the pathogenesis of the deformity have been suggested. We aimed to highlight and discuss the underlying cervical and spine malformation complex in correlation with torticollis via radiographic and tomographic analysis and its connection with a specific syndromic entity. METHODS: Torticollis has been recognised in six patients (2 boys and 4 girls with an age range of 14-18 years), in addition to a couple of parents manifested persistent backpain. A variable spine malformation complex was the main reason behind torticollis. In addition, some patients manifested plagiocephaly, facial asymmetry and scoliosis/kyphoscoliosis. In some patients, conventional radiographs were of limited value because of the overlapping anatomical structures. Three-dimensional reconstruction CT scanning was the modality of choice, which enlightens the path for the phenotypic characterisation. RESULTS: A 16-year-old-boy presented with torticollis in correlation with pathologic aberration of the spine cartilaginous stage was analysed via 3DCT scan. Comprehensive clinical and radiological phenotypes were in favour of spondylomegepiphyseal dysplasia. The genotype showed a mutation of the NKX3-2 (BAPX1) gene compatible with the diagnosis of spondylo-meg-epiphyseal-metaphyseal dysplasia. His younger male sibling and parents were heterozygous carriers. In two patients with pseudoachondroplasia syndrome, in which odontoid hypoplasia associated with cervical spine synchondrosis causing life-threatening torticollis, Cartilage oligomeric matrix protein (COMP) gene mutation was identified. MURCS syndrome has been diagnosed in two unrelated girls. Torticollis associated with cervical kyphosis was the major presentation since early childhood. Interestingly, one girl showed omovertebral bones of the lower cervical and upper thoracic spine. Her karyotype manifested a balanced translocation of 46 XX, t (14q; 15q). CONCLUSION: To detect the underlying etiological diagnosis of torticollis, a skeletal survey was the primary diagnostic tool. Conventional radiographs of the craniocervical junction and spine resulted in confusing readings because of the overlapping anatomical structures. Cranio-cervical malformation complex could have serious neurological deficits, especially for children with indefinite diagnosis of torticollis. The widely used term of congenital muscular torticollis resulted in morbid or mortal consequences. Moreover, some patients received vigorous physical therapy on the bases of muscular torticollis. Sadly speaking, this resulted in grave complications. Understanding the imaging phenotype and the genotype in such patients is the baseline tool for precise and proper management. The value of this paper is to sensitise physicians and orthopaedic surgeons to the necessity of comprehensive clinical and radiological phenotypic characterisations in patients with long term skeletal pathology.

Combining Gene Mutation with Expression of Candidate Genes to Improve Diagnosis of Escobar Syndrome.

Escobar syndrome is a rare, autosomal recessive disorder that affects the musculoskeletal system and the skin. Mutations in the CHRNG and TPM2 genes are associated with this pathology. In this study, we conducted a clinical and genetic investigation of five patients and also explored via in silico and gene expression analysis their phenotypic variability. In detail, we identified a patient with a novel composite heterozygous variant of the CHRNG gene and two recurrent mutations in both CHRNG and TPM2 in the rest of the patients. As for the clinical particularities, we reported a list of modifier genes in a patient suffering from myopathy. Moreover, we identified decreased expression of IGF-1, which could be related to the short stature of Escobar patients, and increased expression of POLG1 specific to patients with TPM2 mutation. Through this study, we identified the genetic spectrum of Escobar syndrome in the Tunisian population, which will allow setting up genetic counseling and prenatal diagnosis for families at risk. In addition, we highlighted relevant biomarkers that could differentiate between patients with different genetic defects.

Craniofacial Malformations as Fundamental Diagnostic Tools in Syndromic Entities.

Background: A long list of syndromic entities can be diagnosed immediately through scrutinizing the clinical phenotype of the craniofacial features. The latter should be assisted via proper radiological interpretations. Patients and Methods: Different children aged from 1 month to 12 years were referred to our departments seeking orthopedic advice. Primarily, all received variable false diagnoses in other institutes. Two unrelated boys of one month and 12 months were falsely diagnosed as having positional plagiocephaly associated with contractures of idiopathic origin. Two unrelated boys of 14 months and 2 years were diagnosed with pseudo-hydrocephalus and non-specific syndrome, and were referred to explore their skeletal development. Two unrelated girls of 4 years old and 12 years old presented with multiple contractures were referred because of progressive scoliosis. A 4-year-old girl was referred with a false provisional diagnosis of facial diplegia. All children underwent detailed clinical, radiological and tomographic phenotypic characterizations and genetic testing, respectively. Results: Idaho syndrome (craniosynostosis associated with multiple dislocations) was the final diagnosis in the two unrelated boys with plagiocephaly and multiple contractures. Two children falsely diagnosed with pseudo-hydrocephalus and non-specific syndrome, were diagnosed with Silver-Russell syndrome (RSS). Contractural arachnodactyly Beals (CAB) was confirmed as the definitive diagnosis in the two unrelated girls with progressive scoliosis and multiple contractures. Parry-Romberg syndrome (PRS) associated with congenital lumbar kyphosis was the final diagnosis of the girl with the diagnosis of facial diplegia. Hypomethylation of ICR1 was confirmed in the RSS patients. Whole exome sequencing (WES) revealed a heterozygous mutation in the PRS patients. WES and array-CGH showed that no relevant variants or copy number variations (CNV) were identified in the CAB patients. Conclusions: On the one hand, newborn children can manifest diverse forms of abnormal craniofacial features, which are usually associated with either major or minor dysmorphic stigmata. A cleft lip/ palate is a major craniofacial malformation, and frontal bossing or a disproportionate craniofacial contour can be falsely considered as a transient plagiocephaly, which is spontaneously resolved by time. On the other hand, many physicians fall into the problem of deeming a countless number of diseases, such as contractures, as an idiopathic or non-specific syndrome. The latter stems from limited clinical experience. Therefore, failing to establish between the onset of the deformity and other inexplicit abnormal features that the patient or their immediate families or relatives carry is the final outcome. In this study, we used, for the first time, a reconstruction CT scan to further delineate the congenital disruption of the craniofacial anatomy and the other skeletal malformation complex.

Craniosynostosis, Scheuermann's disease, and intellectual disability resembling Shprintzen-Goldberg syndrome: a report on a family over 4 generations: Case report.

RATIONALE: Craniosynostosis is a disorder characterized by premature fusion of cranial sutures with subsequent development of abnormal craniofacial contour associated with variable skeletal and extra-skeletal abnormalities. In this family syndromic type of craniosynostosis was recognized and the etiology behind diverse forms of deformities have been diagnosed. PATIENT CONCERNS: The negative impact of the disorder on the child and his family is enormous. Particularly when the diagnosis is late and little can be done. Though counselling the family through discussing the whole picture of the disorder might lessens their concern. DIAGNOSES: Diagnosis is the corner stone of management. In this paper we aimed to sensitize pediatricians, physicians, and orthopedic surgeons concerning the necessity to recognize syndromic associations early on. INTERVENTIONS: Patients with syndromic craniosynostosis are usually associated with a complexity of malformation complex. Craniofacial surgery can be of remarkable help if the diagnosis is made early. It requires a series of corrections to avoid intellectual disability and other neurological deficits.The timing of interventions is strongly correlated on the timing of diagnosis. OUTCOMES: The earliest the diagnoses, the much better the outcomes are. And consequently avert the psychological and the financial cost on the patient and his family. LESSONS: The golden principle of medicine should prevail in all medical disciplines, which states: The more you see, the more you know and conversely the more you know is the more you see.

Are parents of children with Cockayne syndrome manifesting features of the disorder?: Case reports.

RATIONALE: Postnatal growth failure and progressive neurologic dysfunction and increasing multiorgan involvement are the main clinical features of Cockayne syndrome (CS). CS is a rare autosomal recessive disorder of the group of DNA repair diseases. Usually, genetic carriers, such as parents of patients, are not at risk for developing the disease. PATIENT CONCERNS: A series of 14 family subjects (6 children with age range from 6 months to 4 years with CS) and 9 parents (aged from 23 to 34 years) from consanguineous families is reported. DIAGNOSES: Ultraviolet irradiation studies were performed on these children and were indicative of CS. INTERVENTIONS: Cells of skin fibroblast from these children with the disease showed a symmetrical accumulation of chromosomal aberrations and the nuclear lamina aberrations. Our results showed a significant and simultaneous increase of percent of blebbs and invaginations of the nuclear lamina in all cases CS. The pronounced changes in 12.6 times at atypical form (girl); in 8.5 times at severe form (boy) and in 5.6 times at light form (boy). Percentage of metaphases with chromosomal aberration is significantly higher in CS cells: in 4 times at atypical form, in 3 times at hard form, and in 2 times at light form. The parents of these families (consanguineous families) were intellectually variable between normal/borderline intelligence, though most manifested a constellation of skeletal and extraskeletal abnormalities and notably, the characteristic cachectic facial appearance. The parents were considered as manifesting the mild type of CS, because they showed no abnormalities of DNA repair. OUTCOMES: Clinical manifestations in heterozygote carriers of an autosomal recessive disorders is a rare phenomenon as carriers are usually healthy. LESSONS: The interesting finding of the families studied is that there appeared to be a multitude of carriers manifesting with normal to borderline intelligence but with a wide spectrum of skeletal and extraskeletal abnormalities.

How frequent is osteogenesis imperfecta in patients with idiopathic osteoporosis?: Case reports.

RATIONALE: The term idiopathic osteoporosis itself is quite a non-specific disease label, which fails to address the etiological understanding. Bone mineral density alone is not a reliable parameter to detect patients at high risk of fracture. The diversity of the clinical phenotypes of discolored teeth, blueness of the sclera, back and joint pain, cardiovascular disease, Diabetes type II, hearing problems and a long list of orthopedic problems are have to be considered. PATIENTS CONCERNS: Our study has been designed in accordance with the clinical and radiological phenotype of eleven index cases with the provisional diagnosis of OI, which was followed by genotypic confirmation. This was followed by the invitation of siblings, parents, grandparents and other relatives to participate in the interviews, and to discuss the impact of the diagnosis. Proper collaboration with these families facilitated the process to identify other subjects with a history of fractures and other deformities/disabilities which were seemingly correlated to heritable connective tissue disorder. In total, 63 patients (27 children and 36 parents/grandparents and relatives) were enrolled in the study. Two groups of children were not included in our study. We excluded children with incomplete documentation and children who manifested de novo mutation. The term idiopathic osteoporosis (IOP) has been given to these families in other Institutes and was considered as a definite diagnosis. IOP was solely based on T scores, BMD and certain laboratory tests. Surprisingly, no single adult patient underwent clinical and or radiological phenotypic characterization. DIAGNOSES: A constellation of significant disease associations with osteoporotic fracture risk have been encountered. The index cases showed mutations in COL1A1 (17q21.31.q22) and COL1A2 (7q22.1), the genes encoding collagen type I. The phenotype/genotype confirmation in 11 children was the key factor to boost our research and to re-consult each family. Comprehensive clinical and radiological phenotypic documentation has been applied to most of other family subjects who principally received the diagnosis of IOP. INTERVENTIONS: All adult patients had normal serum calcium and only three patients showed an average of low serum phosphate of 0.7-0.61 mmol/l. Serumcrosslaps in six parents was in the average of (2.9-3.8 nM) and PTH levels were normal in all patients (the average showed 8.73 pg/ml). OUTCOMES: Our efforts to minimize and constrain the usage of the term idiopathic osteoporosis and to understand the sequence of pathological events that occurred in these families were emphasized. These efforts evolved into a remarkable and unique constellation of clinical findings. Strikingly, fracture represented a portion in a series of skeletal and extra-skeletal deformities and abnormalities which are all correlated to connective tissue disorder. This was achieved mainly through comprehensive phenotype/genotype confirmation, followed by scrutinizing the records of each family, clinical examination of the adults and revising the archives of our Hospitals and other Institutes. LESSONS: The sequence of diverse pathological events recorded within each family would be almost incomprehensible without a proper etiological understanding of the natural history of each child/family deformity that led to their occurrences. We wish to stress that, our current study is just an attempt to cover only a tiny fraction of the tip of the iceberg and to profoundly explore one of the most under-estimated causes of idiopathic osteoporosis.

Progressive congenital torticollis in VATER association syndrome.

STUDY DESIGN: A family study to reach the diagnosis of a multiple malformation syndrome. OBJECTIVE: To determine the cause of torticollis, in a patient with the VATER association. SUMMARY OF BACKGROUND DATA: The VATER association is a combination of vertebral anomalies, anal stenosis, tracheo-esophageal fistula, and radial anomalies. It needs a multidisciplinary approach with a major input from orthopedic surgeons. Torticollis in this condition has not been reported before. METHODS: Detailed family history and radiologic study using plain radiographs and three-dimensional-reconstruction. RESULTS: Bony abnormalities at the base of the skull and upper cervical vertebrae were found. CONCLUSIONS: It is postulated that the bony abnormalities were the underlying cause of the neurologic problem.

Subtotal amelia in a child with autosomal recessive hypohidrotic ectodermal dysplasia.

We report an inbred Tunisian family, in which the proband manifested signs of hypohidrotic ectodermal dysplasia, subtotal amelia, scoliosis and left renal agenesis. Two other family members had the full clinical criteria of hypohidrotic ectodermal dysplasia, characterized by deficient sweat glands, hypodontia, hypoplasia of the mucous glands, and fine hair. Nine family subjects had variable clinical expression of the disorder.

Massive spinal­ischial dysplasia and extensive spinal dyssygmentation in a Tunisian child with severe form of Cleidocranial dysplasia

Kyphoscoliosis is a complication of some bone dysplasias, including Cleido-cranial dysplasia (CCD). We report on massive spinal dysplasia secondary to severe spinal dyssygmentation associated with marked defective ossification of the ischium, detected in a Tunisian female child with a severe form of Cleido-cranial dysplasia. Literature review on Cleido cranial dysplasia and associated spinal abnormalities showed no previous similar reports as encountered in our patient