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Objective: This case series describes the outcomes of airway management, including airway reconstruction, in 6 patients with campomelic dysplasia and tracheostomy/ventilator dependence secondary to multilevel airway obstruction. Methods: Case series and clinical guidelines are provided for the airway management of patients with campomelic dysplasia. Results: Average age of individuals is 19.4 years. Mean follow-up was 12.2 years. Four individuals underwent open airway reconstruction and achieved decannulation. One patient underwent airway reconstruction with improvement of a complete subglottic stenosis but remains ventilator dependent due to severe scoliosis. The remaining 2 patients did not require additional airway reconstruction, have been liberated from ventilator support, and are under evaluation for tracheostomy tube decannulation. Conclusion: Although campomelic dysplasia was historically considered a lethal form of congenital skeletal dysplasia, with many patients succumbing to respiratory failure due to tracheobronchomalacia in the neonatal period, airway reconstruction and long-term survivorship is feasible in children with campomelic dysplasia and significant airway disease. [ABSTRACT FROM AUTHOR]

Since CRISPR‐based genome editing technology works effectively in the diploid frog Xenopus tropicalis, a growing number of studies have successfully modeled human genetic diseases in this species. However, most of their targets were limited to non‐syndromic diseases that exhibit abnormalities in a small fraction of tissues or organs in the body. This is likely because of the complexity of interpreting the phenotypic variations resulting from somatic mosaic mutations generated in the founder animals (crispants). In this study, we attempted to model the syndromic disease campomelic dysplasia (CD) by generating sox9 crispants in X. tropicalis. The resulting crispants failed to form neural crest cells at neurula stages and exhibited various combinations of jaw, gill, ear, heart, and gut defects at tadpole stages, recapitulating part of the syndromic phenotype of CD patients. Genotyping of the crispants with a variety of allelic series of mutations suggested that the heart and gut defects depend primarily on frame‐shift mutations expected to be null, whereas the jaw, gill, and ear defects could be induced not only by such mutations but also by in‐frame deletion mutations expected to delete part of the jawed vertebrate‐specific domain from the encoded Sox9 protein. These results demonstrate that Xenopus crispants are useful for investigating the phenotype–genotype relationships behind syndromic diseases and examining the tissue‐specific role of each functional domain within a single protein, providing novel insights into vertebrate jaw evolution. [ABSTRACT FROM AUTHOR]

Haploinsufficiency for SOX9, the master chondrogenesis transcription factor, can underlie campomelic dysplasia (CD), an autosomal dominant skeletal malformation syndrome, because heterozygous Sox9 null mice recapitulate the bent limb (campomelia) and some other phenotypes associated with CD. However, in vitro cell assays suggest haploinsufficiency may not apply for certain mutations, notably those that truncate the protein, but in these cases in vivo evidence is lacking and underlying mechanisms are unknown. Here, using conditional mouse mutants, we compared the impact of a heterozygous Sox9 null mutation (Sox9+/-) with the Sox9+/Y440X CD mutation that truncates the C-terminal transactivation domain but spares the DNA-binding domain. While some Sox9+/Y440X mice survived, all Sox9+/-mice died perinatally. However, the skeletal defects were more severe and IHH signaling in developing limb cartilage was significantly enhanced in Sox9+/Y440X compared with Sox9+/-. Activating Sox9Y440X specifically in the chondrocyte-osteoblast lineage caused milder campomelia, and revealed cell- and noncell autonomous mechanisms acting on chondrocyte differentiation and osteogenesis in the perichondrium. Transcriptome analyses of developing Sox9+/Y440X limbs revealed dysregulated expression of genes for the extracellular matrix, as well as changes consistent with aberrant WNT and HH signaling. SOX9Y440X failed to interact with ß-catenin and was unable to suppress transactivation of Ihh in cell-based assays. We propose enhanced HH signaling in the adjacent perichondrium induces asymmetrically localized excessive perichondrial osteogenesis resulting in campomelia. Our study implicates combined haploinsufficiency/hypomorphic and dominant-negative actions of SOX9Y440X, cell-autonomous and noncell autonomous mechanisms, and dysregulated WNT and HH signaling, as the cause of human campomelia. [ABSTRACT FROM AUTHOR]

SOX9 is a crucial transcriptional regulator of cartilage development and homeostasis. Dysregulation of SOX9 is associated with a wide spectrum of skeletal disorders, including campomelic dysplasia, acampomelic campomelic dysplasia, and scoliosis. Yet how SOX9 variants contribute to the spectrum of axial skeletal disorders is not well understood. Here, we report four pathogenic variants of SOX9 identified in a cohort of patients with congenital vertebral malformations. We report a pathogenic missense variant in the transactivation middle (TAM) domain of SOX9 associated with mild skeletal dysplasia and scoliosis. We isolated a Sox9 mutant mouse with an in-frame microdeletion in the TAM domain ( Sox9 Asp272del ), which exhibits skeletal dysplasia including kinked tails, rib cage anomalies, and scoliosis in homozygous mutants. We find that both the human missense and the mouse microdeletion mutations resulted in reduced SOX9 protein stability in cell culture, while Sox9 Asp272del mutant mice show decreased SOX9 expression in the growth plate and annulus fibrosus tissues of the spine. This reduction in SOX9 expression was correlated with the reduction of extracellular matrix components, such as tenascin-X and the Adhesion G-protein coupled receptor ADGRG6. In summary, our work identified and modeled a pathologic variant of SOX9 within the TAM domain and demonstrated its importance for SOX9 protein stability. Our work demonstrates that SOX9 stability is important for the regulation of ADGRG6 expression, which is a known regulator of postnatal spine homeostasis, underscoring the essential role of SOX9 dosage in a spectrum of axial skeleton dysplasia in humans., Competing Interests: Competing interests statement:The authors declare no competing interest.

BackgroundCampomelic dysplasia (CD) is an autosomal dominant skeletal dysplasia syndrome characterized by shortness and bowing of lower extremities, and often accompanied by XY sex reversal. Heterozygous pathogenic variants of SOX9 or rearrangement involving the long arm of chromosome 17 are the causes of disease. However, evidence for pathogenesis of SOX9 haploinsufficiency is insufficient.MethodsWe enrolled a Chinese family where the fetus was diagnosed with CD. The affected fetus was selected for whole-exome sequencing to identify the pathogenic mutations in this family.ResultsAfter data filtering, a novel non-sense SOX9 variant (NM_000346.3; c.1249C > T; p.Q417*) was identified as the pathogenic lesion in the fetus. Further co-segregation analysis using Sanger sequencing confirmed that this novel SOX9 mutation (c.1249C > T; p.Q417*) was a de novo mutation in the affected fetus. This terminated codon mutation identified by bioinformatics was located at an evolutionarily conserved site of SOX9. The bioinformatics-based analysis predicted this variant was pathogenic and affected SOX9 transactivation activity.ConclusionCD is a rare condition, which connected with SOX9 tightly. We identified a novel heterozygous SOX9 variant (p.Q417*) in a Chinese CD family. Our study supports the putative reduced transactivation of SOX9 variants in the pathogenicity of CD.

The transcription factor SOX9 is essential for the development of multiple organs including bone, testis, heart, lung, pancreas, intestine and nervous system. Mutations in the human SOX9 gene led to campomelic dysplasia, a haploinsufficiency disorder with several skeletal malformations frequently accompanied by 46, XY sex reversal. The mechanisms underlying the diverse SOX9 functions during organ development including its post-translational modifications, the availability of binding partners, and tissue-specific accessibility to target gene chromatin. Here we summarize the expression, activities, and downstream target genes of SOX9 in molecular genetic pathways essential for organ development, maintenance, and function. We also provide an insight into understanding the mechanisms that regulate the versatile roles of SOX9 in different organs. [ABSTRACT FROM AUTHOR]

BackgroundCampomelic dysplasia (CD) is a rare disorder that involves the skeletal and genital systems. This condition has been associated with a diverse set of mutations in the SRY-box transcription factor 9 (SOX9) gene.Case presentationWe herein report a case involving a 4-year-old female patient with CD, female sex reversal, type 1 Arnold–Chiari malformation, and bilateral conductive hearing loss and investigate the causal mutation. Whole-exome sequencing analysis detected a novel Trp115X* variant in the SOX9 gene. We performed a literature review of the reported cases and demonstrated that the missense variants were located only in the self-dimerization domain (DIM) and high-mobility group box domains. We also reported that variants in the DIM domain do not cause sex reversal and identified that the amino acid sequences that were mutated in the patients with campomelic dysplasia are evolutionarily conserved among primates.ConclusionsWe suggest that missense variants cannot be located in the K2, PQA, and PQS given that these domains function critically for transcriptional activation or repression of target genes and evolve under purifying selection.

Introduction: Campomelic dysplasia (CD) is a rare autosomal dominant skeletal malformation syndrome characterized by shortness and bowing of the lower extremities with or without XY sex reversal. Diagnosis using ultrasonography is most often made in the latter half of pregnancy. Intragenic heterozygous mutations in SOX9 are responsible for most cases of CD. CD caused by SOX9 deletion is a rare condition. Case presentation: We present a single case report of an individual with cystic hygroma accompanied by CD, which was detected by ultrasound in the first trimester. Chromosomal microarray analysis (CMA) was performed to determine copy number variants, whereas whole exome sequencing (WES) was performed to elucidate single-nucleotide variants. Chorionic villus sampling was performed to enable such analyses. Ultimately, CMA detected a 606 kb deletion in the 17q24.3 region with only one protein-coding gene (SOX9). However, no mutation in the SOX9 protein-coding sequence was detected by WES. Conclusion: When cystic hygroma is detected, prenatal diagnoses for skeletal dysplasia by ultrasound are likely to be confirmed in the first trimester. We propose a comprehensive prenatal diagnostic strategy that combines CMA and WES to diagnose fetuses with cystic hygroma accompanied by skeletal dysplasia. [ABSTRACT FROM AUTHOR]

Campomelic dysplasia (CD) is a rare genetic disease characterized by skeletal dysplasia that also affects several other organ systems. CD is caused by a SOX9 mutation. We here report a case of CD with a 46, XY karyotype and female external genitalia. This child was born with a weight of 3.12 kg after 37 weeks of gestation. She exhibited a number of characteristic features including a small thoracic cage, bowing of both femurs, clubbed feet, hypoplastic scapula, 11 pairs of ribs, a bell-shaped narrow thorax, micrognathia, macroglossia, a cleft palate, a flattened nasal bridge, and low set ears. She experienced additional distress because of the presence of a tracheal ring and because she had tracheomalacia. CD was diagnosed through nucleotide sequence analysis. A frameshift mutation, c.235delC (p.Gln79Argfs*31), was identified in the SOX9 gene that has not previously been reported.

Campomelic dysplasia (CMPD) is a skeletal disorder resulting from SOX9 gene mutations. Palatoplasty is rare due to a high lethality rate in infants from respiratory distress. Our patient had characteristic symptoms of CMPD, including short bowed limbs, macrocephaly, low-set ears, short palpebral fissures, hypertelorism, a flat nasal bridge, a long philtrum, micrognathia, and a cleft palate. We performed a Furlow palatoplasty when the patient was 2 years 9 months of age, after respiratory conditions had stabilized. We reviewed the literature of CMPD cases that underwent palatoplasty and discussed the optimal timing and surgical methods. [ABSTRACT FROM AUTHOR]

Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions, and duplications within a ∼2 Mb region upstream of SOX9 can recapitulate the CD-DSD phenotype fully or partially, suggesting the existence of an unusually large cis-regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ∼1.2-1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harboring candidate craniofacial regulatory elements. In parallel, ChIP-Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple noncoding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS.

Campomelic dysplasia (CD) is a rare form of skeletal dysplasia (incidence 1:200,000 births) which is associated with characteristic phenotypes including bowing of the limbs, a narrow thoracic cage, 11 pairs of ribs, hypoplastic scapulae, macrocephaly, flattened supraorbital ridges and nasal bridge, cleft palate, and micrognathia. In addition to the skeletal abnormalities, hydrocephalus, hydronephrosis, and congenital heart disease have been reported. We describe a preterm neonate who presented with respiratory failure and clinical features of CD. Our case had only 10 pairs of ribs, and to the best of our knowledge this is the first case report of CD with 10 pairs of ribs.

Objective: The aim of this study is to explore the utility of rapid medical trio exome sequencing (ES) for prenatal diagnosis using the skeletal dysplasia as an exemplar.Method: Pregnant women who were referred for genetic testing because of ultrasound detection of fetal abnormalities suggestive of a skeletal dysplasia were identified prospectively. Fetal samples (amniocytes or cord blood), along with parental blood, were send for rapid copy number variations testing and medical trio ES in parallel.Results: Definitive molecular diagnosis was made in 24/27 (88.9%) cases. Chromosomal abnormality (partial trisomy 18) was detected in one case. Sequencing results had explained the prenatal phenotype enabling definitive diagnoses to be made in 23 cases. There were 16 de novo dominant pathogenic variants, four dominant pathogenic variants inherited maternally or paternally, two recessive conditions with pathogenic variants inherited from unaffected parents, and one X-linked condition. The turnaround time from receipt of samples in the laboratory to reporting sequencing results was within 2 weeks.Conclusion: Medical trio ES can yield very timely and high diagnostic rates in fetuses presenting with suspected skeletal dysplasia. These definite diagnoses aided parental counseling and decision making in most of cases. [ABSTRACT FROM AUTHOR]

Campomelic dysplasia (CD) is an autosomal dominant, perinatal lethal skeletal dysplasia characterized by a small chest and short long bones with bowing of the lower extremities. CD is the result of heterozygosity for mutations in the gene encoding the chondrogenesis master regulator, SOX9. Loss‐of‐function mutations have been identified in most CD cases so it has been assumed that the disease results from haploinsufficiency for SOX9. Here, we identified distal truncating SOX9 mutations in four unrelated CD cases. The mutations all leave the dimerization and DNA‐binding domains intact and cultured chondrocytes from three of the four cases synthesized truncated SOX9. Relative to CD resulting from haploinsufficiency, there was decreased transactivation activity toward a major transcriptional target, COL2A1, consistent with the mutations exerting a dominant‐negative effect. For one of the cases, the phenotypic consequence was a very severe form of CD, with a pronounced effect on vertebral and limb development. The data identify a novel molecular mechanism of disease in CD in which the truncated protein leads to a distinct and more significant effect on SOX9 function. [ABSTRACT FROM AUTHOR]

Abstract Campomelic dysplasia (CMPD) is a rare congenital skeletal disorder caused by SOX9 mutations. The patients are often accompanied by craniofacial and oral anomalies such as characteristic facial appearance and cleft palate. In spite of possibility of perinatal lethality, some patients could survive with milder phenotype and appropriate medical treatment. Such patients might cause critical issues in feeding and require oral management. However, there has been less information about oral surgical treatment in CMPD patients. Here, we describe our recent experience of diagnosis and cleft palate repair in a CMPD patient. A 27 month old Japanese female presenting typical CMPD phenotypes was genetically determined and a SOX9Q175Stop mutation was identified. The protein analysis demonstrated that SOX9Q175Stop mutation yields the truncated protein lacking the transactivation site. The affected infant had serious respiratory distress and always required control by an artificial ventilator. Cleft palate reconstruction under general anesthesia was performed to improve her feeding and oral functions. Modified Furlow palatoplasty was applied to minimize surgical invasion in which only a unilateral relaxation incision was designed. Artificial skin material was used to support fragile soft palate tissue. Although there was some risk to cause any serious respiratory issue, her SpO2 was maintained well through the perioperative period. Our case report might provide valuable information for syndromic cleft palate treatments. [ABSTRACT FROM AUTHOR]

Acampomelic campomelic dysplasia (CD) is a type of CD (CD; OMIM #114290), a rare form of congenital short-limbed dwarfism and is due to mutations in SOX9 gene family. Characteristic phenotypes of CD include bowing of the lower limbs, a narrow thoracic cage, 11 pairs of ribs, hypoplastic scapulae, macrocephaly, flattened supraorbital ridges and nasal bridge, cleft palate and micrognathia. The bending of the long bones is not an obligatory feature and is absent in about 10% of cases, referred to as acampomelic CD. A child previously diagnosed with acampomelic CD was brought to our outpatient clinic for cleft palate reconstruction. Our neurosurgeon cautioned us against performing surgery with extension of the neck in view of the possibility of producing quadriparesis, due to narrowing of the spinal canal as part of the osseous anomaly noted in the magnetic resonance imaging study of the spine, thus making the anaesthesia, surgical and post-operative procedures difficult. The cleft palate reconstruction was performed with all precautions and was uneventful.

Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.

Campomelic dysplasia is an autosomal dominant skeletal dysplasia caused by heterozygous SOX9 mutations. Most patients are sporadic due to a de novo mutation. Familial campomelic dysplasia is very rare. We report on a familial campomelic dysplasia caused by maternal germinal mosaicism. Two siblings showed the classic campomelic dysplasia phenotype with a novel SOX9 mutation (NM_000346.3: c.441delC, p.(Asn147Lysfs*36)). Radiological examination of the mother showed mild skeletal changes. Then, her somatic mosaicism of the mutation was ascertained. This is the first report of molecularly confirmed maternal germinal mosaicism for a SOX9 mutation. We suggest that a meticulous clinical examination of the parents, even if they are superficially healthy, is needed to avoid overlooking germinal mosaicism of SOX9 mutations. [ABSTRACT FROM AUTHOR]

Campomelic dysplasia (CD) is a rare form of skeletal dysplasia (incidence 1:200,000 births) which is associated with characteristic phenotypes including bowing of the limbs, a narrow thoracic cage, 11 pairs of ribs, hypoplastic scapulae, macrocephaly, flattened supraorbital ridges and nasal bridge, cleft palate, and micrognathia. In addition to the skeletal abnormalities, hydrocephalus, hydronephrosis, and congenital heart disease have been reported. We describe a preterm neonate who presented with respiratory failure and clinical features of CD. Our case had only 10 pairs of ribs, and to the best of our knowledge this is the first case report of CD with 10 pairs of ribs. [ABSTRACT FROM AUTHOR]

Objective: To report a rare case of somatic mosaicism with a germline component of campomelic dysplasia in a woman undergoing in vitro fertilization with preimplantation genetic diagnosis (IVF-PGD).Design: Case report.Setting: Clinic.Patient(s): A 28-year old G2P0110 and her 34-year old husband had two previous pregnancies complicated by fetal campomelic dysplasia with suspected germline mosaic mutation. The couple, both phenotypically normal, underwent IVF-PGD to reduce their chances of transmission. None of the embryos could initially be determined to be disease free, because all embryos shared either a maternal or a paternal short tandem repeat haplotype with the products of conception from her last pregnancy.Intervention(s): Peripheral-blood cytogenomic single-nucleotide polymorphism (SNP) microarray to identify the carrier of the mutation, and IVF-PGD to identify the disease-free embryo.Main Outcome Measure(s): Disease-free embryo.Result(s): Only one of the five euploid embryos was identified as disease free.Conclusion(s): A woman with suspected germline mosaicism for campomelic dysplasia was found to be a somatic mosaic with a germline component via a peripheral blood SNP microarray test. This identified her solitary disease-free embryo, which was transferred to her uterus but did not result in a viable pregnancy. [ABSTRACT FROM AUTHOR]

Campomelic dysplasia (CD) is a skeletal dysplasia characterized by shortened and bowed long bones, airway instability, the potential for disorders of sexual differentiation (DSD), and Pierre Robin Sequence (PRS) with cleft palate, midface hypoplasia and laryngotrachemomalacia. CD is caused by alterations in the Sex-determining region of the Y chromosome (SRY)-related-box 9 (SOX9), which has important roles in tissue and sexual differentiation. The SOX9 gene and the enhancer regions of SOX9 are located at chromosome 17q24.3. We report a 6-year-old phenotypically female referred to our department because of precocious puberty. The patient was born with Tetralogy of Fallot (TOF) and PRS. Skeletal X-ray examination showed only 11 pairs of ribs and bilateral bowed radiuses. Endocrine evaluations showed that increased levels of serum testosterone, and chromosomal analysis revealed a 46, XY, t(2;17)(p15;q24.2) karyotype. The patient was diagnosed with peripheral precocious puberty caused by over-secretion of testosterone by gonadoblastoma originating from dysgenetic gonads with Y-chromosome-related DSD. Multiple somatic abnormalities and DSD indicated that the patient might have CD. Laparoscopy revealed bilateral dysgenetic gonads, and these were removed in the successive operation to prevent malignant transformation and virilization, caused by dysgenetic gonads with Y chromosomal materials. It is highly suggestive that the chromosomal translocation of 17q 24.2 may cause DSD and multiple somatic abnormalities, including CD, although the identified 17q breakpoint was located outside of known SOX9 enhancer regions. Thus, a hitherto unknown enhancer may be present at 17q24.2. This is the first reported case of CD with a translocation breakpoint at 17q24.2. [ABSTRACT FROM AUTHOR]

SOX9 is responsible for campomelic dysplasia (CMPD). Symptoms of CMPD include recurrent apnea, upper respiratory infection, facial features, and shortening of the lower extremities. The variant acampomelic CMPD (ACMPD) lacks long bone curvature. A patient showed macrocephaly (+3.9 standard deviations [SD]) and minor anomalies, such as hypertelorism, palpebronasal fold, small mandible, and a cleft of soft palate without long bone curvature. From three months of age, he required tracheal intubation and artificial respiration under sedation because of tracheomalacia. Cranial magnetic resonance imaging was normal at one month of age but showed ventriculomegaly, hydrocephaly, and the corpus callosum thinning at two years of age. Exome sequencing revealed a de novo novel mutation, c. 236A > C, p (Q79P), in SOX9 . Sox9 is thought to be crucial in neural stem cell development in the central and peripheral nervous system along with Sox8 and Sox10 in mice. In humans, neuronal abnormalities have been reported in cases of CMPD and ACMPD, including relative macrocephaly in 11 out of 22 and mild lateral ventriculomegaly in 2 out of 22 patients. We encountered a two-year old boy with ACMPD presenting with tracheomalacia and macrocephaly with a SOX9 mutation. We described for the first time an ACMPD patient with acquired diminished white matter and corpus callosal thinning, indicating the failure of oligodendrocyte/astrocyte development postnatally. This phenotype suggests that SOX9 plays a crucial role in human central nervous system development. Further cases are needed to clarify the relationship between human neural development and SOX9 mutations. [ABSTRACT FROM AUTHOR]

The SOX9 transcription factor controls the differentiation of many cell types among vertebrates. The SOX9 gene locus is large and complex and contains various tissue-specific enhancers. Individual enhancers direct specific expression of SOX9 in chondrocytes, Sertoli cells and cranial neural crest cells. Human SOX9 mutations can lead to either the complete Campomelic Dysplasia syndrome, or isolated clinical features, depending upon whether the mutation occurs in the coding region or in enhancer regions. Chromatin Immunoprecipitation has helped to define SOX9 control of target gene expression at the genome wide level in hair follicle stem cells and in chondrocytes where SOX9 binds at super-enhancers. SOX9 binding proximal to promoters controls basal cell activity whereas cell type specificity is directed from distal enhancers. [ABSTRACT FROM AUTHOR]

Background Campomelic dysplasia ( CD) is a semilethal developmental disorder caused by mutations in and around SOX9. CD is characterized by multiple skeletal malformations including bending (campomelia) of long bones. Surviving patients frequently have the acampomelic form of CD ( ACD). Methods This is a single case report on a patient with clinical and radiological features of ACD who has no mutation in the SOX9 protein-coding sequence nor a translocation with breakpoint in the SOX9 regulatory domain. We include functional studies of the novel mutant protein in vitro and in cultured cells. Results The patient was found to have a de novo heterozygous mutation c.-185G>A in the SOX9 5′ UTR. The mutation creates an upstream translation start codon, uAUG, with a much better fit of its flanking sequence to the Kozak consensus than the wild-type AUG. By in vitro transcription-translation and transient transfection into COS-7 cells, we show that the uAUG leads to translation of a short peptide from a reading frame that terminates just after the wild-type AUG start codon. This results in reduced translation of the wild-type protein, compatible with the milder phenotype of the patient. Conclusion Findings support the notion that more mildly affected, surviving CD/ ACD patients carry mutant SOX9 alleles with residual expression of SOX9 wild-type protein. Although rarely described in human genetic disease and for the first time here for CD, mutations creating upstream AUG codons may be more common than generally assumed. [ABSTRACT FROM AUTHOR]

We present a comprehensive review dealing with rare genetic skeletal disorders. More than 400 entities are included in the latest classification. The most severe or lethal phenotypes are identifiable in the prenatal period and the pregnancy can be terminated. Perinatal autopsy and posmortem X-rays are crucial in providing a definitive diagnosis. The number of cases confirmed by genetic testing is increasing. We report our own experience with genetic skeletal disorders based on 41 illustrative fetal and neonatal cases which we encountered over a 10-year period. Thanatophoric dysplasia and osteogenesis imperfecta represent approximately half of the cases coming to autopsy. Achondrogenesis type 2 and hypochondrogenesis, short-rib dysplasia, chondrodysplasia punctata, campomelic dysplasia and achondroplasia are less common. Skeletal dysplasias with autosomal recessive inheritance are the least frequent, e.g. perinatally lethal hypophophatasia, achondrogenesis type 1A, diastrophic dysplasia/atelosteogenesis type 2 or mucolipidosis type 2 (I cell disease).

Campomelic/camptomelic dysplasia is a very rare, severe osteochondrodysplasia characterised by severe skeletal and nonskeletal malformations and lethal outcome mainly in neonatal period. Characteristic abnormality by which the syndrome got its name is short, bowed long bones of lower extremities, most often of femur, manifested by short and bowed legs. Skin dimpling on tibial anterior side is another prominent characteristic of this syndrome. Severe cases are inherited by autosomal dominant trait, by mutation Sox9 gene on chromosome 17, with lethal outcome in the first days of life. Less severe forms of the disease are due to balanced translocation t (13;17) with life span up to the third decade of life. A majority of karyotypic males present as phenotypic females. We report a case of a female neonate, without consanguinity between parents, with characteristic signs of camptomelic dysplasia with short birth length of 46 cm, macrocephaly (head circumference 39 cm), dolichocephaly, hydrocephalus, short trunk and legs. Narrow rib cage, bowed lower extremities, short hand and foot phalanges, nail hypoplasia were noticed. Anterior fontanelle was enlarged, high forehead, face small and flat, hypertelorism, low nasal bridge, micrognathia, low set ears, cleft palate, were found. Characteristic skin dimpling on anterior side of tibia was present on both legs. Bone X-ray studies presented the following changes: anterior bowing of shortened femurs, hip dislocation, cervical vertebrae, scapulas, eleven pairs of slender ribs. Hip luxation. Karyotype was normal for a female, 46 XX. Respiratory insufficiency was present since birth, exacerbated, and led to lethal outcome in the second day of life, as described in the majority of these patients. .

To date, mutations within the coding region and translocations around the SOX9 gene both constitute the majority of genetic lesions underpinning human campomelic dysplasia (CD). While pathological coding-region mutations typically result in a non-functional SOX9 protein, little is known about what mechanism(s) controls normal SOX9 expression, and subsequently, which signaling pathways may be interrupted by alterations occurring around the SOX9 gene. Here, we report the identification of Stat3 as a key modulator of Sox9 expression in nascent cartilage and developing chondrocytes. Stat3 expression is predominant in tissues of mesodermal origin, and its conditional ablation using mesoderm-specific TCre, in vivo, causes dwarfism and skeletal defects characteristic of CD. Specifically, Stat3 loss results in the expansion of growth plate hypertrophic chondrocytes and deregulation of normal endochondral ossification in all bones examined. Conditional deletion of Stat3 with a Sox9Cre driver produces palate and tracheal irregularities similar to those described in Sox9+/- mice. Furthermore, mesodermal deletion of Stat3 causes global embryonic down regulation of Sox9 expression and function in vivo. Mechanistic experiments ex vivo suggest Stat3 can directly activate the expression of Sox9 by binding to its proximal promoter following activation. These findings illuminate a novel role for Stat3 in chondrocytes during skeletal development through modulation of a critical factor, Sox9. Importantly, they further provide the first evidence for the modulation of a gene product other than Sox9 itself which is capable of modeling pathological aspects of CD and underscore a potentially valuable therapeutic target for patients with the disorder. [ABSTRACT FROM AUTHOR]