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Retinoic acid exposures as well as defects in the retinoic acid-degrading enzyme CYP26B1 have teratogenic effects on both limb and craniofacial skeleton. An initial report of four individuals described a syndrome of fetal and infantile lethality with craniosynostosis and skeletal anomalies caused by homozygous pathogenic missense variants in CYP26B1. In contrast, a 22-year-old female was reported with a homozygous missense pathogenic variant in CYP26B1 with complex multisuture craniosynostosis and intellectual disability, suggesting that in some cases, biallelic pathogenic variants of CYP26B1 may be compatible with life. Here we describe four additional living individuals from two families with compound heterozygous pathogenic missense variants in CYP26B1. Structural assessment of these additional missense variants places them further from the catalytic site and supports a model consistent with milder nonlethal disease. In addition to previously reported findings of multisuture craniosynostosis, conductive hearing loss, joint contractures, long slender fingers, camptodactly, broad fingertips, and developmental delay/intellectual disability, skeletal imaging in our cases also revealed gracile long bones, gracile ribs, radioulnar synostosis, and carpal and/or tarsal fusions. These individuals broaden the phenotypic range of biallelic pathogenic variants in CYPB26B1 and most significantly clarify that mortality can range from perinatal lethality to survival into adulthood., (© 2021 Wiley Periodicals LLC.)

Exogenous siRNAs are commonly used to regulate endogenous gene expression levels for gene function analysis, genotype-phenotype association studies and for gene therapy. Exogenous siRNAs can target mRNAs within the cytosol as well as nascent RNA transcripts within the nucleus, thus complicating siRNA targeting specificity. To highlight challenges in achieving siRNA target specificity, we targeted an overlapping gene set that we found associated with a familial form of multiple synostosis syndrome type 4 (SYSN4). In the affected family, we found that a previously unknown non-coding gene TOSPEAK/C8orf37AS1 was disrupted and the adjacent gene GDF6 was downregulated. Moreover, a conserved long-range enhancer for GDF6 was found located within TOSPEAK which in turn overlapped another gene which we named SMALLTALK/C8orf37 . In fibroblast cell lines, SMALLTALK is transcribed at much higher levels in the opposite (convergent) direction to TOSPEAK . siRNA targeting of SMALLTALK resulted in post transcriptional gene silencing (PTGS/RNAi) of SMALLTALK that peaked at 72 h together with a rapid early increase in the level of both TOSPEAK and GDF6 that peaked and waned after 24 h. These findings indicated the following sequence of events: Firstly, the siRNA designed to target SMALLTALK mRNA for RNAi in the cytosol had also caused an early and transient transcriptional interference of SMALLTALK in the nucleus; Secondly, the resulting interference of SMALLTALK transcription increased the transcription of TOSPEAK ; Thirdly, the increased transcription of TOSPEAK increased the transcription of GDF6 . These findings have implications for the design and application of RNA and DNA targeting technologies including siRNA and CRISPR. For example, we used siRNA targeting of SMALLTALK to successfully restore GDF6 levels in the gene therapy of SYNS4 family fibroblasts in culture. To confidently apply gene targeting technologies, it is important to first determine the transcriptional interference effects of the targeting reagent and the targeted gene.

Human multiple synostoses syndrome 3 is an autosomal dominant disorder caused by pathogenic variants in FGF9. Only two variants have been described in FGF9 in humans so far, and one in mice. Here we report a novel missense variant c.566C > G, p.(Pro189Arg) in FGF9. Functional studies showed this variant impairs FGF9 homodimerization, but not FGFR3c binding. We also review the findings of cases reported previously and report on additional features not described previously., (© 2020 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: Distal arthrogryposis (DA) is a group of rare Mendelian conditions that demonstrate heterogeneity with respect to genetics and phenotypes. Ten types of DAs, which collectively involve six genes, have been reported. Among them, the MYH3 gene causes several types of arthrogryposis conditions and therefore has a pivotal role in the skeletal and muscle development of the fetus. For this study, we recruited a five-generation Chinese family with members presenting DA features and phenotypic variability. Further clinical study characterized it as CPSFS1A (Contractures, Pterygia, and Spondylocarpotarsal Fusion Syndrome 1A)., Methods: Genomic DNA was extracted from eight family members, including one fetus. Whole-exome sequencing (WES) was then conducted on the proband's sample, followed by Sanger sequencing as validation for each of the participants. In silico analysis was performed. Western blotting (WB) detection and pathological staining were conducted on skeletal muscle tissue of the induced fetus after prenatal diagnosis., Results: A novel heterozygous pathogenic variant, namely NM_002470.3: c.3044_3047delinsTCAATTTGTT: p.E1015_D1016delinsVNLF in the MYH3 gene, was identified and shown to be cosegregated with the condition in the subject family. This variant resulted in the replacement of amino-acid residues E1015 and D1016 by a string of VNLFs. The pregnancy was selectively terminated because the fetus was genetically affected. However, the WB and pathological results did not indicate a significant change in the norm., Conclusions: Our study expanded the variant spectrum of CPSFS1A, in addition to which it provided solid evidence for the appropriateness of genetic counseling and pregnancy management for the family. The results may also provide further insight into the molecular mechanism of MYH3., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Intradiploic hematomas are extremely rare, particularly in newborns. Caused by bleeding between the inner and outer tables of the calvarium, they manifest with bony swelling of the skull. The authors present the first case of an intraosseous hematoma associated with synostosis, and the first report in a female patient. The clinical, radiological, surgical, and pathological characteristics of this lesion are discussed.

Multiple synostoses syndrome (SYNS1; OMIM# 186500) is a rare autosomal dominant disorder reported in a few cases worldwide. We report a Chinese pedigree characterized by proximal symphalangism, conductive hearing loss, and distinctive facies. We examined the genetic cause and reviewed the literature to discuss the pathogeny, treatment, and prevention of SYNS1. Audiological, ophthalmological, and radiological examinations were evaluated. Whole-exome sequencing (WES) was performed to identify mutations in the proband and her parents. Sanger sequencing was used to verify the results for the proband, parents, and grandmother. The literature on the genotype-phenotype correlation was reviewed. The patient was diagnosed with multiple synostoses syndrome clinically. WES and bioinformatic analysis revealed a novel missense mutation in the NOG gene, c.554C>G (p.Ser185Cys), cosegregated in this family. The literature review showed that the phenotype varies widely, but the typical facies, conductive hearing loss, and proximal symphalangism occurred frequently. All reported mutations are highly conserved in mammals based on conservation analysis, and there are regional hot spots for these mutations. However, no distinct genotype-phenotype correlations have been identified for mutations in NOG in different races. Regular systematic examinations and hearing aids are beneficial for this syndrome. However, the outcomes of otomicrosurgery are not encouraging owing to the regrowth of bone. This study expanded the mutation spectrum of NOG and is the first report of SYNS1 in a Chinese family. Genetic testing is recommended as part of the diagnosis of syndromic deafness. A clinical genetic evaluation is essential to guide prevention, such as preimplantation genetic diagnosis., (© 2020 Wiley Periodicals, Inc.)

Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) is an extremely rare autosomal recessive limb abnormality characterized by the fusion of third and fourth fingers. To date, only homozygous missense and frameshift mutations have been reported in BHLHA9 associated to MSSD. In this study, we report a patient who presented with clinical and radiological features of MSSD. A customized skeletal dysplasia NGS panel revealed the presence of two novel compounds heterozygous variants in BHLHA9: NM_001164405.1: c.[226A>T][269G>C]; p.[(Lys76*)][(Arg90Pro)]. Thus, this is the first case of MSSD in a nonconsanguineous family., (© 2020 Wiley Periodicals, Inc.)

Spondylocarpotarsal synostosis syndrome, a rare syndromic skeletal disorder characterized by disrupted vertebral segmentation with vertebral fusion, scoliosis, short stature, and carpal/tarsal synostosis, has been associated with biallelic truncating mutations in the filamin B gene or monoallelic mutations in the myosin heavy chain 3 gene. We herein report the case of a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome who had a homozygous frameshift mutation in the refilin A gene (RFLNA) [c.241delC, p.(Leu81Cysfs*111)], which encodes one of the filamin-binding proteins. Refilins, filamins, and myosins play critical roles in forming perinuclear actin caps, which change the nuclear morphology during cell migration and differentiation. The present study implies that RFLNA is an additional causative gene for spondylocarpotarsal synostosis syndrome in humans and a defect in forming actin bundles and perinuclear actin caps may be a critical mechanism for the development of spondylocarpotarsal synostosis syndrome.

Spondylocarpotarsal synostosis syndrome (SCT) is a rare group of skeletal dysplasias, characterized by disproportionate short stature with a short trunk, abnormal segmentation of the spine with vertebral fusion, scoliosis and lordosis, carpal and tarsal synostosis, and mild facial dysmorphisms. While the majority of the cases show autosomal recessive inheritance, only a few cases of vertical transmissions, with MYH3 mutations, have been reported. Here we report a case with typical SCT, carrying a novel heterozygous mutation in MYH3. This observation supports the hypothesis of a pathogenic link between autosomal dominant SCT and heterozygous mutations in MYH3. Of note, our case showed basilar invagination on brain magnetic resonance imaging at the age of 10 years. Basilar invagination could be a rare complication of both autosomal recessive and dominant SCT, indicating that prompt investigation are warranted for SCT patients.

Background: Saethre-Chotzen syndrome is an autosomal dominantly inherited disorder caused by mutations in the twist family basic helix-loop-helix transcription factor 1 (TWIST1) gene. Surgical procedures are frequently required to reduce morphological and functional defects in patients with Saethre-Chotzen syndrome. Therefore, the development of noninvasive procedures to treat Saethre-Chotzen syndrome is critical. We identified that periostin, which is an extracellular matrix protein that plays an important role in both bone and connective tissues, is downregulated in craniosynostosis patients., Methods: We aimed to verify the effects of different concentrations (0, 50, 100, and 200 μg/l) of recombinant mouse periostin in Twist1 +/- mice (a mouse model of Saethre-Chotzen syndrome) coronal suture cells in vitro and in vivo. Cell proliferation, migration, and osteogenic differentiation were observed and detected. Twist1 +/- mice were also injected with recombinant mouse periostin to verify the treatment effects., Results: Cell Counting Kit-8 results showed that recombinant mouse periostin inhibited the proliferation of suture-derived cells in a time- and concentration-dependent manner. Cell migration was also suppressed when treated with recombinant mouse periostin. Real-time quantitative PCR and Western blotting results suggested that messenger ribonucleic acid and protein expression of alkaline phosphatase, bone sialoprotein, collagen type I, and osteocalcin were all downregulated after treatment with recombinant mouse periostin. However, the expression of Wnt-3a, Wnt-1, and β-catenin were upregulated. The in vivo results demonstrated that periostin-treated Twist1 +/- mice showed patent coronal sutures in comparison with non-treated Twist1 +/- mice which have coronal craniosynostosis., Conclusion: Our results suggest that recombinant mouse periostin can inhibit coronal suture cell proliferation and migration and suppress osteogenic differentiation of suture-derived cells via Wnt canonical signaling, as well as ameliorate coronal suture fusion in Twist1 +/- mice.

Mesomelia-synostoses syndrome (MSS) is a rare, autosomal-dominant, syndromal osteochondrodysplasia characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations due to a non-recurrent deletion at 8q13 that always encompasses two coding-genes, SULF1 and SLCO5A1. To date, five unrelated patients have been reported worldwide, and MMS was previously proposed to not be a genomic disorder associated with deletions recurring from non-allelic homologous recombination (NAHR) in at least two analyzed cases. We conducted targeted gene panel sequencing and subsequent array-based copy number analysis in an 11-year-old undiagnosed Japanese female patient with multiple congenital anomalies that included mesomelic limb shortening and detected a novel 590 Kb deletion at 8q13 encompassing the same gene set as reported previously, resulting in the diagnosis of MSS. Breakpoint sequences of the deleted region in our case demonstrated the first LINE-1s (L1s)-mediated unequal NAHR event utilizing two distant L1 elements as homology substrates in this disease, which may represent a novel causative mechanism of the 8q13 deletion, expanding the range of mechanisms involved in the chromosomal rearrangements responsible for MSS., (© 2017 Wiley Periodicals, Inc.)

Background: Carpal synostoses are congenital defects characterised by complete or incomplete coalition of two or more carpal bones. Although most of these defects are discovered only incidentally, sometimes they become clinically manifest. Among the different types of carpal coalition, the synostosis between capitate and trapezoid bones is quite rare, with only sparse data available in the literature. The aim of this report was to describe a case of capitate-trapezoid synostosis (CTS) observed in an ancient human skeleton, as well as to scrutinise the pertinent literature in order to assess for the characteristics of this type of defect, including its potential relevance to clinical practice., Materials and Methods: We studied the skeletal remains of an Early Bronze Age male warrior affected by incomplete CTS. Macroscopic and radiological examination of the defect was carried out. We also performed a comprehensive PubMed search in the Medline and other specialty literature databases to retrieve and analyse data relevant to the subject under consideration., Results and Conclusions: The present case is the most ancient CTS ever found. In those literature-reported cases accompanied by careful anatomical description, such as the present one, incomplete coalition invariably occurs between the dorsal surfaces of the two bones, this characteristic emerging as a distinctive morphological trait. Literature analysis further suggests that the true prevalence of CTS is likely to be higher than estimates based on data gathered from radiology series, and that this defect may be associated with pain and carpal bossing more frequently than generally thought.

Spondylocarpotarsal synostosis syndrome (SCT) is a rare Mendelian disorder (OMIM #272460) characterized by prenatal vertebral fusion, scoliosis, short stature and carpal and tarsal synostosis. SCT is typically known as an autosomal recessive disease caused by variants in the FLNB gene. The genetic basis of the rarer cases of vertical transmissions remains unknown. In two independent families with symptoms related to autosomal dominant SCT, we identified - by exome sequencing - two protein-altering variants in the embryonic myosin heavy chain 3 (MYH3) gene. As MYH3 variants are also associated with distal arthrogryposis (DA1, DA2A, DA2B) and autosomal dominant multiple pterygium syndromes (MPS), the present study expands the phenotypic spectrum of MYH3 variants to autosomal dominant SCT. Vertebral, carpal and tarsal fusions observed in both families further confirm that MYH3 plays a key role in skeletal development.

Objective: To describe the intraoperative findings and outcomes of stapedectomy surgery in Teunissen-Cremers syndrome., Patients: A family of three patients with bilateral conductive hearing loss because of Teunissen-Cremers syndrome., Intervention: Six exploratory tympanotomies and stapedectomies, including one revision operation., Main Outcome Measures: Intraoperative findings and postoperative hearing results., Results: There was an increased distance between the incus and the vestibule, a thicker long process of the incus, and slight variation in the relative position of the ossicles in all patients. Surgery resulted in closure of the air-bone gap to less than 10 dB in all five operated ears., Conclusion: We describe anatomic abnormalities of the ossicular chain in Teunissen-Cremers syndrome. Prosthesis availability should include prostheses that can adapt to these potential anatomic abnormalities. Stapedectomy resulted in good long-term hearing outcomes in this series.

Fibroblast growth factor receptor 2 (FGFR2) signaling is critical for proper craniofacial development. A gain-of-function mutation in the 2c splice variant of the receptor's gene is associated with Crouzon syndrome, which is characterized by craniosynostosis, the premature fusion of one or more of the cranial vault sutures, leading to craniofacial maldevelopment. Insight into the molecular mechanism of craniosynostosis has identified the ERK-MAPK signaling cascade as a critical regulator of suture patency. The aim of this study is to investigate the role of FGFR2c-induced ERK-MAPK activation in the regulation of coronal suture development. Loss-of-function and gain-of-function Fgfr2c mutant mice have overlapping phenotypes, including coronal synostosis and craniofacial dysmorphia. In vivo analysis of coronal sutures in loss-of-function and gain-of-function models demonstrated fundamentally different pathogenesis underlying coronal suture synostosis. Calvarial osteoblasts from gain-of-function mice demonstrated enhanced osteoblastic function and maturation with concomitant increase in ERK-MAPK activation. In vitro inhibition with the ERK protein inhibitor U0126 mitigated ERK protein activation levels with a concomitant reduction in alkaline phosphatase activity. This study identifies FGFR2c-mediated ERK-MAPK signaling as a key mediator of craniofacial growth and coronal suture development. Furthermore, our results solve the apparent paradox between loss-of-function and gain-of-function FGFR2c mutants with respect to coronal suture synostosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Spondylocarpotarsal synostosis (SCT) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in Filamin B (FLNB). FLNB acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems, yet the disease mechanisms for SCT remain unclear. Employing a Flnb knockout mouse, we found morphologic and molecular evidence that the intervertebral discs (IVDs) of Flnb-/-mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the IVD, particularly the annulus fibrosus (AF). In Flnb-/-mice, the AF cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue. We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFβ signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf. These findings indicate that FLNB is involved in attenuation of TGFβ/BMP signaling and influences AF cell fate. Furthermore, we demonstrate that the IVD disruptions in Flnb-/-mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration.

Digit formation is a process, which requires the proper segmentation, formation and growth of phalangeal bones and is precisely regulated by several important factors. One such factor is Ihh, a gene linked to BDA1 and distal symphalangism in humans. In existing mouse models, mutations in Ihh have been shown to cause multiple synostosis in the digits but lead to perinatal lethality. To better study the exact biological and pathological events which occur in these fused digits, we used a more viable Prx1-Cre;Ihh(fl/fl) model in which Cre recombinase is expressed during mesenchymal condensation in the earliest limb buds at E9.5 dpc and found that mutant digits continuously fuse postnatally until phalanges are finally replaced by an unsegmented "one-stick bone". Mutant mice displayed osteocalcin-positive mature osteoblasts, but had reduced proliferation and abnormal osteogenesis. Because of the close interaction between Ihh and PTHrP during endochondral ossification, we also examined the digits of Prx1-Cre;PTH1R(fl/fl) mice, where the receptor for PTHrP was conditionally deleted. Surprisingly, we found PTH1R deletion caused symphalangism, demonstrating another novel function of PTH1R signaling in digit formation. We characterized the symphalangism process whereby initial cartilaginous fusion prevented epiphyseal growth plate formation, resulting in resorption and replacement of the remaining cartilage by bony tissue. Chondrocyte differentiation displayed abnormal directionality in both mutants. Lastly, Prx1-Cre;Ihh(fl/fl);Jansen Tg mice, in which a constitutively active PTH1R allele was introduced into Ihh mutants, were established to address the possible involvement of PTH1R signaling in Ihh mutant digits. These rescue mice failed to show significantly improved phenotype, suggesting that PTH1R signaling in chondrocytes is not sufficient to restore digit formation. Our results demonstrate that Ihh and PTH1R signaling in limb mesenchyme are both essential to regulate proper development of digit structures, although they appear to use different mechanisms., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Scaphocephaly is the most common single suture craniosynostosis. Surgical technique has evolved from simple strip craniectomy over π-procedures and vertex craniectomies to extensive cranial remodeling which is preferred procedure nowadays. The purpose of this paper is to present our modification of Renier's standard "H" technique and its preliminary results in detail. Eleven patients with scaphocephaly were surgically treated from January 2011 until January 2014. Only children with isolated sagittal synostosis were included in the study. Our modified Renier's technique reduces the possibility of lesion of superior sagittal sinus, dividing parietal bone in three bone fragments, thus achieving shortening of the scull in AP diameter without detaching the bone from the superior sagittal sinus. The possibility for potential secondary stenosis is minimized using extended V-shaped osteotomies with rounding of the bone edges, as well as making wide neocoronal and neolambdoid sutures. Cosmetic results were estimated as very pleasing immediately after surgery by both the parents and the surgeons in all cases. The majority of patients presented in our study were categorized as Sloan Class 1. Improvement or normalization of the cranial index was accomplished in all patients. No revision surgeries were required during the follow-up. Triple square extended osteotomies technique is a fast, simple, and efficient surgical option for children with sagittal synostosis and can be safely applied in the first months of life in children even under weight of 6 kilos. Preliminary results are encouraging and deserve a longer follow-up and comparative surgical analysis to verify its usefulness in the future.

We describe a 0.73 Mb duplication of chromosome 22q11.21 between LCR-B and LCR-D and a missense mutation in a conserved C2H2 zinc finger domain of SALL4 in a cognitively normal patient with multiple skeletal anomalies including radioulnar synostosis, thumb aplasia, butterfly vertebrae, rib abnormalities, and hypoplasia of the humeral and femoral epiphyses. 22q11.21 is a common site for microdeletions and their reciprocal microduplications as a result of non-allelic homologous recombination between its multiple low copy repeat regions (LCR). DiGeorge /Velocardiofacial syndrome (DG/VCFS) is classically caused by a 3 Mb deletion between LCR-A and LCR-D or a 1.5 Mb deletion between LCR-A and LCR-B. The reciprocal syndrome to DG/VCFS is the recently described 22q11.2 microduplication, which usually presents with the typical 3 Mb or 1.5 Mb duplication. Numerous atypical deletions and duplications have been reported between other LCRs. Typically, SALL4-related Duane-radial ray syndrome is caused by deletions or nonsense mutations; the only missense SALL4 mutation described prior was thought to result in gain of function and produced cranial midline defects. The skeletal anomalies presented in this report have not been previously described in association with 22q11.2 microduplication nor SALL4 mutations., (© 2015 Wiley Periodicals, Inc.)

We report this 47-year-old man who presented with polytrauma following a fall from a roof in March 2011. He sustained a head injury and a complex, comminuted forearm fracture. He underwent an open reduction and internal fixation of the fracture at the time of injury, but later developed a rigid type 2 diaphyseal radioulnar synostosis, with loss of forearm rotation. Synostosis excision and a radial artery perforator-based adipofascial interposition flap to prevent recurrence has resulted in a good functional outcome and no recurrence at 2.5 years follow-up., (2015 BMJ Publishing Group Ltd.)

TCF12 mutations have been reported very recently in coronal synostosis. We report several cases of familial coronal synostosis among four families harbouring novel TCF12 mutations. We observed a broad interfamilial phenotypic spectrum with features overlapping with the Saethre-Chotzen syndrome. TCF12 molecular testing should be considered in patients with unilateral- or bilateral-coronal synostosis associated or not with syndactyly, after having excluded mutations in the TWIST1 gene and the p.Pro250Arg mutation in FGFR3.

Ectrodactyly is a rare developmental anomaly of the distal part of the forelimb. It is characterized by the presence of an abnormal longitudinal soft tissue and osseous separation or cleft between the digits and the metacarpal bones. It can be associated with hypoplasia, aplasia and malformation of one or more bones of the antebrachium, carpus, metacarpus and digits. Unilateral ectrodactyly and moderate lameness were diagnosed in a young female dog. The dog was treated surgically with reconstruction of soft tissues and stabilization of the metacarpal bones by two nylon cerclage sutures. After three years a mild residual lameness was present. Radiographic signs of synostosis between the metacarpal bones II, III and IV with presence of a cleft between carpal bones II and III were observed.

Background: The squamous segment of occipital bone consists of cartilaginous and membranous origin. The cartilaginous part develops to supra-occipital bone. The membranous part has three primary ossification centers on each side. The first pair ossification center lies above the cartilaginous part between the superior nuchal line and the highest nuchal line and fuse with the cartilaginous part to form a supra-occipital segment of occipital bone. The second and third pairs have two nuclei each forming lateral and medial plates. All of these ossification centers fuse to form squamous segments of occipital bone. The fusion failure between ossification centers of second and third pair nuclei with each other or supra-occipital segment causes separated bone(s) called interparietal bone(s) or os incae. The interparietal bone should be differentiated from Wormian (intrasutural) bone. The incidence from various studies ranges from 0.37% to 9.50% of the population., Objective: To study the incidence and variation of interparietal bone in Northeastern Thailand as compared with other studies., Material and Method: A total of 400 Thai native skulls (276 male and 124 female) from the collection of Anatomical Museum of the Faculty of Medicine Khon Kaen University aged from 16 to 93 years old were examined by naked eye and photographed. Wormian bone was excluded by shape and site. The statistical method used was percentage of relative frequency., Results: The incidence of interparietal bone in Northeastern Thailand is 7.25% (29 from 400). Males have a two times higher incidence rate than females, (8.33% versus 4.84%). Eleven patterns of interparietal bone were found. Fusion failure of a third pair ossification center is more common than second pair, Conclusion: Knowledge of interparietal bone is useful for neurosurgeons and radiologists to avoid missed diagnosis of skull fracture. Presented interparietal bone may cause difficulty in surgery of occipital and parietal bone. Forensic scientist can use interparietal bone for personal identification.

Background: Congenital radioulnar synostosis (CRUS) causes a spectrum of presentations, most commonly a restriction of forearm rotation. Because most of these children are not treated operatively, many are not followed clinically after the diagnosis has been made. This report describes that a subset of the Cleary and Omer type IV synostoses (anterior dislocation of the radial head) can present with a progressive block to elbow flexion that worsens with growth. The location of this synostosis allows the physis of the radial head to grow untethered. The enlarged radial head can impinge upon the capitellum, blocking elbow flexion and snapping on the annular ligament. We propose excision of the radial head as a method of treating the anteriorly dislocated radial head in type IV synostoses., Methods: We evaluated 4 patients with Cleary and Omer type IV synostoses who presented with an anteriorly dislocated radial head impinging on elbow flexion with snapping of the annular ligament. Each patient was treated with excision of the radial head., Results: In 4 patients excision of the radial head was performed through a lateral Kocher approach. At follow-up, all patients showed relief from their pain and mechanical symptoms, with return of baseline range of motion. One complication which occurred was transient radial nerve neuropraxia., Conclusions: Although surgery is rarely needed for CRUS, excision of the radial head may be indicated if progressive loss of elbow flexion occurs secondary to impingement of the anteriorly dislocated radial head with the distal humerus in patients with type IV synostosis. We report that excision of the radial head can successfully treat this condition. Patients with type IV CRUS should be educated about the potential for loss of elbow flexion and/or followed until skeletal maturity to evaluate for this potential condition., Level of Evidence: Case series consistent with level IV evidence; therapeutic study.

We report on a patient with a clinical phenotype showing all the features of the multiple synostoses syndrome or the facioaudiosymphalangism syndrome, including symphalangism, condunction deafness, and the typical facies. Previously, it was shown that this condition is genetically heterogeneous with initially mutations described in the NOG gene, coding for Noggin, an extracellular antagonist of bone morphogenetic proteins. Noggin also interacts with growth differentiation factor 5 (GDF5), in which mutations have also been described in families with symphalangism. The latter is also the case for the BMP receptor BMPR1B to which GDF5 binds. Finally, a mutation in another growth factor, fibroblast growth factor 9, was found in a family with multiple synostoses syndrome. In our patient, we could, however, not show a causative mutation in any of these genes, providing evidence for further genetic heterogeneity of this syndrome.

Purpose: The objectives were to study the morphology of fused vertebrae in thoracolumbar region., Materials and Methods: The study included 729 thoracolumbar vertebrae which were macroscopically observed for the fusion and morphological details were observed., Results: It was observed that, there was fusion in three of our specimens. One specimen was having fusion between the two typical thoracic vertebrae. The other one had fusion among the three typical thoracic vertebrae. The third specimen had fusion between the twelveth thoracic vertebrae and the first lumbar vertebra. The average length of body of thoracic vertebrae was 1.8 mms, vertebral foramen diameter was 1.4 mms, length of lamina was 1.9 mms and the length of spinous process was 2.6 mms. The same parameters for the fused vertebrae of two typical thoracic was 3.2 mms, 1.1 mms, 4 mms and 4.7 mms respectively. The parameters of fused three typical thoracic vertebrae were 5.2 mms, 1.4 mms, 6.6 mms and 7.9 mms respectively. The average morphometric parameters of the fused thoracolumbar vertebrae were 3.7 mms, 1.4 mms, 4 mms and 3.5 mms respectively., Conclusions: The present study has provided additional information on the anatomy and morphology of dorsolumbar spine synostosis with their embryological basis and clinical implications. We believe that the details are clinically important as they might be associated with neurological signs and symptoms.

Premature fusion of cranial sutures is a common problem with an incidence of 3-5 per 10,000 live births. Despite progress in understanding molecular/genetic factors affecting suture function, the complex process of premature fusion is still poorly understood. In the present study, corresponding excised segments of nine patent and nine prematurely fused sagittal sutures from infants (age range 3-7 months) with a special emphasis on their hierarchical structural configuration were compared. Cell, tissue and architecture characteristics were analysed by transmitted and polarised light microscopy, 2D-histomorphometry, backscattered electron microscopy and energy-dispersive-x-ray analyses. Apart from wider sutural gaps, patent sutures showed histologically increased new bone formation compared to reduced new bone formation and osseous edges with a more mature structure in the fused portions of the sutures. This pattern was accompanied by a lower osteocyte lacunar density and a higher number of evenly mineralised osteons, reflecting pronounced lamellar bone characteristics along the prematurely fused sutures. In contrast, increases in osteocyte lacunar number and size accompanied by mineralisation heterogeneity and randomly oriented collagen fibres predominantly signified woven bone characteristics in patent, still growing suture segments. The already established woven-to-lamellar bone transition provides evidence of advanced bone development in synostotic sutures. Since structural and compositional features of prematurely fused sutures did not show signs of pathological/defective ossification processes, this supports the theory of a normal ossification process in suture synostosis - just locally commencing too early. These histomorphological findings may provide the basis for a better understanding of the pathomechanism of craniosynostosis, and for future strategies to predict suture fusion and to determine surgical intervention.

Purpose: The objectives were to study the anatomical features of fused vertebra in the cervical region., Materials and Methods: The study included 363 cervical vertebras which were macroscopically observed for the fusion and their morphology was studied., Results: Among our specimens, one fusion was observed between the C1 and C2 and the other was between C2 and C3. The mean anteroposterior diameter of normal atlas and axis were 42.1 +/- 0.9 mm and 46 +/- 0.5 mm respectively. The fused C1-C2 had 39 +/- 0.6 mm anteroposterior diameter. The mean lengths of anterior arch of normal atlas and body of axis were 16 +/- 0.9 mm and 23 +/- 0.7 mm respectively and the fused C1-C2 body length was 30 +/- 0.3 mm. The mean anteroposterior diameter of normal C2 and C3 vertebra were 46 +/- 0.5 mm and 47 +/- 0.8 mm respectively and of fused C2-C3 was 44 +/- 0.2 mm. The body length of C2 was 23 +/- 0.7 mm and C3 was 33 +/- 0.1 mm. The body length of fused C2-C3 was 36 +/- 0.8 mm., Conclusion: The present study has provided additional information on the anatomy, morphology of cervical spine synostosis with their embryological basis and clinical implications.

Congenital fusion of the mandible to the maxilla (syngnathia) is a rare disorder. The first case was reported in 1936 and only a few cases have been reported in the literature since then. This paper reports three new cases of syngnathia. Clinical and radiographic features are presented, as well as surgical management and complications., (Copyright © 2012 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Growth and differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) family, is essential for cartilage, bone, and joint formation. Antagonists such as noggin counteract BMP signaling by covering the ligand's BMP type I (BMPRI) and type II (BMPRII, ActRII, ActRIIB) interaction sites. The mutation GDF5-S94N is located within the BMPRII interaction site, the so-called knuckle epitope, and was identified in patients suffering from multiple synostoses syndrome (SYNS). SYNS is characterized by progressive symphalangism, carpal/tarsal fusions, deafness and mild facial dysmorphism. Here we present a novel molecular mechanism of a GDF5 mutation affecting chondrogenesis and osteogenesis. GDF5-S94N exhibits impaired binding to BMPRII causing alleviated Smad and non-Smad signaling and reduced chondrogenic differentiation of ATDC5 cells. Surprisingly, chondrogenesis in mouse micromass cultures was strongly enhanced by GDF5-S94N. By using quantitative techniques (SPR, reporter gene assay, ALP assay, qPCR), we uncovered that this gain of function is caused by strongly reduced affinity of GDF5-S94N to the BMP/GDF antagonist noggin and the consequential lack of noggin inhibition. Thus, since noggin is upregulated during chondrogenic differentiation, GDF5-S94N exceeds the GDF5 action, which results in the phenotypic outcome of SYNS. The detailed molecular characterization of GDF5-S94N as a noggin-resistant growth factor illustrates the potential of GDF5 mutants in applications with defined therapeutical needs.

A girl was born with a deformed position of the left forearm in pronation. On examination, supination was highly limited. Conventional radiography revealed a proximal radioulnar synostosis. The right forearm showed no abnormalities. Radioulnar synostosis is a pathological connection between the radius and the ulna, usually located in the proximal forearm. In 60% of the patients, this congenital lesion presents bilaterally.

This paper presents a case report of persistent low back pain and suspected lumbar radiculopathy. A synostosis at the level of the proximal tibiofibular joint was diagnosed. After successful resection of the synostosis, the low back symptoms resolved completely. This is the first report of a proximal tibiofibular synostosis as a possible cause of referred pain proximally.

Carpal coalition is an anomaly that is usually discovered as an incidental finding on roentgenograms. The most common site is between the lunate and the triquetrum, though fusion of almost every combination of carpal bones has been reported. Carpal coalition can be isolated but has also been associated with numerous congenital malformation syndromes. In this article, we report the case of a 12-year-old boy with left-sided asymptomatic fusion of the trapezoid and trapezium, fusion of the radius and scaphoid, and hypoplasia of the thumb.

The structure of the joint between the body and the greater cornu in the human hyoid bone was examined histologically in 259 cadavers (16-98 years). Joints were classified into three grades based on histological observations. Grade I showed fibrocartilage without degenerative change in the marginal region of the joint. Grade II showed prominent calcification or ossification on the outer margin of the joint without fusion. Grade III showed bony fusion. Histological changes with age were revealed by a comparison of the prevalences of these three grades among individuals of three age groups: young adult (16-39 years), middle aged (40-69 years), and elderly (70+ years). The frequency of hyoid bones with diarthrodial structure of this joint was compared between the age groups. The mean age of subjects with each grade of histological changes was calculated. Results show that, with age, the proportion of Grade I decreased significantly (P < 0.05) and that of Grade III increased significantly. Joints with diarthrodial structure decreased significantly with age relative to all subjects (P < 0.05). Clefts with necrotic tissue were observed in cartilage along with progressive calcification. The mean age of subjects with the histological changes was significantly higher than that of individuals without such changes (P < 0.05). Calcification and ossification of joints were induced with age from fibrous tissue and cartilage on the outer margin of a joint. The authors suggest that the age changes in the joint between the body and greater cornu of the hyoid bone may affect the mobility of this joint and may be related to masticatory and swallowing functions., (Copyright © 2011 Wiley-Liss, Inc.)

Object: The object of this report is to present a conceptual and technical approach for expanding the cranial vault, by distraction osteogenesis, in patients with craniocephalic disproportion secondary to pancraniosynostosis and in patients with complex syndromic craniofaciosynostoses undergoing operations for aesthetic improvement., Methods: The clinical characteristics, techniques used, outcome and complications for all patients who underwent cranial vault expansions with distraction osteogenesis in Children's Hospital of Denver were reviewed., Results: Twenty-six cranial vault expansions were done in 24 patients. Nineteen patients presented with intracranial hypertension. Twelve of these had pancraniosynostosis and 8 had a syndromic diagnosis. Large segments of cranial bone were translated in a controlled manner for distances up to 30 mm. All but one of the patients with intracranial hypertension experienced complete resolution., Conclusions: Cranial vault expansion by distraction osteogenesis has the great advantage, as the name implies, of generating new and vascularized autologous bone of the correct shape and in correct locations. The technique, although not simple and not risk free, is much less technically complicated and places patients at lower risk for the most serious complications than does single-stage vault expansion. Less soft tissue dissection and less devascularization of bone are required and there are no postoperative dead spaces. Distraction osteogenesis facilitates far greater vault expansions than do single-stage procedures and can be accomplished in any desired direction.

Congenital bony fusion of the maxilla and mandible, especially as an isolated occurrence, is a very rare condition. The very few cases reported in the literature are mostly inadequate in description and confusing in nomenclature. An isolated case of syngnathia in a 60-year-old female patient with unilateral bony fusion (synostosis) of the maxilla and mandible associated with fibrous adhesions (synechiae) of the opposite site is reported. The existent literature is also reviewed.

We report on a girl with Giuffrè-Tsukahara syndrome manifesting microcephaly, mental retardation, radio-ulnar synostosis, short stature and scoliosis. Skewed X-inactivation was not observed in our patient. We reviewed previous reports and provide evidence in support of X-linked dominant inheritance of this condition.

Summary: This report summarizes the clinical management of an infant with a proximal radio-ulnar synostosis and inherited bone marrow failure syndrome (PRUS/IBMFS). Molecular studies were negative for the characteristic HOXA11 mutation described earlier. He was successfully treated with a non-myeloablative hematopoietic stem cell transplantation from an human leukocyte antigen-identical sibling donor at the age of 3 months. We reviewed the literature on PRUS/IBMFS with an emphasis on the current understanding of the molecular mechanisms involved in the disease pathogenesis. Absence of the HOXA11 mutation in this case implies that molecular mechanisms beyond the HOXA11 gene, yet to be discovered, may contribute for the development of PRUS/IBMFS.

Objective: Proximal radioulnar synostosis is a rare upper limb malformation. The elbow is first identifiable at 35 days (after conception), at which stage the cartilaginous anlagen of the humerus, radius and ulna are continuous. Subsequently, longitudinal segmentation produces separation of the distal radius and ulna. However, temporarily, the proximal ends are united and continue to share a common perichondrium. We investigated the hypothesis that posterior congenital dislocation of the radial head and proximal radioulnar fusion are different clinical manifestations of the same primary developmental abnormality., Materials and Methods: Records were searched for "proximal radioulnar fusion/posterior radial head dislocation" in patients followed at the local Children's Hospital and Rehabilitation Centre for Children. Relevant radiographic, demographic and clinical data were recorded. Ethics approval was obtained through the University Research Ethics Board., Results: In total, 28 patients met the inclusion criteria. The majority of patients (16) had bilateral involvement; eight with posterior dislocation of the radial head only; five had posterior radial head dislocation with radioulnar fusion and two had radioulnar fusion without dislocation. One patient had bilateral proximal radioulnar fusion and posterior dislocation of the left radial head. Nine patients had only left-sided involvement, and three had only right-sided involvement.The degree of proximal fusion varied, with some patients showing 'complete' proximal fusion and others showing fusion that occurred slightly distal to the radial head: 'partially separated.' Associated disorders in our cohort included Poland syndrome (two patients), Cornelia de Lange syndrome, chromosome anomalies (including tetrasomy X) and Cenani Lenz syndactyly., Conclusion: The suggestion of a developmental relationship between posterior dislocation of the radial head and proximal radioulnar fusion is supported by the fact that both anomalies can occur in the same patient. Furthermore, both anomalies can be seen in different patients with the same genetic diagnosis, further supporting the notion that these defects are developmentally related. Posterior dislocation of the radial head and radioulnar fusion are considered to be related primary developmental anomalies of radioulnar differentiation/segmentation. We speculate that the eventual specific defect of this spectrum is influenced by very subtle differences in developmental timing. This is in contrast to patients with transverse forearm defects who can also display radial head dislocation but in an anterior or lateral direction. This direction of dislocation is seen when an abnormal force is exerted on a normally formed radial head later in development or postnatally in disorders such as multiple osteochondromatosis and various mesomelic dysplasias, or as a result of trauma.

Background: Atlanto-occipital fusion may be symptomatic or asymptomatic in nature. The anomaly may be incidentally detected at autopsies or during routine cadaveric dissections. The fusion of the atlas with occipital bone may result in the compression of vertebral artery and first cervical nerve., Methods: A total of 55 dried occipital bones in the Department of Anatomy, Universiti Kebangsaan Malaysia (UKM) and Department of Anatomy, Universiti Malaya (UM) were included in the study. The presence of atlantooccipital fusion was closely observed and morphometric measurements were taken., Results: Out of 55 dried occipital bones studied, we observed atlanto-occiptalization in two bones (3.63 %). A total of 53 occipital bones (96.37 %) did not exhibit any anomalous fusions. Out of the two anomalous atlanto-occiptal fusions, one was complete while the other had unilateral right-sided fusion of the atlas with the occipital bone., Conclusion: Atlanto-occipitalization may result in the compression of vertebral artery thereby influencing the blood flow to the brain. Atlanto-occipitalization may also result in compression of the first cervical nerve. The action of the postural muscles on the extensor surface may be affected as a result of this anomaly. The present article discusses the clinical implications of atlanto-occipitalization, which may be beneficial for neurosurgeons, neurologists and radiologists in day-to-day clinical practice (Fig. 3, Ref. 17).