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Skeletal dysplasias are group of rare genetic diseases resulting from mutations in genes encoding structural proteins of the cartilage extracellular matrix (ECM), signaling molecules, transcription factors, epigenetic modifiers, and several intracellular proteins. Cell division, organelle maintenance, and intracellular transport are all orchestrated by the cytoskeleton-associated proteins, and intracellular processes affected through microtubule-associated movement are important for the function of skeletal cells. Among microtubule-associated motor proteins, kinesins in particular have been shown to play a key role in cell cycle dynamics, including chromosome segregation, mitotic spindle formation, and ciliogenesis, in addition to cargo trafficking, receptor recycling, and endocytosis. Recent studies highlight the fundamental role of kinesins in embryonic development and morphogenesis and have shown that mutations in kinesin genes lead to several skeletal dysplasias. However, many questions concerning the specific functions of kinesins and their adaptor molecules as well as specific molecular mechanisms in which the kinesin proteins are involved during skeletal development remain unanswered. Here we present a review of the skeletal dysplasias resulting from defects in kinesins and discuss the involvement of kinesin proteins in the molecular mechanisms that are active during skeletal development.

Osteofibrous dysplasia (OFD) is a rare, benign, fibro-osseous lesion that occurs most commonly in the tibia of children. Tibial involvement leads to bowing and predisposes to the development of a fracture which exhibit significantly delayed healing processes, leading to prolonged morbidity. We previously identified gain-of-function mutations in the MET gene as a cause for OFD. In our present study, we test the hypothesis that gain-of-function MET mutations impair bone repair due to reduced osteoblast differentiation. A heterozygous Met exon 15 skipping (Met Δ15 -HET) mouse was created to imitate the human OFD mutation. The mutation results in aberrant and dysregulation of MET-related signaling determined by RNA-seq in the murine osteoblasts extracted from the wide-type and genetic mice. Although no gross skeletal defects were identified in the mice, fracture repair was delayed in Met Δ15 -HET mice, with decreased bone formation observed 2-week postfracture. Our data are consistent with a novel role for MET-mediated signaling regulating osteogenesis., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman-Handmaker type (DDSH) and nonlethal Rolland-Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz-Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2., (© 2024. The Author(s).)

Secondary osteosarcoma is a rare complication of primary malignancies and benign bone lesions. There are various types of diseases that cause secondary osteosarcoma. A 15-year-old male presented at our medical center complaining of pain and redness in the right lower leg. He had been diagnosed with osteofibrous dysplasia in the right tibia when he was 2 years old and since then had been followed up. Although he had a pathological fracture of the right tibia at the age of 7, his fracture healed with a plaster cast and did not require surgery. At the time of the patient's last visit, a radiograph revealed a periosteal reaction as well as erosion of the bone cortex. Magnetic resonance imaging revealed an infiltrative area in the soft tissue surrounding the osteofibrous dysplasia lesion in the tibia. Consequent to pathological examination (through bone biopsy), the patient was diagnosed with secondary osteosarcoma. The patient underwent chemotherapy and extensive resection with liquid nitrogen. He has been progressing satisfactorily after the operation. The present case is the first report of secondary osteosarcoma associated with osteofibrous dysplasia. During the long-term follow-up of osteofibrous dysplasia, oncologists should be aware of the possibility of secondary osteosarcoma., (© 2022. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Introduction: Dominant pathogenic mutations in the TRPV4 gene give rise to a wide spectrum of abnormal phenotypes, including bone dysplasia as well as spinal muscular atrophy and hereditary motor and sensory neuropathy. Spondyloepimetaphyseal dysplasias (SEMDs) are autosomal dominant skeletal dysplasias characterized by mild epiphyseal dysplasia, flared metaphyses, prominent joints, spondyler dysplasia, and brachydactyly with various carpal, metacarpal, and finger malformations., Case Presentation: We present a boy who has the clinical and radiological signs of SEMD-M with a dominant TRPV4 mutation. He also has some striking findings that have not been seen in these patients before, and they may be able to provide assistance to medical professionals in the process of diagnosis.These include a shorter distance between his lumbar vertebrae, congenital contractures, and an arachnoid cyst., (© 2022. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Case: We present a case of dysplasia epiphysealis hemimelica (DEH) involving the posteromedial distal femur in a 4-year-old girl. The patient underwent lesion resection with internal fixation of the articular cartilage followed by autologous chondrocyte implantation (ACI) to restore the articular surface and epiphysis. At the 7-year follow-up, the patient had no pain or difficulty with participation in sports. Advanced imaging showed a stable articular surface with evidence of durable cartilage integration., Conclusion: DEH is a rare disease often treated by resection. In cases where the articular surface of the knee is involved, we have demonstrated that augmentation with ACI can be an effective treatment option., ((C) 2022 All Rights Reserved.The Journal of Bone and Joint Surgery, Inc.)

Small patella syndrome (SPS) is a rare autosomal dominant disorder caused by mutations in TBX4 gene which encodes a transcription factor of FGF10 . However, how TBX4 mutations result in SPS is poorly understood. Here, a novel TBX4 mutation c.1241C>T (p.P414L) was identified in a SPS family and series of studies were performed to evaluate the influences of TBX4 mutations (including c.1241C>T and two known mutations c.256G>C and c.743G>T). Results showed that mesenchymal stem cells (MSCs) with stable overexpression of either TBX4 wild-type ( TBX4 wt ) or mutants ( TBX4 mt ) were successfully generated. Immunofluorescence study revealed that both the overexpressed TBX4 wild-type and mutants were evenly expressed in the nucleus suggesting that these mutations do not alter the translocation of TBX4 into the nucleus. Interestingly, MSCs overexpression of TBX4 mt exhibited reduced differentiation activities and decreased FGF10 expression. Chromatin immunoprecipitation (ChIP) study demonstrated that TBX4 mutants still could bind to the promoter of FGF10 . However, dual luciferase reporter assay clarified that the binding efficiencies of TBX4 mutants to FGF10 promoter were reduced. Taken together, MSCs were firstly used to study the function of TBX4 mutations in this study and the results indicate that the reduced binding efficiencies of TBX4 mutants (TBX4 mt ) to the promoter of FGF10 result in the abnormal biological processes which provide important information for the pathogenesis of SPS.

Aims: Osteofibrous dysplasia (OFD) is a rare benign lesion predominantly affecting the tibia in children. Its potential link to adamantinoma has influenced management. This international case series reviews the presentation of OFD and management approaches to improve our understanding of OFD., Methods: A retrospective review at three paediatric tertiary centres identified 101 cases of tibial OFD in 99 patients. The clinical records, radiological images, and histology were analyzed., Results: Mean age at presentation was 13.5 years (SD 12.4), and mean follow-up was 5.65 years (SD 5.51). At latest review, 62 lesions (61.4%) were in skeletally mature patients. The most common site of the tibial lesion was the anterior (76 lesions, 75.2%) cortex (63 lesions, 62.4%) of the middle third (52 lesions, 51.5%). Pain, swelling, and fracture were common presentations. Overall, 41 lesions (40.6%) presented with radiological deformity (> 10°): apex anterior in 97.6%. A total of 41 lesions (40.6%) were treated conservatively. Anterior bowing < 10° at presentation was found to be related to successful conservative management of OFD (p = 0.013, multivariable logistic regression). Intralesional excision was performed in 43 lesions (42.6%) and a wide excision of the lesion in 19 (18.8%). A high complication rate and surgical burden was found in those that underwent a wide excision regardless of technique employed. There was progression/recurrence in nine lesions (8.9%) but statistical analysis found no predictive factors. No OFD lesion transformed to adamantinoma., Conclusion: This study confirms OFD to be a benign bone condition with low rates of local progression and without malignant transformation. It is important to distinguish OFD from adamantinoma by a histological diagnosis. Focus should be on angular deformity, monitored with full-length tibial radiographs. Surgery is indicated in symptomatic patients and predicted by the severity of the initial angular deformity. Surgery should focus more on the deformity rather than the lesion. Cite this article: Bone Joint J  2022;104-B(2):302-308.

Osteocraniostenosis (OCS, OMIM #602361) is a severe, usually lethal condition characterized by gracile bones with thin diaphyses, a cloverleaf-shaped skull and splenic hypo/aplasia. The condition is caused by heterozygous mutations in the FAM111A gene and is allelic to the non-lethal, dominant disorder Kenny-Caffey syndrome (KCS, OMIM #127000). Here we report two new cases of OCS, including one with a detailed pathological examination. We review the main diagnostic signs of OCS both before and after birth based on our observations and on the literature. We then review the current knowledge on the mutational spectrum of FAM111A associated with either OCS or KCS, including three novel variants, both from one of the OCS fetuses described here, and from further cases diagnosed at our centers. This report refines the previous knowledge on OCS and expands the mutational spectrum that results in either OCS or KCS.

The human skeleton of a young adult male with marked asymmetry of the bilateral upper extremities was excavated from the Mashiki-Azamabaru site (3000-2000 BCE) on the main island of Okinawa in the southwestern archipelago of Japan. The skeleton was buried alone in a corner of the cemetery. In this study, morphological and radiographic observations were made on this skeleton, and the pathogenesis of the bone growth disorder observed in the left upper limb was discussed. The maximum diameter of the midshaft of the humerus was 13.8 mm on the left and 21.2 mm on the right. The long bones comprising the left upper extremity lost the structure of the muscle attachments except for the deltoid tubercle of the humerus. The bone morphology of the right upper extremity and the bilateral lower extremities was maintained and was close to the mean value of females from the Ohtomo site in northwestern Kyushu, Japan, during the Yayoi period. It is assumed that the anomalous bone morphology confined to the left upper extremity was secondary to the prolonged loss of function of the muscles attached to left extremity bones. In this case, birth palsy, brachial plexus injury in childhood, and acute grey matter myelitis were diagnosed. It was suggested that this person had survived into young adulthood with severe paralysis of the left upper extremity due to injury or disease at an early age., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Keiko Ogami-Takamura et al.)

Acrocapitofemoral dysplasia (ACFD) is a rare autosomal recessive skeletal dysplasia characterized by short stature with short limb dwarfism, brachydactyly, and a narrow thorax. Major radiographic features are egg-shaped capital femoral epiphyses with a short femoral neck and cone-shaped epiphyses, mainly in the hands and hips. To date, only four child patients from two families have been reported. We describe two adult patients with ACFD with a novel homozygous c.478C>T (p.Arg160Cys) mutation in IHH in the third family of the literature. The reported cases showed a middle phalanges which fused with distal phalanges in the fifth toes, the typical configuration of metacarpals, radial angulation and extremely short femoral neck. These findings could help the diagnosis of ACFD in adult patients. We hope that this new family will be a helpful guide for predicting and managing the prognosis of diagnosed children., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Case: A 11-year-old boy with no medical history presented with a protective limp and worsening mechanical pain in his left knee. No recent traumatic or infectious history was reported. Radiographs and ultrasonography showed multiple intra-articular loose bodies with osteocartilaginous signal. Dysplasia epiphysealis hemimelica (DEH) was confirmed by magnetic resonance imaging (MRI) and computed tomography (CT) scan. This is the first report that describes the presence of loose bodies in a knee without previous surgery as a possible case of DEH., Conclusion: We emphasize the use of CT scan and MRI before any surgical procedure when intra-articular loose bodies are unexpectedly discovered., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B679)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies., (© 2021. The Author(s).)

Fibrous dysplasia is an unusual pathologic condition caused by abnormal bone metabolism. Temporal bone involvement is often seen, but it is uncommon to find fibrous dysplasia limited to the middle ear, especially originating in and confined to a single ossicle. Here we report a case of osteofibrous dysplasia limited exclusively to an ossicle (malleus) causing gradual conductive hearing loss, which recovered after eventual complete removal of the dysplastic area. The lesion showed firm attachment to adjacent structures and initial removal was not possible. This report provides information to help other otologic surgeons facing similar conditions., Competing Interests: Declaration of Competing Interest All authors have no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Skeletal dysplasia is a common, clinically and genetically heterogeneous disorder in the human population. An increasing number of different genes are being identified causing this disorder. We used whole exome sequencing (WES) for detection of skeletal dysplasia causing mutation in a fetus affected to severe lethal skeletal dysplasia., Patient: Fetus was assessed by ultrasonography in second trimester of pregnancy. He suffers from severe rhizomelic dysplasia and also pathologic shortening of ribs. WES was applied to finding of causal mutation. Furthermore, bioinformatics analysis was performed to predict mutation impact., Results: Whole exome sequencing (WES) identified a homozygous frameshift mutation in the TMEM263 gene in a fetus with severe lethal skeletal dysplasia. Mutations of this gene have been previously identified in dwarf chickens, but this is the first report of involvement of this gene in human skeletal dysplasia. This gene plays a key role in the growth hormone signaling pathway., Conclusion: TMEM263 can be considered as a new gene responsible for skeletal dysplasia. Given the complications observed in the affected fetus, the mutation of this gene appears to produce much more intense complications than that found in chickens and is likely to play a more important role in bone development in human.

Objectives: Acromesomelic dysplasia, type Maroteaux, is an autosomal recessive skeletal dysplasia caused by biallelic loss of function variations of NPR2 , which encodes a cartilage regulator C-type natriuretic peptide receptor B. NPR2 variations impair skeletal growth. It is a rare type of dwarfism characterized by shortening of the middle and distal segments of the limbs with spondylar dysplasia., Methods: We performed detailed clinical and radiological evaluation and sequence analysis for NPR2 ., Results: Herein, we report nine patients from eight families with two novel NPR2 pathogenic variants., Conclusions: This study describes typical clinical phenotypes of Maroteaux type acromesomelic dysplasia, and enriches the variant spectrum of NPR2 by reporting one nonsense and one missense novel variant. We emphasize the importance of detailed clinical evaluation before genetic testing in diagnosing rare skeletal disorders., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

The major mineralized tissues are bone and teeth, which share several mechanisms governing their development and mineralization. This crossover includes the hormones that regulate circulating calcium and phosphate concentrations, and the genes that regulate the differentiation and transdifferentiation of cells. In developing endochondral bone and in developing teeth, parathyroid hormone-related protein (PTHrP) acts in chondrocytes to delay terminal differentiation, thereby increasing the pool of precursor cells. Chondrocytes and (in specific circumstances) pre-odontoblasts can also transdifferentiate into osteoblasts. Moreover, bone and teeth share outcomes when affected by systemic disorders of mineral homeostasis or of the extracellular matrix, and by adverse effects of treatments such as bisphosphonates and fluoride. Unlike bone, teeth have more permanent effects from systemic disorders because they are not remodelled after they are formed. This Review discusses the normal processes of bone and tooth development, followed by disorders that have effects on both bone and teeth, versus disorders that have effects in one without affecting the other. The takeaway message is that bone specialists should know when to screen for dental disorders, just as dental specialists should recognize when a tooth disorder should raise suspicions about a possible underlying bone disorder.

TRPV4-related disorders constitute a broad spectrum of clinical phenotypes including several genetic skeletal and neuromuscular disorders, in which clinical variability and somewhat overlapping features are present. These disorders have previously been considered to be clinically distinct phenotypes before their molecular basis was discovered. However, with the identification of TRPV4 variants in the etiology, they are referred as TRPV4-related disorders (TRPV4-pathies), and are now mainly grouped into skeletal dysplasias and neuromuscular disorders. The skeletal dysplasia group includes metatropic dysplasia, parastremmatic dysplasia, spondyloepiphyseal dysplasia Maroteaux type, spondylometaphyseal dysplasia Kozlowski type, autosomal dominant brachyolmia, and familial digital arthropathy-brachydactyly, whereas the neuromuscular group includes congenital distal spinal muscular atrophy (SMA), scapuloperoneal SMA and Charcot-Marie-Tooth neuropathy type 2C with common manifestations of peripheral neuropathy, joint contractures, and respiratory system involvement. Apart from familial digital arthropathy-brachydactyly, skeletal dysplasia associated with TRPV4 pathogenic variants share some clinical features such as short stature with short trunk, spinal and pelvic changes with varying degrees of long bone involvement. Of note, there is considerable phenotypic overlap within and between both groups. Herein, we report on the clinical and molecular spectrum of 11 patients from six different families diagnosed with TRPV4-related disorders. This study yet represents the largest cohort of patients with TRPV4 variants from a single center in Turkey., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Studies exploring molecular mechanisms underlying congenital skeletal disorders have revealed novel regulators of skeletal homeostasis and shown protein glycosylation to play an important role., Objective: To identify the genetic cause of rhizomelic skeletal dysplasia in a consanguineous Pakistani family., Methods: Clinical investigations were carried out for four affected individuals in the recruited family. Whole genome sequencing (WGS) was completed using DNA from two affected and two unaffected individuals from the family. Sequencing data were processed, filtered and analysed. In silico analyses were performed to predict the effects of the candidate variant on the protein structure and function. Small interfering RNAs (siRNAs) were used to study the effect of Gnpnat1 gene knockdown in primary rat chondrocytes., Results: The patients presented with short stature due to extreme shortening of the proximal segments of the limbs. Radiographs of one individual showed hip dysplasia and severe platyspondyly. WGS data analyses identified a homozygous missense variant c.226G>A; p.(Glu76Lys) in GNPNAT1 , segregating with the disease. Glucosamine 6-phosphate N-acetyltransferase, encoded by the highly conserved gene GNPNAT1 , is one of the enzymes required for synthesis of uridine diphosphate N-acetylglucosamine, which participates in protein glycosylation. Knockdown of Gnpnat1 by siRNAs decreased cellular proliferation and expression of chondrocyte differentiation markers collagen type 2 and alkaline phosphatase, indicating that Gnpnat1 is important for growth plate chondrocyte proliferation and differentiation., Conclusions: This study describes a novel severe skeletal dysplasia associated with a biallelic, variant in GNPNAT1 . Our data suggest that GNPNAT1 is important for growth plate chondrogenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Vertebral deformities in salmonid interspecific hybrids, some of which were triploidised, were assessed across three separate year classes during the freshwater life stage. Initially, eggs from a farmed Atlantic salmon Salmo salar were crossed with the sperm from a S. salar, arctic char Salvelinus alpinus or brown trout Salmo trutta. For S. salar × S. trutta, half the eggs were triploidised. In a second- and third-year class, the eggs from a farmed S. salar were crossed with the sperm from either a S. salar or a S. trutta, and half of each group was triploidised. In the two initial-year classes, all hybrids were larger than the S. salar controls, and triploid S. salar × S. trutta were larger than diploid counterparts. In the third-year class, the S. salar × S. trutta were smaller than the S. salar, in contrast to the initial 2 year classes, although the triploid hybrids were still larger than the diploids. In the third-year class, a high degree of spontaneous triploidy was also observed in the putative diploid groups (between 16 and 39%). Vertebral deformities were consistently higher in pressure-shocked triploids than diploids, irrespective of hybridisation, but there was no consistent effect of hybridisation among experiments. Although this study was not able to explain the contrasting results for vertebral deformities between year classes, triploid S. salar × S. trutta can demonstrate impressive freshwater growth that could be of interest for future farming programmes., (© 2020 The Authors. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of The Fisheries Society of the British Isles.)

As a first attempt to assess bone health in cleaner fish production, wild and cultured ballan wrasse Labrus bergylta and lumpfish Cyclopterus lumpus were examined by radiology. In C. lumpus, wild fish (57%) had more vertebra deformities (≥1 deformed vertebrae) than cultured fish (2-16%). One wild C. lumpus had lordosis and another was missing the tail fin. In L. bergylta, wild fish (11%) had fewer vertebra deformities than cultured individuals (78-91%). Among the cultured L. bergylta, 17-53% of the fish had severe vertebra deformities (≥6 deformed vertebrae) with two predominate sites of location, one between vertebra 4 and 10 (S1) in the trunk, and one between 19 and 26 (S2) in the tail. Fusions dominated S1, while compressions dominated S2. Although wild L. bergylta had a low vertebra deformity level, 83% had calluses and 14% had fractures in haemal/neural spines and/or ribs. The site-specific appearance and pathology of fracture and callus in wild L. bergylta suggests these are induced by chronic mechanical stress, and a possible pathogenesis for fish hyperostosis is presented based on this notion. In conclusion, good bone health was documented in cultured C. lumpus, but cultured L. bergylta suffered poor bone health. How this affects survival, growth, swimming abilities and welfare in cultured wrasse should be further investigated. SIGNIFICANCE STATEMENT: Skeletal deformities were studied in ballan wrasse and lumpfish of both wild and cultured origin for the first time to identify potential welfare issues when deploying them as cleaner fish in salmon sea cages. While cultured lumpfish showed good bone health, cultured wrasse had a high occurrence of vertebra deformities, which is expected to impact lice eating efficiency and animal welfare negatively. These deformities are most likely induced early in development., (© 2020 The Authors. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of The Fisheries Society of the British Isles.)

KBG syndrome is a rare genetic disease characterized mainly by skeletal abnormalities, distinctive facial features, and intellectual disability. Heterozygous mutations in ANKRD11 gene, or deletion of 16q24.3 that includes ANKRD11 gene are the cause of KBG syndrome. We describe two patients presenting with short stature and partial facial features, whereas no intellectual disability or hearing loss was observed in them. Two ANKRD11 variants, c.4039&#95;4041del (p. Lys1347del) and c.6427C > G (p. Leu2143Val), were identified in this study. Both of them were classified as variants of uncertain significance (VOUS) by ACMG/AMP guidelines and were inherited from their mothers. ANKRD11 could enhance the transactivation of p21 gene, which was identified to participate in chondrogenic differentiation. In this study, we demonstrated that the knockdown of ANKRD11 could reduce the p21-promoter luciferase activities while re-introduction of wild type ANKRD11, but not ANKRD11 variants (p. Lys1347del or p. Leu2143Val), could restore the p21 levels. Thus, our study report two loss-of-function ANKRD11 variants which might provide new insight on pathogenic mechanism that correlates ANKRD11 variants with the short stature phenotype of KBG syndrome., (© 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

A 6-y-old female dromedary camel ( Camelus dromedarius L.) was presented for assessment of firm, bilateral swellings rostral and ventral to the eyes. Serum biochemistry revealed hyperglycemia (28.5 mmol/L), hypocalcemia (1.27 mmol/L), hyperphosphatemia (3.39 mmol/L), hypoproteinemia (total protein 50 g/L), and hypoalbuminemia (20 g/L). Based on the poor prognosis associated with the presumptive diagnosis of fibrous osteodystrophy, the camel was euthanized. Gross postmortem findings revealed expanded fibrous tissue replacing the maxilla and mandible, and bilaterally prominent parathyroid glands. Histology of the maxilla revealed proliferative loose fibrous tissue with widely scattered, regularly spaced, small spicules of mineralized bone. The parathyroid glands were prominent bilaterally; the internal and external parathyroid glands were composed of plump cells with abundant pale basophilic cytoplasm and open nuclei. The pathologic findings were consistent with the antemortem diagnosis of fibrous osteodystrophy. The camel's diet, which was not specifically balanced for a camel, included grass hay, sweet feed, and alfalfa pellets. The camel's caregivers reported feeding her treats of cookies. A feed analysis was not available. The biochemistry abnormalities and clinical and postmortem findings, along with a diet that was not balanced for a camel, are consistent with a diagnosis of nutritional secondary hyperparathyroidism.

ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder, geleophysic dysplasia 1 (GPHYSD1), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 is a matricellular protein previously shown to interact with latent transforming growth factor-β binding protein 1 and influence assembly of fibrillin 1 microfibrils. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for O -fucosylation by protein O- fucosyltransferase 2 (POFUT2). O- fucose-modified TSRs are subsequently elongated to a glucose β1-3-fucose (GlcFuc) disaccharide by β1,3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS), which is characterized by skeletal defects similar to GPHYSD1. Several ADAMTSL2 TSRs also have consensus sequences for C- mannosylation. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O- fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used MS to identify glycan modifications at predicted consensus sequences on mouse ADAMTSL2. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O -fucosylation sites and variable mannose stoichiometry at C- mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2 -/- but not in B3GLCT -/- cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients. In contrast, secretion was significantly reduced for ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6), and S641L eliminated O- fucosylation of TSR3. These results provide evidence that abnormalities in GPHYSD1 patients with this mutation are caused by loss of O- fucosylation on TSR3 and impaired ADAMTSL2 secretion., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Zhang et al.)

Background: Osteofibrous dysplasia-like adamantinoma (OFD-AD) and classic adamantinoma (AD) are rare, neoplastic diseases with only limited data supporting current treatment protocols. We believe that our retrospective multicenter cohort study is the largest analysis of patients with adamantinoma to date. The primary purpose of this study was to describe the disease characteristics and evaluate the oncological outcomes. The secondary purpose was to identify risk factors for local recurrence after surgical treatment and propose treatment guidelines., Methods: Three hundred and eighteen confirmed cases of OFD-AD and AD for which primary treatment was carried out between 1985 and 2015 were submitted by 22 tertiary bone tumor centers. Proposed clinical risk factors for local recurrence such as size, type, and margins were analyzed using univariable and multivariate Cox regression analysis., Results: Of the 318 cases, 128 were OFD-AD and 190 were AD. The mean age at diagnosis was 17 years (median, 14.5 years) for OFD-AD and 32 years (median, 28 years) for AD; 53% of the patients were female. The mean tumor size in the OFD-AD and AD groups combined was 7.8 cm, measured histologically. Sixteen percent of the patients sustained a pathological fracture prior to treatment. Local recurrence was recorded in 22% of the OFD-AD cases and 24% of the AD cases. None of the recurrences in the OFD-AD group progressed to AD. Metastatic disease was found in 18% of the AD cases and fatal disease, in 11% of the AD cases. No metastatic or fatal disease was reported in the OFD-AD group. Multivariate Cox regression analysis demonstrated that uncontaminated resection margins (hazard ratio [HR] = 0.164, 95% confidence interval [CI] = 0.092 to 0.290, p < 0.001), pathological fracture (HR = 1.968, 95% CI = 1.076 to 3.600, p = 0.028), and sex (female versus male: HR = 0.535, 95% CI = 0.300 to 0.952, p = 0.033) impacted the risk of local recurrence., Conclusions: OFD-AD and AD are parts of a disease spectrum but should be regarded as different entities. Our results support reclassification of OFD-AD into the intermediate locally aggressive category, based on the local recurrence rate of 22% and absence of metastases. In our study, metastatic disease was restricted to the AD group (an 18% rate). We advocate wide resection with uncontaminated margins including bone and involved periosteum for both OFD-AD and AD., Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

This study has mainly a descriptive aim, in which crude prevalence of minor skeletal congenital defects is calculated and sex differences are tested. Prevalence is compared with other studies to recognize regional patterns. Association with age-at-death and year-of-birth is tested to identify impact of environmental stress on minor congenital defects presence. Testing association between defects will identify defects with a probable identical etiology. Chi-square was used to identify sex differences, between studies differences, and to test relationships between defects and Spearman correlation to verify correlation intensity. T-test was used to test age-at-death and year-of-birth differences in defects prevalence. There were no statistically significant differences in prevalence of minor skeletal defects for sex and age-at-death. There were statistically significant differences in year-of-birth for sternal aperture and pectus excavatum (crude prevalence was higher for those who were born earlier). There was a statistical significant association between pectus excavatum and manubrium mesosternal joint and atlas posterior/lateral bridging and notochord defects. For most defects, this study has lower prevalence than other studies. From 18 minor axial skeletal congenital defects analyzed, prevalence ranges from absent to 26.3 (notochord defects). Pectus excavatum and manubrium mesosternal joint might have a similar etiology as well as atlas posterior/lateral bridging and notochord defects. This study has lower prevalence, for almost all defects, than other studies. None of the minor congenital defects tested might, at this time, be considered useful stress markers.

Background: The clinical and molecular characteristics of osteofibrous dysplasia (OFD)-like adamantinoma (AD) differ from those of classic AD. Most reports about OFD-like AD are case reports or small case series. More cases from different centers are still warranted., Methods: The orthopedic oncology database of our institution was searched to identify patients with AD. The cases of OFD-like and classic AD of the long bones were retrospectively analyzed. Between December 1999 and August 2016, 23 patients were treated for AD, comprising seven with OFD-like AD and 16 with classic AD. The outcomes were compared between AD subtypes., Results: In the OFD-like AD group, four lesions were treated with extensive curettage, while three were treated with wide resection. The median follow-up duration in the OFD-like AD group was 66 months (range 43-131 months). At the end of follow-up, there was only one case of local recurrence (LR) in the OFD-like AD group, giving a LR rate of 14.3% (1/7). No distant metastasis or progression to classic AD was detected in the OFD-like AD group. In the classic AD group, the treatments were below-the-knee amputation in one patient with extensive tibial and fibular lesions, curettage with a bone graft in one patient who was diagnosed with OFD based on a core needle biopsy, hemi-cortical excision and reconstruction in two patients, and segmental resection and reconstruction in 12 patients. At the end of follow-up, there were three cases of LR in the classic AD group, giving a LR rate of 18.8% (3/16); two patients developed lung metastasis after LR and died of the disease at 88 and 126 months after the first surgery in our hospital, respectively. The classic AD group had a metastatic rate of 12.5% (2/16), a final limb salvage rate of 75%, and estimated 5- and 10-year survival rates of 88.9% and 77.1%, respectively., Conclusions: OFD-like AD has a better outcome than classic AD. For OFD-like AD, extensive curettage is suggested if the tumor extent allows. For classic AD, aggressive resection with wide margins is essential to achieve local control. A long-term follow-up is necessary due to the possibility of late complications.

Background: Acromicric dysplasia is a rare heritable short-stature syndrome with joint stiffness and varying degrees of cutaneous hardness. Stiff skin syndrome is a rare connective tissue disorder characterized by diffusely thick and hard skin from the time of birth. Heterozygous point mutations in the FBN1 have been proposed as the predominant cause of both diseases., Methods: By performing skin biopsy, X-ray imaging, electrocardiography, as well as whole-genome sequencing and Sanger sequencing, we diagnosed an 8-year-old Chinese boy as acromicric dysplasia with severe skin stiffness caused by a heterogeneous mutation in the FBN1., Results: The patient presented with skin tightness, wrist and ankle stiffness, short stature and limbs, several deformed joints in the extremities, cone-shaped epiphyses, and distinct facial features. He also had a patent foramen ovale and frequent respiratory infections. Skin biopsy showed thickened dermis and excessive collagen aggregation. Alcian blue staining indicated dermal mucopolysaccharide deposition. Mutation analysis revealed a heterozygous missense mutation, c.5243G>A (p.Cys1748Tyr), in exon 42 of the FBN1., Conclusion: This is a report about acromicric dysplasia with stiff skin syndrome-like severe cutaneous presentation caused by a single hotspot mutation, further revealing the gene pleiotropy of FBN1., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, LLC.)

Case: We report a rare case of dysplasia epiphysealis hemimelica in an 11-year-old male child involving the patella. The patient noticed swelling in the right knee 6 months before presentation. On evaluation, there was a mass lesion originating from superior pole of the patella extending into the suprapatellar pouch. On opening the knee joint, it was found to be mainly cartilaginous in nature. Surgical excision of the mass was carried out., Conclusion: Trevor disease should be considered in the differential diagnosis of a mass originating from the patella in children. The recommended treatment is complete excision of the mass.

Human disorders of the post-squalene cholesterol biosynthesis pathway frequently result in skeletal abnormalities, yet our understanding of the mechanisms involved is limited. In a forward-genetic approach, we have found that a late-onset skeletal mutant, named koliber nu7 , is the result of a cis -acting regulatory mutation leading to loss of methylsterol monooxygenase 1 ( msmo1 ) expression within pre-hypertrophic chondrocytes. Generated msmo1 nu81 knockdown mutation resulted in lethality at larval stage. We demonstrated that this is a result of both cholesterol deprivation and sterol intermediate accumulation by creating a mutation eliminating activity of Lanosterol synthase (Lss). Our results indicate that double lss nu60 ;msmo1 nu81 and single lss nu60 mutants survive significantly longer than msmo1 nu81 homozygotes. Liver-specific restoration of either Msmo1 or Lss in corresponding mutant backgrounds suppresses larval lethality. Rescued mutants develop dramatic skeletal abnormalities, with a loss of Msmo1 activity resulting in a more-severe patterning defect of a near-complete loss of hypertrophic chondrocytes marked by col10a1a expression. Our analysis suggests that hypertrophic chondrocytes depend on endogenous cholesterol synthesis, and blocking C4 demethylation exacerbates the cholesterol deficiency phenotype. Our findings offer new insight into the genetic control of bone development and provide new zebrafish models for human disorders of the cholesterol biosynthesis pathway., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Purpose: Fibrous dysplasia (FD) is a benign fibro-osseous developmental disorder of growing bone, sometimes involving the craniofacial skeleton (CFD). We wish to present a patient series with CFD of the orbital region and discuss treatment modalities., Methods: Twelve patients were referred for orbital CFD in the Nantes University Hospital between 2000 and 2018 and studied according to the clinical parameters, radiological features, and modalities of treatment., Results: The mean age was 25.6 years. Ten patients exhibited facial asymmetry with vertical globe dystopia (75%), proptosis (58%) and facial bump (50%). The disease was monostotic in 83% of patients, involving the frontal bone (25%), the sphenoidal bone (33%), the fronto-sphenoidal complex (25%), and the skull base (17%). Unilateral radiological proptosis was found in 7 patients, with a mean protrusion 3.9mm. The optic canal was involved in 75% of patients, with no functional impairment. Three patients were treated with bisphosphonate therapy to stop progression of the disease; 6 patients were given a bone remodelling procedure with good aesthetic outcomes., Conclusion: The orbit is a rare localization for FD causing aesthetic and functional disabilities. Medical and surgical treatment can be proposed as part of a multidisciplinary approach., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Objective: The ubiquity of cribra orbitalia in skeletal samples has led to rigorous debate over their etiology, with most concluding that nutrition, physiological stressors, and environmental disease vectors synergistically contribute to lesion development. To parse the relative contributions of these etiological factors in the prehistoric Andes, this spatial paleopathological meta-analysis investigates the relationship between population-wide prehistoric Andean cribra orbitalia rates and geographic, climatic, and hydrological variables., Methods: Crude prevalence patterns of cribra orbitalia from 61 archaeological sites were plotted and analyzed with geostatistical methods to explore spatial patterns in the distribution of anemia-associated lesions. Multiple linear regression modeling was performed on 19 spatial variables suspected to contribute to various forms of anemia that result in cribrotic lesions., Results: Spatially-clustered high cribra orbitalia rates exist around the Central Peruvian coast, but are paradoxically low on the Ecuadorian coast. Multiple regression shows that elevation, temperature, and precipitation were not predictive of lesion rates. Multiple regression models show that aridity and seasonal variability in freshwater supply, together, explained a third of the variation in lesion rates., Conclusion: While cribra orbitalia has long been tied to coastal proximity, these results suggest environmental constraints such as the need for water storage could have promoted malnutrition and pathogenic infection more than mere coastal proximity., Limitations of This Study: This analysis is limited by the paucity of data from highland sites and by the assumption that burials are local to the excavation site., Suggestions for Future Research: Future studies will integrate isotopic and remotely-sensed data into models to explore links between water security, nutrition, and disease., (Copyright © 2019. Published by Elsevier Inc.)

CATSHL syndrome, characterized by camptodactyly, tall stature and hearing loss, is caused by loss-of-function mutations of fibroblast growth factor receptors 3 (FGFR3) gene. Most manifestations of patients with CATSHL syndrome start to develop in the embryonic stage, such as skeletal overgrowth, craniofacial abnormalities, however, the pathogenesis of these phenotypes especially the early maldevelopment remains incompletely understood. Furthermore, there are no effective therapeutic targets for this skeleton dysplasia. Methods: We generated fgfr3 knockout zebrafish by CRISPR/Cas9 technology to study the developmental mechanisms and therapeutic targets of CATSHL syndrome. Several zebrafish transgenic lines labeling osteoblasts and chondrocytes, and live Alizarin red staining were used to analyze the dynamical skeleton development in fgfr3 mutants. Western blotting, whole mount in situ hybridization, Edu labeling based cell proliferation assay and Wnt/β-catenin signaling antagonist were used to explore the potential mechanisms and therapeutic targets. Results: We found that fgfr3 mutant zebrafish, staring from early development stage, showed craniofacial bone malformation with microcephaly and delayed closure of cranial sutures, chondroma-like lesion and abnormal development of auditory sensory organs, partially resembling the clinical manifestations of patients with CATSHL syndrome. Further studies showed that fgfr3 regulates the patterning and shaping of pharyngeal arches and the timely ossification of craniofacial skeleton. The abnormal development of pharyngeal arch cartilage is related to the augmented hypertrophy and disordered arrangement of chondrocytes, while decreased proliferation, differentiation and mineralization of osteoblasts may be involved in the delayed maturation of skull bones. Furthermore, we revealed that deficiency of fgfr3 leads to enhanced IHH signaling and up-regulated canonical Wnt/β-catenin signaling, and pharmacological inhibition of Wnt/β-catenin could partially alleviate the phenotypes of fgfr3 mutants. Conclusions: Our study further reveals some novel phenotypes and underlying developmental mechanism of CATSHL syndrome, which deepens our understanding of the pathogenesis of CATSHL and the role of fgfr3 in skeleton development. Our findings provide evidence that modulation of Wnt/β-catenin activity could be a potential therapy for CATSHL syndrome and related skeleton diseases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

KBG syndrome (MIM #148050) is an autosomal dominant disorder characterized by developmental delay, intellectual disability, distinct craniofacial anomalies, macrodontia of permanent upper central incisors, skeletal abnormalities, and short stature. This study describes clinical features of 28 patients, confirmed by molecular testing of ANKRD11 gene, and three patients with 16q24 deletion encompassing ANKRD11 gene, diagnosed in a single center. Common clinical features are reported, together with uncommon findings, clinical expression in the first years of age, distinctive associations, and familial recurrences. Unusual manifestations emerging from present series include juvenile idiopathic arthritis, dysfunctional dysphonia, multiple dental agenesis, idiopathic precocious telarche, oral frenula, motor tics, and lipoma of corpus callosum, pilomatrixoma, and endothelial corneal polymorphic dystrophy. Facial clinical markers suggesting KBG syndrome before 6 years of age include ocular and mouth conformation, wide eyebrows, synophrys, long black eyelashes, long philtrum, thin upper lip. General clinical symptoms leading to early genetic evaluation include developmental delay, congenital malformations, hearing anomalies, and feeding difficulties. It is likely that atypical clinical presentation and overlapping features in patients with multiple variants are responsible for underdiagnosis in KBG syndrome. Improved knowledge of common and atypical features of this disorder improves clinical management., (© 2020 Wiley Periodicals, Inc.)

Competing Interests: Competing interests: None declared.

Our previous studies confirmed that prenatal caffeine exposure (PCE) could induce susceptibility to osteoarthritis in adult offspring rats due to poor chondrocyte differentiation, but its mechanism remains to be further investigated. This study aimed to explore whether subchondral bone dysplasia mediates susceptibility to osteoarthritis in adult offspring rats induced by PCE. Pregnant Wistar rats were treated with caffeine (120 mg/kg.d) or saline from gestational day (GD) 9 to 20. The female offspring were euthanized to collect femurs at GD20, postnatal week (PW) 6, and PW28 (non-ovariectomy and ovariectomy groups) to detect osteoarthritis-like phenotype, subchondral bone mass, ossification center development, and other evidence. The results showed that PCE increased the Mankin score of pathological articular cartilage, but decreased articular cartilage thickness and subchondral bone mass, which were more obvious after ovariectomy. Meanwhile, the correlation analysis results demonstrated that the Mankin score of articular cartilage was significantly negatively correlated with subchondral bone mass, and the thickness of articular cartilage was significantly positively correlated with subchondral bone mass. Further, the length and area of the primary and secondary ossification centers, the number of osteoblasts, and the related genes' expression of osteogenic differentiation (e.g., Runx2, BSP, ALP, and OCN) were all significantly decreased in the PCE group before and after birth. Taken together, PCE induced susceptibility to osteoarthritis in adult female offspring, which was likely related to the subchondral bone dysplasia and reduction of subchondral bone mass production due to developmental disorder of primary and secondary ossification centers caused by osteoblast differentiation disability before and after birth., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus.

Context: The WNT/β-catenin pathway is central to the pathogenesis of various human diseases including those affecting bone development and tumor progression., Objective: To evaluate the role of a gain-of-function variant in CTNNB1 in a child with a sclerosing bone dysplasia and an adrenocortical adenoma., Design: Whole exome sequencing with corroborative biochemical analyses., Patients: We recruited a child with a sclerosing bone dysplasia and an adrenocortical adenoma together with her unaffected parents., Intervention: Whole exome sequencing and performance of immunoblotting and luciferase-based assays to assess the cellular consequences of a de novo variant in CTNNB1., Main Outcome Measure(s)/result: A de novo variant in CTNNB1 (c.131C>T; p.[Pro44Leu]) was identified in a patient with a sclerosing bone dysplasia and an adrenocortical adenoma. A luciferase-based transcriptional assay of WNT signaling activity verified that the activity of β-catenin was increased in the cells transfected with a CTNNB1p.Pro44Leu construct (P = 4.00 × 10-5). The β-catenin p.Pro44Leu variant was also associated with a decrease in phosphorylation at Ser45 and Ser33/Ser37/Thr41 in comparison to a wild-type (WT) CTNNB1 construct (P = 2.16 × 10-3, P = 9.34 × 10-8 respectively)., Conclusion: Increased β-catenin activity associated with a de novo gain-of-function CTNNB1 variant is associated with osteosclerotic phenotype and adrenocortical neoplasia., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Osteocraniostenosis (OCS) is a rare genetic disorder characterised by premature closure of cranial sutures, gracile bones and perinatal lethality. Previously, diagnosis has only been possible postnatally on clinical and radiological features. This study describes the first prenatal diagnosis of OCS., Case Presentation: In this case prenatal ultrasound images were suggestive of a serious but non-lethal skeletal dysplasia. Due to the uncertain prognosis the parents were offered Whole Exome Sequencing (WES), which identified a specific gene mutation in the FAMIIIa gene. This mutation had previously been detected in two cases and was lethal in both perinatally. This established the diagnosis, a clear prognosis and allowed informed parental choice regarding ongoing pregnancy management., Conclusions: This case report supports the use of targeted WES prenatally to confirm the underlying cause and prognosis of sonographically suspected abnormalities.

Osteosarcoma (OS) is the primary bone malignancy in children and adolescents, with a high incidence of lung metastasis and poor prognosis. Here, we report that growth hormone receptor (GHR) is overexpressed in OS samples compared with osteofibrous dysplasia. We subsequently demonstrated that GHR knockdown inhibited colony formation, promoted cell apoptosis and decreased the number of cells at G2/M phase in 143B and U2OS cells. Furthermore, knockdown of GHR inhibited tumor growth in vivo. Together, these findings indicate that GHR modulates cell proliferation and metastasis through the phosphoinositide 3-kinase/AKT signaling pathway and may be suitable for use as a putative biomarker of OS., (© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113 ∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113 ∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Case: We describe the case of a dysplasia epiphysealis hemimelica (DEH) lesion affecting uniquely the lunate bone in a 16-year-old boy causing pain, stiffness, and decreased range of motion. Surgical excision was performed, leading to resolution of primary symptoms with residual limitations in terminal wrist extension., Conclusions: From our review of the literature, we believe this case to be the first report of a DEH lesion affecting solely the lunate bone. Although conservative and surgical management have both been described with DEH cases, we report a positive outcome following the excision of a symptomatic lesion.

Background: The bone morphogenetic protein (BMP) pathway is known to play an imperative role in bone, cartilage, and cardiac tissue formation. Truncating, heterozygous variants, and deletions of one of the essential receptors in this pathway, Bone Morphogenetic Protein Receptor Type1A (BMPR1A), have been associated with autosomal dominant juvenile polyposis. Heterozygous deletions have also been associated with cardiac and minor skeletal anomalies. Populations with atrioventricular septal defects are enriched for rare missense BMPR1A variants., Methods: We report on a patient with a homozygous missense variant in BMPR1A causing skeletal abnormalities, growth failure a large atrial septal defect, severe subglottic stenosis, laryngomalacia, facial dysmorphisms, and developmental delays., Results: Functional analysis of this variant shows increased chondrocyte death for cells with the mutated receptor, increased phosphorylated R-Smads1/5/8, and loss of Sox9 expression mediated by decreased phosphorylation of p38., Conclusion: This homozygous missense variant in BMPR1A appears to cause a distinct clinical phenotype., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Osteogenesis imperfecta (OI) type I caused by the null allele of COL1A1 gene is in the majority in clinical OI cases. Currently, heterozygous Mov-13 mice generated by virus insertion in the first intron of col1a1 is the exclusive model to modulate OI type I, in spite of the gradually recovered bone mineral and mechanical properties. A newly designed heterozygous col1a1 ± 365 OI mouse was produced in the present study by partial exons knockout (exon 2-exon 5, 365 nt of mRNA) using CRISPR/Cas9 system. The deletion resulted in generally large decrease in type I collagen synthesis due to frameshift mutation and premature chain termination, closely mimicking the pathogenic mechanism in affected individuals. And the strain possessed significantly sparse mineral scaffolds, bone loss, lowered mechanical strength and broken bone metabolism by 8 and 20 weeks compared to their littermates, suggesting a sustained skeletal weakness. Notably, the remarkable down-regulation of Yes-associated protein (YAP), one of the key coactivator in Hippo signaling pathway, was first found both in the femur and adipose derived mesenchymal stem cells (ADSCs) under osteogenic differentiation of col1a1 ± 365 mice, which might be responsible for the reduced osteogenic potential and brittle bones. Still, further research was needed in order to illuminate the underlying mechanism., (Copyright © 2019 Elsevier Inc. All rights reserved.)