Radiographic and Tomographic Study of the Cranial Bones in Children with the Idiopathic Type of West Syndrome.

BACKGROUND: Neither radiological phenotypic characteristics nor reconstruction CT scan has been used to study the early anatomical disruption of the cranial bone in children with the so-called idiopathic type of West syndrome. MATERIAL AND METHODS: The basic diagnostic measures and the classical antiepileptic treatments were applied to these children in accordance with the conventional protocol of investigations and treatment for children with West syndrome. Boys from three unrelated families were given the diagnosis of the idiopathic type of West syndrome, aged 7, 10 and 12 years old. Parents underwent extensive clinical examinations. Three parents (age range of 28-41 year) were included in this study. All children showed a history of intellectual disabilities, cryptogenic epileptic spasms and fragmented hypsarrhythmia. These children and their parents were referred to our orthopedic departments because of variable skeletal deformities. Variable forms of skeletal deformities were the motive for the families to seek orthopedic advice. A constellation of flat foot, torticollis and early-onset osteoarthritis were observed by the family doctor. Apparently, and from the first clinical session in our practice, we felt that all these children are manifesting variable forms of abnormal craniofacial contour. Thereby, we immediately performed detailed cranial radiological phenotypic characterization of every affected child, as well as the siblings and parents, and all were enrolled in this study. All affected children underwent whole-exome sequence analysis. RESULTS: The craniofacial phenotype of all children revealed apparent developmental anatomical disruption of the cranial bones. Palpation of the skull bones showed unusual palpable bony ridges along different sutural locations. A 7-year-old child showed abnormal bulging over the sagittal suture, associated with bilateral bony ridges over the squamosal sutures. AP skull radiograph of a 7-year-old boy with West syndrome showed facial asymmetry with early closure of the metopic suture, and other sutures seemed ill-defined. A 3D reconstruction CT scan of the skull showed early closure of the metopic suture. Another 3D reconstruction CT scan of the skull while the patient was in flexion showed early closure of the squamosal sutures, pressing the brain contents upward, causing the development of a prominent bulge at the top of the mid-sagittal suture. A reformatted 3D reconstruction CT scan confirmed the bilateral closure of the squamosal suture. Examination of the parents revealed a similar skull radiographic abnormality in his mother. A 3D reformatted frontal cranial CT of a 35-year-old mother showed early closure of the metopic and sagittal sutures, causing a mid-sagittal bony bulge. A 10-year-old boy showed an extremely narrow frontal area, facial asymmetry and a well palpable ridge over the lambdoid sutures. A 3D axial reconstruction CT scan of a 10-year-old boy with West syndrome illustrated the asymmetry of the posterior cranial bones along the lambdoid sutures. Interestingly, his 28-year-old mother has been a client at the department of spine surgery since she was 14 years old. A 3D reconstruction CT scan of the mother showed a noticeable bony ridge extending from the metopic suture upwards to involve the sagittal suture (red arrow heads). The black arrow shows a well demarcated bony ridge over the squamosal suture. A 3D reconstruction CT scan of the skull and spine showed the thick bony ridge of the metopic and the anterior sagittal as well as bilateral involvement of the squamosal, causing apparent anterior narrowing of the craniofacial contour. Note the lumbar scoliosis. A 12-year-old boy showed brachycephaly. A lateral skull radiograph of a 12-year-old boy with West syndrome showed premature sutural fusion, begetting an abnormal growth pattern, resulting in cranial deformity. The nature of the deformity depends on which sutures are involved, the time of onset and the sequence in which individual sutures fuse. In this child, brachycephalic secondary to craniosynostosis, which occurred because of bilateral early ossification of the coronal sutures, led to bi-coronal craniosynostosis. Thickened frontal bones and an ossified interclinoid ligament of the sella turcica were encountered. The lateral skull radiograph of a 38-year-old mother with a history of poor schooling achievements showed a very similar cranial contour of brachycephaly, thickening of the frontal bones and massive ossification of the clinoid ligament of the sella turcica. Maternal history revealed a history of multiple spontaneous miscarriages in the first trimester of more than five times. Investigating his parents revealed a brachycephalic mother with borderline intelligence. We affirm that the pattern of inheritance in the three boys was compatible with the X-linked recessive pattern of inheritance. Whole-exome sequencing showed non-definite phenotype/genotype correlation. CONCLUSIONS: The aim of this study was sixfold: firstly, to refute the common usage of the term idiopathic; secondly, we feel that it could be possible that West syndrome is a symptom complex rather than a separate diagnostic entity; thirdly, to further detect the genetic carrier, we explored the connection between the cranial bones in children with West syndrome with what has been clinically observed in their parents; fourthly, the early life anatomical disruptions of the cranial bones among these children seem to be heterogeneous; fifthly, it shows that the progressive deceleration in the development of this group of children is highly connected to the progressive closure of the cranial sutures; sixthly, we affirm that our findings are novel.

Cutaneous, Cranial, and Skeletal Defects in Children and Adults with Focal Dermal Hypoplasia.

BACKGROUND: The diagnostic process for children and adults manifesting a constellation of ectodermal abnormalities requires a conscientious and highly structured process. MATERIAL AND METHODS: Six girls (aged 6-month-8 years) and two older girls (aged 13 and 16 years) were born with variable skin lesions of varying intensities associated with noticeable cranial and skeletal malformation complexes. Cleft palate, abnormal dentition, and multiple papillomas were evident around the mouth, mostly bilateral but asymmetrical in the upper and lower limbs. Exaggerated frontal bossing (macrocephaly) and in some patients' microcephaly with variable skeletal defects of the craniocervical junction and diverse forms of lower limb deformities of syndactyly, polydactyly, and split-hand/foot (ectrodactyly). RESULTS: All patients manifested the constellation of abnormalities with variable intensities ranging between alopecia, papillomas, striated skin pigmentations split-hand/foot (ectrodactyly), and major bone defects. A 3D reconstruction CT scan was directed mainly to further scrutinize children with pseudo cleft lip, submucus cleft, and cleft palate. Interstingly, they manifested massive demineralization of the cranium associated with severely defective dentition. A spine 3D reconstruction CT scan in two girls showed marked cystic cavitation of the upper jaw associated with excessive cavitation of the mastoid, causing tremendous frailty of the mastoid bone. A 3D sagittal CT scan showed odontoid hypoplasia and C1-2 instability associated with the rudimentary atlas and the persistence of extensive synchondrosis of the cervico-thoracic spine. The overall clinical and radiological phenotypic characterizations were consistent with the diagnosis of focal dermal hypoplasia (Goltz syndrome). Two children manifested heterozygous mutations in the PORCN gene, chromosome Xp11. CONCLUSIONS: In this study, we believe it's a good opportunity to share our novel scientific findings, which are intriguing and can be inspiring to readers, and to further aid the current scientific literature with exceptionally new unveiling results. This is the first comprehensive study of the cranio-skeletal malformation complex in children with GS.

Analysis of a non-lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons.

Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss-of-function mutations in ZMPSTE24, whereas mutations preserving residual enzymatic activity of the ZMPSTE24 protein lead to the milder mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. Remarkably, we identified a homozygous, presumably loss-of-function mutation in ZMPSTE24 [c.28_29insA, p.(Leu10Tyrfs*37)] in two consanguineous Pakistani families segregating MADB. To clarify how lethal consequences are prevented in affected individuals, functional analysis was performed. Expression experiments supported utilization of two alternative translation initiation sites, preventing complete loss of protein function consistent with the relatively mild phenotypic outcome in affected patients. One of these alternative start codons is newly formed at the insertion site. Our findings indicate that the creation of new potential start codons through N-terminal mutations in other disease-associated genes should generally be taken into consideration in the variant interpretation process.

The Tomographic Study and the Phenotype of Wormian Bones.

BACKGROUND: We describe patients who were recognized via conventional radiographs of the skull as manifesting wormian bones. Wormian bones are not a specific diagnostic entity and can be seen in variable forms of syndromic disorders. MATERIALS AND METHODS: Seven children and three adults (of 10-28 years) were seen and diagnosed in our departments. The principal complaints for the pediatric and adult group were: ligamentous hyperlaxity, a history of delayed walking and occasional fractures, which later in life started to manifest a constellation of neurological symptoms such as nystagmus, persistent headache, and apnea. Conventional radiographs were the first traditional tools used to recognize wormian bones. We performed 3D reconstruction CT scans to further understand the precise etiology and the nature of these wormian bones and attempted to connect them with a broad spectrum of unpleasant clinical presentations. Our group of patients was consistent with the phenotypic and genotypic diagnoses of osteogenesis imperfecta type I and type IV as well as patients with multicentric carpotarsal osteolysis syndrome. RESULTS: Three-dimensional reconstruction CT scan of the skulls confirmed that these worm-like phenotypes are in fact stemmed from the progressive softening of the sutures. The overall phenotype of the melted sutures is akin to overly stretched pastry. The most concerning sutures in this pathological process are the lambdoid. The overstretching of the lambdoid sutures was responsible for the development of sub-clinical basilar impression/invagination. Patients with certain forms of skeletal dysplasia such as osteogenesis imperfecta type I and IV manifested the heterozygous mutation of COL1A1/COLA2, shown as typical overstretching of the sutures. Similarly, patients with multicentric carpotarsal osteolysis syndrome with a heterozygous missense mutation of MAFB also manifested the phenotype of overly stretched pastry along the skull sutures. CONCLUSION: What we encountered via 3D reconstruction CT scan in our group of patients was entirely different than the traditional description that can be found in all relevant literature of the last decades. The worm-like phenomenon is in fact a pathological sequel occurring as a result of a progressive softening of the sutures, which results in the overstretching of the lambdoid sutures, a pathological process roughly similar to an overly stretched soft pastry. This softening is totally connected to the weight of the cerebrum (the occipital lobe of the cerebrum). The lambdoid sutures represent the weight-bearing zone of the skull. When these joints are loose and soft, they adversely alter the anatomical structures of the skull and lead to a highly hazardous derangement of the craniocervical junction. The latter causes the pathological upward invasion of the dens into the brain stem, leading to the development of morbid/mortal basilar impression/invagination.

The articular and the craniocervical abnormalities are of confusing age of onset in patients with Maroteaux-Lamy disease (MPS VI).

BACKGROUND: Maroteaux-Lamy disease (MPS Type VI) is an autosomal recessive lysosomal storage disorder. Skeletal abnormalities are vast. Early recognition may facilitate timely diagnosis and intervention, leading to improved patient outcomes. The most challenging is when patients manifest a constellation of craniocervical and articular deformities with variable age of onset. METHODS: We collected 15 patients with MPS VI (aged from 6 years-58 years). From within our practice in Pediatric Orthopedics, we present patients with MPS type VI who were found to manifest a diverse and confusing clinical presentation of hip deformities and cervical cord compression. Stem cell transplants were proposed as treatment tool and enzyme replacement therapy has been instituted in some patients. RESULTS: The spectrum of the clinical involvement in our group of patients was supported firstly via the clinical phenotype followed by assessment of the biochemical defect, which has been detected through the deficiency of N-acetylgalactosamine-4-sulfatase (arylsulphatase B) leading to increased excretion of dermatan sulphate. Secondly, through the molecular genetic results, which showed homozygous or compound heterozygous mutation in the ARSB gene on chromosome 5q14. Hip replacements and decompression operations have been performed to restore function and to alleviate pain in the former and life saving procedure in the latter. CONCLUSIONS: The efforts in searching for the etiological diagnosis in patients with skeletal dysplasia/MPSs has not been rewarding as many had anticipated. This emerged from several facts such as improper clinical documentation, missing diagnostic pointers in radiographic interpretations, limited knowledge in skeletal dysplasia and its variants, and the reliance on underpowered studies. Physicians and radiologists are required to appreciate and assess the diverse phenotypic and the radiographic variability of MPS VI. The importance of considering MPS in the differential diagnosis of other forms skeletal dysplasia is mandatory. Finally, we stress that the value of early diagnosis is to overcome dreadful complications.

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.

An exceptional biallelic N-terminal frame shift mutation in ZMPSTE24 leads to non-lethal progeria due to possible utilization of a downstream alternative start codon.

Biallelic mutations in ZMPSTE24 are known to be associated with autosomal recessive mandibuloacral dysplasia with type B lipodystrophy (MADB) and lethal restrictive dermopathy (RD), respectively. Disease manifestation is depending on the remaining enzyme activity of the mutated ZMPSTE24 protein. To date, complete loss of function has exclusively been reported in RD cases. In this study, we identified a novel N-terminal homozygous frameshift mutation (c.28_29insA) in a consanguineous family segregating with MADB. An in-depth analysis of the mutated sequence revealed, that the one base pair insertion creates a novel downstream in-frame start codon, which supposedly serves as an alternative translation initiation site (TIS). This possible rescue mechanism would explain the relatively mild clinical outcome in the studied individuals. Our findings demonstrate the necessity for careful interpretation of N-terminal variants potentially effecting translation initiation.

Infantile systemic hyalinosis: Variable grades of severity.

BACKGROUND: Infantile systemic hyalinosis (ISH) is an autosomal recessively inherited disorder. The classical natural history of the disease is characterised by hypotonia, multiple contractures, skin lesions, osteopenia, joint pain, bone fractures, persistent diarrhoea and growth deficiency. MATERIALS AND METHODS: Two children manifested the severe type of ISH underwent genotypic confirmation. In order to identify which other family members have inherited the disease. We included siblings and cousins in this study. The baseline tool to study other family subjects was based on the phenotypic characterisations of each child. RESULTS: . Two children with the severe type of ISH showed craniosynostosis (brachycephaly and scaphocephaly) associated with multiple contractures, progressive joint osteolysis ending up with multiple joint dislocations. The full exome sequencing was carried out, revealing a previously reported heterozygous nonsense mutation с.1294С>Т and a novel heterozygous non-synonymous substitution c. 58T>A in ANTRX2 gene. Three children (sibling and cousins) manifested variable clinical manifestations relevant to ISH. Specifically, asymptoamtic skin and skeletal abnormalities of hypoplastic clavicles and 'shepherd's crook' deformity and coxa vara. CONCLUSION: It is mandatory to perform extensive family pedigree search to detect asymptomatic clinical features in siblings and cousins in families with first degree related marriages. Interestingly, in the mild and the moderate types of ISH, we observed undescribed combination of asymptomatic skin and skeletal abnormalities. This is a comparative study between the severe and the mild/moderate types in a group of children from consanguineous families. Our current study extends the phenotypic characterisations of ISH.

Clinical Phenotype and Bone Biopsy Characteristics in a Child with Proteus Syndrome.

Proteus syndrome is a rare genetic disorder, which is characterized by progressive, segmental, or patchy overgrowth of diverse tissues of all germ layers, including the skeleton. Here, we present a 9-year-old girl with a somatic-activating mutation (c.49G > A; p.Glu17Lys) in AKT1 gene in a mosaic status typical for Proteus syndrome. She presented with hemihypertrophy of the right lower limb and a "moccasin" lesion among others. A transiliac bone biopsy was analyzed for bone histology/histomorphometry as well as bone mineralization density distribution (BMDD) and osteocyte lacunae sections (OLS) characteristics based on quantitative backscattered electron imaging. Bone histomorphometry revealed highly increased mineralizing surface (Z-score + 2.3) and mineral apposition rate (Z-score + 19.3), no osteoclasts (Z-score - 2.1), and an increased amount of primary bone in the external cortex. BMDD abnormalities included a decreased mode calcium concentration in cancellous bone (Z-score - 1.7) and an increased percentage of highly mineralized cortical bone area (Z-score + 2.4) compared to reference. OLS characteristics showed several differences compared to reference data; among them, there were the highly increased OLS-porosity, OLS-area, and OLS-perimeter on the external cortex (Z-scores + 6.8, + 4.4 and 5.4, respectively). Our findings suggest that increased bone formation reduced matrix mineralization in cancellous bone while the enhanced amount of primary bone in the external cortex increased the portion of highly mineralized cortical bone and caused OLS-characteristics abnormalities. Our results indicate further that remodeling of primary bone might be disturbed or delayed in agreement with the decreased number of osteoclasts observed in this child with Proteus syndrome.

Progressive Deformity of the Lower Limbs in a Patient with KID (Keratitis-Ichthyosis-Deafness) Syndrome.

PURPOSE: Progressive deformity of the lower limbs can be encountered in a long list of syndromic associations. The baseline tool in the management of such disorders is to approach to a definite diagnosis. METHODS: We describe a 4-year-old girl who presented with the clinical phenotype and genotype of congenital erythrokeratoderma, keratosis, and sensorineural hearing loss (keratitis-ichthyosis-deafness syndrome) (KID syndrome). She manifested progressive contractures of the knees associated with talipes equinovarus of the feet. The latter deformities were the main reasons behind her severe retardation in acquiring the normal locomotor functions. RESULTS: The analysis revealed mutations in intron 1 of the GJB2 gene of C.32G>A (p.Gly11Glu) and c.35delG in the compound heterozygous state. The presence in the genotype of the "dominant" mutation c.32G>A (p.Glu11Glu) was compatible with the clinical phenotype of KID syndrome. CONCLUSION: Surgical interventions through the extension of the hamstring tendons have been performed successfully via the application of an external distraction apparatus, namely, Volkov- Oganesyan. The latter procedures resulted in total release of her awkward knee contractures. Eventually, the child was able to regain the physiological alignment of her lower limbs and resume walking. To the best of our knowledge, the overall management of this child could be the first in the literature.

Skeletal phenotype/genotype in progressive pseudorheumatoid chondrodysplasia.

BACKGROUND: Axial and extra-axial deceleration in function and progressive joint pain with subsequent development of antalgic gait associated with swellings, and stiffness of the joints with loss of the physiological spine biomechanics were the natural history in this group of patients. Clinical and radiological phenotypes have been analysed carefully to further understand the aetiology behind. METHODS: Seven patients (three children around the age of 9-11 and one child of 17 years old). Three adults aging 25, 30, 33 and 40 years old were seen and examined. The paediatric group of patients were initially diagnosed with myopathy followed later by juvenile rheumatoid arthritis in other institutions. Clinical and imaging documentation were collected in our departments, followed by mutation screening, was carried out by bidirectional sequencing of the WISP3 gene. RESULTS: Clinical and radiological phenotypic studies confirmed the diagnosis of progressive pseudorheumatoid chondrodysplasia. A constellation of abnormalities such as early senile hyperostosis of the spine (Forestier disease), osteoarthritis of the hips showed progressive diminution and irregularities of the hip joint spaces associated with progressive capital femoral epiphyseal dysplasia and coxa vara have been encountered. Loss-of-function homozygous mutations (c.667T>G, p.Cys223Gly) and (c.170C>A, p.Ser57*) in the WISP3 gene were identified in our patients. CONCLUSION: The definite diagnosis was not defined via vigorous myopathic and rheumatologic investigations. Detailed clinical examination and skeletal survey, followed by genotypic confirmation, were our fundamental pointers to rule out the false diagnosis of juvenile rheumatoid arthritis and rheumatoid polyarthritis in the adult group of patients. We wish to stress that the clinical/radiological phenotype is the baseline tool to establish a definite diagnosis and to guide the geneticist toward proper genotype.Key Points•Joint pain and difficulties in walking/climbing the stairs are characteristic features encountered in early childhood. False diagnosis of juvenile rheumatoid arthritis can be made at this point.•False positive-like muscular wasting resembling myopathy results in ensuing vigorous troublesome investigations.•Flattened vertebral bodies associated with defective ossification of the anterior end plates are characteristic features of progressive pseudorheumatoid chondrodysplasia.•Joint expansions, which are usually accompanied by narrowing of the articular ends of the appendicular skeletal system, show a clear radiological phenotype of pseudorheumatoid chondrodysplasia.

Leri-Weill Dyschondrosteosis Syndrome: Analysis via 3DCT Scan.

Background: Leri-Weill dyschondrosteosis (LWD) is a pseudoautosomal form of skeletal dysplasia, characterized by abnormal craniofacial phenotype, short stature, and mesomelia of the upper and lower limbs. Methods: We describe two female patients with LWD. Their prime clinical complaints were severe bouts of migraine and antalgic gait. Results: Interestingly, via a 3D reconstruction CT scan we encountered several major anomalies. Notable features of craniosynostosis through premature fusion of the squamosal sutures and partial closure of the coronal sutures were the reason behind the development of abnormal craniofacial contour. A 3D reconstruction CT scan showed apparent bulging of the clavarium through the partially synostosed coronal and totally synostosed squamosal sutures. Additional deformities include deficient number of ribs (10 ribs on both sides), defective ossification of the ischium and dysplasia of the iliac-ischial junction, and coxa valga have been noted. Conclusions: The constellation of observed deformities can be considered as a novel features associated with LWD.

The Managment of cervical spine abnormalities in children with spondyloepiphyseal dysplasia congenita: Observational study.

Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant disorder, characterized by disproportionate dwarfism with short spine, short neck associated with variable degrees of coxa vara. Cervical cord compression is the most hazardous skeletal deformity in patients with SEDC which requires special attention and management.Ten patients with the clinical and the radiographic phenotypes of spondyloepiphyseal dysplasia congenita have been recognized and the genotype was compatible with single base substitutions, deletions or duplication of part of the COL2A1 gene (6 patients out of ten have been sequenced). Cervical spine radiographs showed apparent atlantoaxial instability in correlation with odontoid hypoplasia or os-odontoideum.Instability of 8 mm or more and or the presence of symptoms of myelopathy were the main indications for surgery. Posterior cervical fusion from the occiput or C1-3, decompression of C1-2 and application of autorib transfer followed by halo vest immobilization have been applied accordingly.Orthopedic management of children with spondyloepiphyseal dysplasia congenita (SEDC) should begin with the cervical spine to avoid serious neurological deficits and or mortality.

A constellation of orthopaedic deformities in connection with cartilage oligomeric matrix protein mutation.

BACKGROUND: Trendelenburg's gait can be observed in Legg-Calvé-Perthes disease, antalgic gait observed in osteoarthropathy and waddling gait is usually seen in genu varum and circumduction gait in patients with genu valgum. Disabling pain was a prime manifestation in slipped capital femoral epiphysis (SCFE). Limited joint range of motion with an inability to bear full weight on an affected extremity with swaying and wide-based gait is seen in patients with malalignment of the lower limbs. All the above-mentioned deformities have been labelled as idiopathic. The main objective of this article is to approach to the aetiology understanding. PATIENTS AND METHODS: Ten children (3 girls and 7 boys with age average of 9 years) presented with variable deformities; Perthes-like deformity, genu varum/valgum and osteoarthropathy and one patient with SCFE. Clinical and radiological phenotypes were the baseline tool of diagnosis. Genotypic characterisations were performed. RESULTS: Diverse clinical presentations of Perthes-like disease, osteoarthropathy, genu varum/valgum and SCFE were the most prominent skeletal abnormalities in patients manifested cartilage oligomeric matrix protein (COMP) gene mutation. CONCLUSION: : The value of presenting this article is fourfold; first to signify that mutation study was essential for the increment of knowledge related to the genotype-phenotype relationships. Second, to indicate that professional awareness is needed to differentiate between the hidden pathologies in patients with Perthes-like deformity, genu varum, genu valgum and early osteoarthritis in correlation with COMP gene mutation. Third, it is mandatory to question the validity of the term idiopathic. Fourth, this article is an attempt to sensitise orthopaedic physicians and surgeons that deformities might be stemmed from diverse forms of intrinsic bone disorders.

Bone matrix hypermineralization associated with low bone turnover in a case of Nasu-Hakola disease.

Analysis of tissue from a 34-years-old male patient from Austrian origin with a history of multiple fractures associated with painful episodes over the carpal, tarsal and at the end of the long bones respectively is presented. Radiographic images and axial 3DCT scans showed widespread defects in trabecular bone architecture and ill-defined cortices over these skeletal sites in the form of discrete cystic-like lesions. Family history indicated two sisters (one half and one full biological sisters) also with a history of fractures. Whole exome sequencing revealed two heterozygous missense mutations in TYROBP (MIM 604142; NM_003332.3) gene encoding for a cell-surface adaptor protein, which is part of a signaling complex triggering activation of immune responses. It is expressed in cells of the ectoderm cell linage such as NK and dendritic cells, macrophages, monocytes, myeloid cells, microglia cells and osteoclasts. The phenotype and genotype of the patient were consistent with the diagnosis of Nasu-Hakola disease (NHD) (OMIM 221770). Investigations at the bone material level of a transiliac bone biopsy sample from the patient using polarized light microscopy and backscatter electron imaging revealed disordered lamellar collagen fibril arrangement and extensively increased matrix mineralization. These findings are the first bone material data in a patient with NHD and point toward an osteoclast defect involvement in this genetic condition.

Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management.

OBJECTIVES: There are several types of metaphyseal chondrodysplasia and various clinical types have been differentiated. The Schmid type of metaphyseal chondrodysplasia is the most common. Diffuse metaphyseal flaring, irregularity, and growth plate widening, which are most severe in the knees, are the most striking radiological features of this disease. The Schmid type of metaphyseal dysostosis is characterized by failure of normal mineralization of the zone of provisional calcification, leading to widened physes and enlarged knobby metaphyses, effectively causing shortening of the tubular bones, splaying of the metaphyses, coxa vara, and bow legs. Orthopaedic interventions were primarily performed on the lower extremities. METHODS: Twelve children (seven girls and five boys) aged 7-10 years were enrolled in this study. Moderate short stature was a uniform feature associated with predominant involvement of the proximal femora and bow legs resulted in the development of angular deformities. A waddling gait was a consequence of coxa vara in eight children. Valgus osteotomy of the proximal femur was planned after physeal closure for the group of children with coxa vara. Hemiepiphysiodesis was performed to re-align the genu varum in three children. RESULTS: Other forms of metaphyseal dysostosis were ruled based on full clinical and radiographic phenotypes, with confirmation through molecular pathology. Mutations in the COL10A1 gene located on chromosome 6q21-q22.3 were confirmed. Re-alignment was accomplished in our group of patients. CONCLUSION: The most striking clinical features of Schmid metaphyseal chondrodysplasia which appear within the first 2-3 years of life are: moderate short limbs and short stature, a waddling gait, and increasing shortness of stature with age. The Schmid type of metaphyseal chondrodysplasia is a disorder that arises from defective type X collagen, which is typically found in the hypertrophic zone of the physes. Moderate short stature and a waddling gait associated with pain are the most common clinical presentations. Osteotomies to correct bow legs are sometimes combined with lengthening procedures. Recurrence of the deformities with growth is not uncommon; therefore, hemiepiphysiodesis or stapling might be indicated in some cases.

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.

Lower limbs deformities in patients with McCune-Albright syndrome: Tomography and treatment.

BACKGROUND: The skeletal changes in McCune-Albright disease are usually severe because of the polyostotic form of the disease. Trendelenberg gait and limited mobility are the most common presenting features. The constellation of Café-au lait spots and polyostotic bone involvement is commonly referred to as McCune-Albright's syndrome (MAS). MATERIALS AND METHODS: One boy and 4 girls (7-16 years) were sought in our departments from 1998 to 2012. Limb length discrepancy was the main clinical presentation. Repetitive micro-fractures caused the development of 'Shepherd crook' deformity with pain were the main burden. RESULTS: Because of the repetitive micro-fractures and the significant deformity that distorted the integrity of the long bones which were associated with pain. We referred to re-alignment valgus osteotomy with internal fixation to preserve proper alignment. Moreover, guided growth technique with 8-plates was performed in 1 case. CONCLUSION: Tendency to progressive unilateral lower limb deformity in patients with MAS is usually associated with thinning and expansion of the cortex and distortion of the normal lower limb integrity secondary to repetitive micro-fractures. The latter is a situation which warrants surgical treatment to re-align the deformity and to preserve function. Prophylactic intramedullary nailing via the application of locking nails to ensure stabilisation of the femoral neck was found to be effective. However, nevertheless, the mosaic nature of MAS means any cell, tissue and organ in any site of the body could be affected to varying degrees. The clinical manifestations are a diversity of the disorder ranging from mild clinical signs to severe life-threatening disease.

Can Multiple Hereditary Exostoses Overlap With Mesomelic Dysplasia?

BACKGROUND: We studied an unusual combination of severe short stature, mesomelia (Leri-Weill dyschondrosteosis syndrome), and multiple exostosis in several family subjects over three generations. The pattern of inheritance was compatible with autosomal dominant. METHODS: Of 21 affected members over three generations, shortness of stature, associated with mesomelia resembling Leri-Weill dyschondrosteosis syndrome with no exostoses was evident in three family subjects. The rest of the family subjects manifested with normal height, and yet multiple exostoses. In this family, the skeletal manifestations were sufficiently variable for the presentation to be with either short stature or scoliosis, a Madelung' deformity, or with severe hallux valgus associated with exostosis and with Leri-Weill dyschondrosteosis syndrome. RESULTS: Subjects with structural chromosomal aberrations of the proband IV-7, who manifested with normal height but with multiple exostoses were excluded via 20 CAG-banded mitoses (there were no microdeletions or microduplication after performing Array-CGH-analysis). In addition, DNA examination for subject IV-8 (male cousin of the proband showed short stature and Leri-Weill dyschondrosteosis syndrome) revealed no evidence of SHOX deletions. CONCLUSION: We described a multigenerational non-consanguineous North African family , in which mesomelic dysplasia, whose clinical and radiological phenotypes resembled dyschondrosteosis, was a prominent feature in three family subjects. Multiple exostoses were evident in several other family subjects (most were with normal height). We would like to emphasize the variability in the phenotypic expression of multiple exostosis, especially the confusion that might arise when the condition appears both clinically and radiologically to be more complicated, and the overall picture might then be overlapped with one of the other bone dysplasias such as Leri-Weill dyschondrosteosis syndrome.