Indian patients with CHST3-related chondrodysplasia with congenital joint dislocations.

CHST3-related chondrodysplasia with congenital joint dislocations (CDCJD, #MIM 143095), is a rare genetic skeletal disorder caused by biallelic loss of function variants in CHST3. CHST3 is critical for the sulfation of chondroitin sulfate. This study delineates the clinical presentation of nine individuals featuring the key symptoms of CDCJD; congenital joint (knee and elbow) dislocations, short trunk short stature progressive vertebral anomalies, and metacarpal shortening. Additional manifestations include irregular distal femoral epiphysis, supernumerary carpal ossification centers, bifid humerus, club foot, and cardiac abnormalities. Sanger sequencing was carried out to investigate molecular etiology in eight patients and exome sequencing in one. Genetic testing revealed five homozygous variants in CHST3 (four were novel and one was previously reported). All these variants are located on sulfotransferase domain of CHST3 protein and were classified as pathogenic/ likely pathogenic. We thus report on nine individuals with CHST3-related chondrodysplasia with congenital joint dislocations from India and suggest monitoring the health of cardiac valves in this condition.

Spondyloepimetaphyseal dysplasia with joint laxity type 2: Aggregating the literature and reporting on the life of a 66-year-old man.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (SEMDJL2), is a rare bone dysplasia that results from hotspot (amino acids148/149) mutations in KIF22. Clinically, affected individuals present with generalized joint laxity, limb malalignment, midface hypoplasia, gracile digits, postnatal short stature, and occasionally, tracheolaryngomalacia; additionally, radiological features include severe epi-metaphyseal abnormalities and slender metacarpals. This report evaluates the progression of SEMDJL2 throughout the life of the oldest individual reported in the literature-a 66-year-old man with a pathogenic KIF22 variant (c.443C > T, p.Pro148Leu). The proband developed many of the clinical and radiological alterations consistent with the presentation of other individuals in the literature. Interestingly, throughout his life, joint limitation progressed, beginning with knee and elbow stricture (year 20), and later, limitation of the shoulders, hips, ankles, and wrists (year 40). This differs from previous case reports, where joint limitation is identified in 1-to-2 joints. Cumulatively, the progressive body-wide joint limitation resulted in early retirement (year 45) and difficulty completing daily tasks and managing personal hygiene culminating in the need for assisted living (year 65). In conclusion, we report on the clinical and radiological developments of a 66-year-old man with SEMDJL2, that developed significant joint limitation in adulthood.

Genetically predicted C-reactive protein mediates the association between rheumatoid arthritis and atlantoaxial subluxation.

Objective: Investigating the causal relationship between rheumatoid arthritis (RA) and atlantoaxial subluxation (AAS) and identifying and quantifying the role of C-reactive protein (CRP) as a potential mediator. Methods: Using summary-level data from a genome-wide association study (GWAS), a two-sample Mendelian randomization (MR) analysis of genetically predicted rheumatoid arthritis (14,361 cases, and 43,923 controls) and AAS (141 cases, 227,388 controls) was performed. Furthermore, we used two-step MR to quantitate the proportion of the effect of c-reactive protein-mediated RA on AAS. Results: MR analysis identified higher genetically predicted rheumatoid arthritis (primary MR analysis odds ratio (OR) 0.61/SD increase, 95% confidence interval (CI) 1.36-1.90) increased risk of AAS. There was no strong evidence that genetically predicted AAS had an effect on rheumatoid arthritis risk (OR 1.001, 95% CI 0.97-1.03). The proportion of genetically predicted rheumatoid arthritis mediated by C-reactive protein was 3.7% (95%CI 0.1%-7.3%). Conclusion: In conclusion, our study identified a causal relationship between RA and AAS, with a small proportion of the effect mediated by CRP, but a majority of the effect of RA on AAS remains unclear. Further research is needed on additional risk factors as potential mediators. In clinical practice, lesions of the upper cervical spine in RA patients need to be given more attention.

Association of Estrogen Receptor 1 and Tumor Necrosis Factor α Polymorphisms with Temporomandibular Joint Anterior Disc Displacement without Reduction.

OBJECTIVES: The aim of this study was to investigate the role of ESR1 rs1643821 and TNF-α rs1800629 as potential genetic factors regulating anterior disc displacement without reduction-mediated inflammatory pathway. BACKGROUND: The temporomandibular joint is a complex synovial joint that allows mandibular movement in three directions. Although temporomandibular disorders are widespread, limited data is available on the biochemical characteristics of the displaced disc and quality of the surrounding soft tissue. Changes in degenerative tissue provoke disc displacement which involves secretion of inflammatory markers and sequential conversion of fibroblast-like cells into chondrocyte-like cells. Due to the high occurrence in female adolescents, the potential role of sex hormones in temporomandibular joint disorders has been speculated. Furthermore, anterior disc displacement without reduction severely affects the quality of life. METHODS: 124 Caucasian patients with a history of at least one anterior disc displacement without reduction within 3 months were enrolled. Anterior disc displacement without reduction was diagnosed based on clinical examination, diagnostic criteria (DC)/TMD, and cone-beam computed tomography/magnetic resonance imaging (CBCT/MRI). The control group consisted of 126 patients with no temporomandibular joint disorders. Genotyping of two single nucleotide polymorphisms, estrogen receptor 1 (ESR1) rs1643821, and tumor necrosis factor α (TNF-α) rs1800629 was performed. RESULTS: ESR1 rs1643821 showed significant P values (using chi-square analysis) revealing the difference in anterior disc displacement without reduction frequencies while TNF-α rs1800629 polymorphism was found to be statistically insignificant when compared to the control group. Furthermore, patients with a genotype of ESR1 rs1643821 showed a decreased probability (OR = 0.412) against anterior disc displacement without reduction when compared to the GG genotype (OR = 1). CONCLUSION: ESR1 rs1643821 with A allele frequency was lower in patients with anterior disc displacement without reduction compared to the control group. Thus, the rs1643821 variant is significantly associated with susceptibility to the anterior disc displacement without a reduction in European Caucasians. Conversely, TNF-α rs1800629 was a statistically insignificant factor against anterior disc displacement without reduction when compared to the control group.

Recurrent c.776T>C mutation in CHST3 with four other novel mutations and a literature review.

The chondrodysplasia with congenital joint dislocations, CHST3 type, which was distinguished by predominantly contractures, marked vertebral changes, and normal facial appearance. Although, some clinical clues can be used for differential diagnosis, it is mostly too difficult to discriminate one type from another on basis of clinical findings only. Eight patients with multiple dislocations from five unrelated families were included in this study to elucidate molecular diagnoses. Clinical exome sequencing (CES) was performed on one patient from each family. Variable degree vertebral changes, pes equinovarus, and kyphoscoliosis accompanied multiple dislocations and short stature. In CES analyses, all mutations showed in CHST3. Previously reported c.776T>C homozygous mutations were detected in two families, compound heterozygous novel c.740G>C and c.881T>C mutations were found in one family, and homozygous novel c.564C>A and c.963G>A mutations were also determined in remaining two families, separately. Biallelic CHST3 c.776T>C mutations are most frequent mutation in CHST3 and have been reported predominantly in Turkish patients which may be remarkable for genotype-ethnicity correlation in chondrodysplasia with congenital joint dislocations, CHST3 type. It is suggested that c.776T>C mutation can be accepted as a recurrent mutation in CHST3 for Turkish patients who are suspected of having chondrodysplasia with congenital joint dislocations, CHST3 type.

A case study of atypical Larsen syndrome with absent hallmark joint dislocations.

BACKGROUND: A family with skeletal and craniofacial anomalies is presented. Whole-exome sequencing (WES) analysis indicated a diagnosis of Larsen syndrome, although their clinical presentation does not include the hallmark joint dislocations typically observed in Larsen syndrome. METHODS: Patient consent for the sharing of de-identified clinical and genetic information, along with use of photographs for publication, was obtained. WES and variant segregation analysis by WES were performed by commercial laboratory, GeneDx (Gaithersburg, MD), on peripheral blood samples from the proband, her brother, and her parents using methods detailed on their website for test XomeDx Whole Exome Sequencing Trio (https://www.genedx.com/test-catalog/available-tests/xomedx-whole-exome-sequencing-trio/). WES uses next-generation sequencing (NGS) technology to assess for variants within the coding regions, or exons, of approximately 23,000 genes. For the FLNB gene (NM_001457.3), 100% of the coding region was covered at a minimum of 10x. GeneDx uses Sanger sequencing to confirm NGS variants. RESULTS: WES revealed a heterozygous pathogenic variant, p.Glu227Lys (c.679G>A), in the FLNB gene in three out of the four family members tested. This variant is associated with Larsen syndrome, a skeletal dysplasia condition with a wide range of phenotypic variability that usually includes congenital joint dislocations. CONCLUSION: This is a highly unusual presentation of Larsen syndrome in which the identifying hallmark trait is absent in the patients' phenotypes.

Exome sequencing reveals blended phenotype of double heterozygous FBN1 and FBN2 variants in a fetus.

We report a 29 week fetus with arthrogryposis multiplex congenita, multiple joint dislocations, scoliosis and dysmorphism who was detected to be double heterozygote for putatively pathogenic FBN1 (NM_000138.4:c.6004C > T; p.Pro2002Ser) and FBN2 (NM_001999.3:c.2945G > T; p.Cys982Phe) variants on exome sequencing. The de-novo status of these variants is not confirmed as parental genotypes could not be ascertained. A comparison of the post-mortem findings of the fetus with reported phenotypes of Beals and Marfan syndromes indicated overlapping clinical features suggestive of a blended phenotype.

The pathogenesis of congenital radial head dislocation/subluxation.

The pathogenesis of congenital radial head dislocation/subluxation is unknown and has not been previously investigated. In this review, we explore the pathogenesis and define five different primary insults: collagen abnormalities, abnormal endochondral ossification of the developing growth plate, abnormalities of forearm ossification outside the growth plate, disproportionate growth of the radius and ulna, and altered HOX D expression/activity. Finally, the clinical relevance of our review is discussed.

A novel multiple joint dislocation syndrome associated with a homozygous nonsense variant in the EXOC6B gene.

We report two brothers from a consanguineous couple with spondyloepimetaphyseal dysplasia (SEMD), multiple joint dislocations at birth, severe joint laxity, scoliosis, gracile metacarpals and metatarsals, delayed bone age and poorly ossified carpal and tarsal bones, probably representing a yet uncharacterized SEMD with laxity and dislocations. This condition has clinical overlap with autosomal dominantly inherited SEMD with joint laxity, leptodactylic type caused by recurrent missense variants in the kinesin family member 22 gene (KIF22). Single-nucleotide polymorphism array analysis and whole-exome sequencing in the two affected siblings revealed a shared homozygous nonsense variant [c.906T>A/p.(Tyr302*)] in EXOC6B as the most likely cause. EXOC6B encodes a component of the exocyst complex required for tethering secretory vesicles to the plasma membrane. As transport of vesicles from the golgi apparatus to the plasma membrane occurs through kinesin motor proteins along microtubule tracks, the function of EXOC6B is linked to KIF22 suggesting a common pathogenic mechanism in skeletal dysplasias with joint laxity and dislocations.

The C342R mutation in FGFR2 causes Crouzon syndrome with elbow deformity.

Crouzon syndrome is an autosomal dominant craniosynostosis syndrome caused by mutation in the fibroblast growth factor receptor 2 (FGFR-2). Numerous findings from animal studies imply a critical role for FGFRs in the regulation of skeletal development. Here, we report 2 unrelated patients with Crouzon syndrome accompanied by elbow deformity. Subsequently, we analyzed the sequence of the FGFR2 gene and found that both of the patients carried the Cys342Arg mutation. The findings suggest that the C342R mutation in FGFR2 may cause Crouzon syndrome and elbow deformity in Chinese patients.

Tenascin-X haploinsufficiency associated with Ehlers-Danlos syndrome in patients with congenital adrenal hyperplasia.

CONTEXT: The gene for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CYP21A2, is flanked by the gene encoding tenascin-X (TNXB), a connective tissue extracellular matrix protein that has been linked to both autosomal dominant and autosomal recessive Ehlers-Danlos syndrome (EDS). A contiguous deletion of CYP21A2 and TNXB has been described. OBJECTIVE: The objective of the study was to determine the frequency and clinical significance of TNXB haploinsufficiency in CAH patients. DESIGN, SETTING, AND PARTICIPANTS: A total of 192 consecutive unrelated CAH patients being seen as part of an observational study at the National Institutes of Health Clinical Center (Bethesda, MD) were prospectively studied during 2006-2010. Patients were evaluated for clinical evidence of EDS, including cardiac evaluation. DNA was analyzed by PCR, multiplex ligation-dependent probe amplification, Southern blot, and TNXB sequencing. Tenascin-X expression was evaluated by Western blot analysis of fibroblasts and immunostaining of the skin. CAH patients with TNXB haploinsufficiency were compared with age-matched CAH patients with normal TNXB (controls). Phenotyping of 7 parents with TNXB haploinsufficiency was performed. MAIN OUTCOME MEASURES: The frequency of TNXB haploinsufficiency among CAH patients and the frequency of EDS symptomatology among CAH patients with TNXB haploinsufficiency and controls. RESULTS: TNXB haploinsufficiency, here termed CAH-X syndrome, was present in 7% of CAH patients. Twelve of 91 patients carrying a CYP21A2 deletion (13%) carried a contiguous deletion that extended into TNXB. One patient carried a TNXB premature stop codon. Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P < .001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings. CONCLUSIONS: Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion.

[Larsen-syndrome: final diagnosis following multiple surgical interventions]. / Harmincéves betegút után igazolt Larsen-szindróma.

Larsen-syndrome is a rare genetic skeletal dysplasia belonging to the group of actin-binding filamin B associated diseases. The features include congenital dislocations of the large joints, scoliosis and cervical kyphosis, short, broad, spatulate distal phalanges, and distinctive craniofacies. Diagnosis is based on clinical and radiographic findings and confirmed by molecular genetic testing. The authors have performed filamin B molecular genetic analysis since 2005 and have found several cases with unusual phenotypes since. This case report presents the diagnostic difficulties of a 30-year-old woman, who was operated several times with congenital hip dislocations and foot deformities. The craniofacial features, short, broad, spatulate fingers, scoliosis and cervical kyphosis directed diagnosis towards Larsen-syndrome and molecular genetic analysis confirmed a previously-described heterozygous missense mutation (c.G679A). They conclude that genetic analysis performed in time would prevent additional superfluous long diagnostic procedures in patients with rare diseases and would ensure adequate supportive therapy and management of the symptoms.

A case of familial paediatric atlantoaxial subluxation.

INTRODUCTION: Fixed atlantoaxial rotary subluxation (FAARS) is a rare cause of torticollis in children. Familial FAARS has not been described in the literature previously. We present case reports of two siblings who both developed spontaneous atlantoaxial rotary subluxation and discuss the possible causes. Both patients were treated conservatively and made a successful recovery. METHODS: The notes and images of two siblings were reviewed following permission from their parents. A literature search was also performed to look at what is currently known about atlantoaxial subluxation. RESULTS: Both siblings were successfully treated with halter traction and subsequent collar treatment. Os terminale was iden- tified on the CT images of both children. CONCLUSIONS: Atlantoaxial rotary subluxation should be considered as a cause of torticollis in children and can occasionally occur spontaneously. Both siblings had os terminale and it raises the possibility that this may predispose children to develop- ing FAARS. There may also be an underlying previously unidentified familial cause. Appropriate imaging followed by prompt treatment in halter traction is usually successful. If a diagnosis of FAARS is confirmed in a paediatric patient, the clinician should have a high index of suspicion when a sibling presents with torticollis or associated neck pain subsequently.

Whole-exome sequencing identifies mutations of KIF22 in spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL), leptodactylic (lepto-SEMDJL) or Hall type, is an autosomal-dominant skeletal dysplasia manifesting with short stature, joint laxity with dislocation(s), limb malalignment, and spinal deformity. Its causative gene mutation has not yet been discovered. We captured and sequenced the exomes of eight affected individuals in six unrelated kindreds (three individuals in a family and five simplex individuals). Five novel sequence variants in KIF22, which encodes a member of the kinesin-like protein family, were identified in seven individuals. Sanger sequencing of KIF22 confirmed that c.443C>T (p.Pro148Ser) cosegregated with the phenotype in the affected individuals in the family; c.442C>T (p.Pro148Leu) or c.446G>A (p.Arg149Gln) was present in four of five simplex individuals, but was absent in unaffected individuals in their family and 505 normal cohorts. KIF22 mRNA was detected in human bone, cartilage, joint capsule, ligament, skin, and primary cultured chondrocytes. In silico analysis of KIF22 protein structure indicates that Pro148 and Arg149 are important in maintaining hydrogen bonds in the ATP binding and motor domains of KIF22. We conclude that these mutations in KIF22 cause lepto-SEMDJL.

Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (lepto-SEMDJL, aka SEMDJL, Hall type), is an autosomal dominant skeletal disorder that, in spite of being relatively common among skeletal dysplasias, has eluded molecular elucidation so far. We used whole-exome sequencing of five unrelated individuals with lepto-SEMDJL to identify mutations in KIF22 as the cause of this skeletal condition. Missense mutations affecting one of two adjacent amino acids in the motor domain of KIF22 were present in 20 familial cases from eight families and in 12 other sporadic cases. The skeletal and connective tissue phenotype produced by these specific mutations point to functions of KIF22 beyond those previously ascribed functions involving chromosome segregation. Although we have found Kif22 to be strongly upregulated at the growth plate, the precise pathogenetic mechanisms remain to be elucidated.

Absence of the dens in a 9.5-year-old rottweiler with non-progressive clinical signs.

Absence of the dens is rarely described in large breed dogs. In this rottweiler, mild neurological deficits seen at 6 mo of age did not progress for the 9.5 y of the dog's life despite lack of surgical intervention. This finding underscores the marked differences between small and large breeds.