Zebrafish model for spondylo-megaepiphyseal-metaphyseal dysplasia reveals post-embryonic roles of Nkx3.2 in the skeleton.

The regulated expansion of chondrocytes within growth plates and joints ensures proper skeletal development through adulthood. Mutations in the transcription factor NKX3.2 underlie spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD), which is characterized by skeletal defects including scoliosis, large epiphyses, wide growth plates and supernumerary distal limb joints. Whereas nkx3.2 knockdown zebrafish and mouse Nkx3.2 mutants display embryonic lethal jaw joint fusions and skeletal reductions, respectively, they lack the skeletal overgrowth seen in SMMD patients. Here, we report adult viable nkx3.2 mutant zebrafish displaying cartilage overgrowth in place of a missing jaw joint, as well as severe dysmorphologies of the facial skeleton, skullcap and spine. In contrast, cartilage overgrowth and scoliosis are absent in rare viable nkx3.2 knockdown animals that lack jaw joints, supporting post-embryonic roles for Nkx3.2. Single-cell RNA-sequencing and in vivo validation reveal increased proliferation and upregulation of stress-induced pathways, including prostaglandin synthases, in mutant chondrocytes. By generating a zebrafish model for the skeletal overgrowth defects of SMMD, we reveal post-embryonic roles for Nkx3.2 in dampening proliferation and buffering the stress response in joint-associated chondrocytes.

[Advances in genetic research on Non-syndromic congenital joint synostosis].

Congenital joint synostosis (CJS) is a functional impairment resulting from failure in joint morphogenesis during embryonic development. Clinically, it may be classified as syndromic (sCJS) and non-syndromic (nsCJS) disorders. Common sCJS include chromosomal disorders such as Klinefelter syndrome and single-gene disorders like Apert/Pfeiffer/Crouzon syndromes, Holt-Oram syndrome, Ehlers-Danlos syndrome, and Radial-ulnar synostosis with thrombocytopenia, presenting with multiple system/organ anomalies. By contrast, nsCJS manifest with only joint abnormalities, affecting one or multiple joints. This review has focused on human nsCJS and its genetic etiology. To date, variants in seven genes (NOG, GDF5, FGF9, GDF6, FGF16, SMAD6, and MECOM) have been identified as causative factors for nsCJS. This review has focused on such genes and provided a comprehensive review for the clinical phenotypes, genetic patterns, common variants, and underlying mechanisms associated with nsCJS based on a literature review. In addition, it has also analyzed other candidate genes for nsCJS within the context of relevant signaling pathways involved in joint morphogenesis.

Bilateral non-traumatic elbow luxation in a Yorkshire terrier puppy.

A 10-week-old Yorkshire terrier had lameness of the right forelimb with complete lateral radioulnar luxation at the humerus, consistent with Type III congenital elbow luxation; this is rarely treated in the presence of multiple skeletal deformities. Lateral subluxation of the radial head at the left elbow was diagnosed as Type I congenital elbow luxation. Procurvatum, distal valgus, and external torsion were present in both antebrachiae. Surgical stabilization of the right elbow was performed with temporary transarticular pins in the humeroulnar and radioulnar joints. A custom-made orthosis was applied to support the surgical reduction for 20 wk. Recurrent luxation was not observed. After complete right-sided function was established, the left forelimb showed noticeable instability in the antebrachium, and the puppy frequently fell while running. The lateral collateral ligament of the left elbow was augmented using screws and synthetic ligaments 22 wk after the right-side surgery. Congruity of the left elbow joint improved, and the puppy could bear full weight on the left forelimb, although slight deficits in movement and falling were observed. We demonstrate the effectiveness of combining a temporary transarticular pin and custom-made orthosis while treating Type III congenital elbow luxation and the inadequacy of collateral ligament augmentation alone for treating Type I congenital elbow luxation with antebrachium deformities. Key clinical message: Herein, we observed that a combination of a temporary transarticular pin and a custom-made orthosis was effective for the treatment of Type III congenital elbow luxations.

Luxation bilatérale non traumatique du coude chez un chiot Yorkshire terrier. Un Yorkshire terrier de 10 semaines présentait une boiterie du membre antérieur droit avec une luxation radio-ulnaire latérale complète au niveau de l'humérus, compatible avec une luxation congénitale du coude de type III; ceci est rarement traité en présence de multiples déformations squelettiques. La subluxation latérale de la tête radiale au niveau du coude gauche a été diagnostiquée comme une luxation congénitale du coude de type I. Procurvatum, valgus distal et torsion externe étaient présents dans les deux sections antébrachiales. La stabilisation chirurgicale du coude droit a été réalisée avec des broches trans-articulaires temporaires dans les articulations huméro-ulnaire et radio-ulnaire. Une orthèse sur mesure a été appliquée pour soutenir la réduction chirurgicale pendant 20 semaines. Aucune luxation récurrente n'a été observée. Une fois la fonction complète du côté droit établie, le membre antérieur gauche a montré une instabilité notable de la section antébrachiale et le chiot tombait fréquemment en courant. Le ligament collatéral latéral du coude gauche a été augmenté à l'aide de vis et de ligaments synthétiques 22 semaines après la chirurgie du côté droit. La congruence de l'articulation du coude gauche s'est améliorée et le chiot pouvait supporter tout son poids sur le membre antérieur gauche, bien que de légers déficits de mouvement et des chutes aient été observés. Nous démontrons l'efficacité de la combinaison d'une broche trans-articulaire temporaire et d'une orthèse sur mesure dans le traitement de la luxation congénitale du coude de type III et l'insuffisance de l'augmentation du ligament collatéral seule pour traiter la luxation congénitale du coude de type I avec des déformations de la section antébrachiale.Message clinique clé:Ici, nous avons observé qu'une combinaison d'une broche trans-articulaire temporaire et d'une orthèse sur mesure était efficace pour le traitement des luxations congénitales du coude de type III.(Traduit par Dr Serge Messier).

Dysregulated BMP signaling through ACVR1 impairs digit joint development in fibrodysplasia ossificans progressiva (FOP).

The development of joints in the mammalian skeleton depends on the precise regulation of multiple interacting signaling pathways including the bone morphogenetic protein (BMP) pathway, a key regulator of joint development, digit patterning, skeletal growth, and chondrogenesis. Mutations in the BMP receptor ACVR1 cause the rare genetic disease fibrodysplasia ossificans progressiva (FOP) in which extensive and progressive extra-skeletal bone forms in soft connective tissues after birth. These mutations, which enhance BMP-pSmad1/5 pathway activity to induce ectopic bone, also affect skeletal development. FOP can be diagnosed at birth by symmetric, characteristic malformations of the great toes (first digits) that are associated with decreased joint mobility, shortened digit length, and absent, fused, and/or malformed phalanges. To elucidate the role of ACVR1-mediated BMP signaling in digit skeletal development, we used an Acvr1R206H/+;Prrx1-Cre knock-in mouse model that mimics the first digit phenotype of human FOP. We have determined that the effects of increased Acvr1-mediated signaling by the Acvr1R206H mutation are not limited to the first digit but alter BMP signaling, Gdf5+ joint progenitor cell localization, and joint development in a manner that differently affects individual digits during embryogenesis. The Acvr1R206H mutation leads to delayed and disrupted joint specification and cleavage in the digits and alters the development of cartilage and endochondral ossification at sites of joint morphogenesis. These findings demonstrate an important role for ACVR1-mediated BMP signaling in the regulation of joint and skeletal formation, show a direct link between failure to restrict BMP signaling in the digit joint interzone and failure of joint cleavage at the presumptive interzone, and implicate impaired, digit-specific joint development as the proximal cause of digit malformation in FOP.

A lifespan approach to osteoarthritis prevention.

Prevention is an attractive solution for the staggering and increasingly unmanageable burden of osteoarthritis. Despite this, the field of osteoarthritis prevention is relatively immature. To date, most of what is known about preventing osteoarthritis and risk factors for osteoarthritis is relative to the disease (underlying biology and pathophysiology) of osteoarthritis, with few studies considering risk factors for osteoarthritis illness, the force driving the personal, financial and societal burden. In this narrative review we will discuss what is known about osteoarthritis prevention, propose actionable prevention strategies related to obesity and joint injury which have emerged as important modifiable risk factors, identify where evidence is lacking, and give insight into what might be possible in terms of prevention by focussing on a lifespan approach to the illness of osteoarthritis, as opposed to a structural disease of the elderly. By targeting a non-specialist audience including scientists, clinicians, students, industry employees and others that are interested in osteoarthritis but who do not necessarily focus on osteoarthritis, the goal is to generate discourse and motivate inquiry which propel the field of osteoarthritis prevention into the mainstream.

Spectrum of mucocutaneous, ocular and facial features and delineation of novel presentations in 62 classical Ehlers-Danlos syndrome patients.

Classical Ehlers-Danlos syndrome (cEDS) is characterized by marked cutaneous involvement, according to the Villefranche nosology and its 2017 revision. However, the diagnostic flow-chart that prompts molecular testing is still based on experts' opinion rather than systematic published data. Here we report on 62 molecularly characterized cEDS patients with focus on skin, mucosal, facial, and articular manifestations. The major and minor Villefranche criteria, additional 11 mucocutaneous signs and 15 facial dysmorphic traits were ascertained and feature rates compared by sex and age. In our cohort, we did not observe any mandatory clinical sign. Skin hyperextensibility plus atrophic scars was the most frequent combination, whereas generalized joint hypermobility according to the Beighton score decreased with age. Skin was more commonly hyperextensible on elbows, neck, and knees. The sites more frequently affected by abnormal atrophic scarring were knees, face (especially forehead), pretibial area, and elbows. Facial dysmorphism commonly affected midface/orbital areas with epicanthal folds and infraorbital creases more commonly observed in young patients. Our findings suggest that the combination of ≥1 eye dysmorphism and facial/forehead scars may support the diagnosis in children. Minor acquired traits, such as molluscoid pseudotumors, subcutaneous spheroids, and signs of premature skin aging are equally useful in adults.

Medical Infrared Imaging of Normal and Dysplastic Elbows in Dogs.

OBJECTIVE: To investigate the ability of medical infrared imaging to differentiate between normal canine elbows and those with abnormal elbows (elbow dysplasia). STUDY DESIGN: Prospective cohort study. ANIMALS: Dogs with normal (n = 15) and abnormal (n = 14) elbows. METHODS: Infrared imaging was performed on all dogs and data analyzed via descriptive statistics and image pattern analysis software. Animals with elbow dysplasia had arthroscopic procedures to confirm the presence of elbow disease. RESULTS: Computer recognition pattern analysis was up to 100% correct in identifying abnormal elbows and normal elbows, with the medial images most consistent. The caudal, lateral, and cranial images correctly identified 83-100% abnormal elbows. The caudal and lateral images correctly identified 83% normal elbows. A significant difference in temperature was found between normal and abnormal elbows for the cranial full region of interest, lateral images, and each quadrant. CONCLUSION: Medical infrared imaging was able to correctly identify known abnormal and known normal elbows in dogs.

[ASBMR 2013 REPORT. Meeting Report on the ASBMR. Topics for basic research at ASBMR 2013].

This is the brief report on basic research at ASBMR 2013 held in Baltimore, MD, USA. I focused on the research about osteoarthritis and skeletal development and introduce a part of current topics referring to past reports.

Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.

Conditional inactivation of Has2 reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb.

The glycosaminoglycan hyaluronan (HA) is a structural component of extracellular matrices and also interacts with cell surface receptors to directly influence cell behavior. To explore functions of HA in limb skeletal development, we conditionally inactivated the gene for HA synthase 2, Has2, in limb bud mesoderm using mice that harbor a floxed allele of Has2 and mice carrying a limb mesoderm-specific Prx1-Cre transgene. The skeletal elements of Has2-deficient limbs are severely shortened, indicating that HA is essential for normal longitudinal growth of all limb skeletal elements. Proximal phalanges are duplicated in Has2 mutant limbs indicating an involvement of HA in patterning specific portions of the digits. The growth plates of Has2-deficient skeletal elements are severely abnormal and disorganized, with a decrease in the deposition of aggrecan in the matrix and a disruption in normal columnar cellular relationships. Furthermore, there is a striking reduction in the number of hypertrophic chondrocytes and in the expression domains of markers of hypertrophic differentiation in the mutant growth plates, indicating that HA is necessary for the normal progression of chondrocyte maturation. In addition, secondary ossification centers do not form in the central regions of Has2 mutant growth plates owing to a failure of hypertrophic differentiation. In addition to skeletal defects, the formation of synovial joint cavities is defective in Has2-deficient limbs. Taken together, our results demonstrate that HA has a crucial role in skeletal growth, patterning, chondrocyte maturation and synovial joint formation in the developing limb.

Research Note: Comparing methods to assess Valgus-Varus deformity in broiler chickens.

Valgus-varus deformity (VVD) is one of the leg disorders affecting health and welfare of broiler chickens. In research, several protocols are used to determine the prevalence and/or severity of VVD. This study aimed to investigate effects of five different protocols on the angulation of the tibiotarsal-tarsometatarsal joint. Angulation was determined (1) in living chickens with fixation at the femorotibiotarsal joint; (2) in dead chickens without fixation; (3) in dead chickens with fixation; (4) in dissected legs, including muscles, but without skin; (5) in dissected legs, without muscles, but with intact joints. Fixation of the leg at the femorotibiotarsal joint largely reduced the angulation of the tibiotarsal-tarsometatarsal joint. When fixation was used, no differences in angulation were found when broilers were live, dead or legs were dissected, but when no fixation was used, angulation was considerably higher, due to a large lateral deviation of the leg. It can be concluded that in intact chickens, fixation of the femorotibiotarsal joint is essential to determine VVD angulation in an appropriate way.

Antenatal ultrasound and MRI findings of Pena-Shokeir syndrome.

INTRODUCTION: Pena-Shokeir syndrome is an autosomal recessive disorder characterized by arthrogryposis, facial anomalies (micrognathia), camptodactyly, polyhydramnios and lung hypoplasia. CASE REPORT: We report prenatal ultrasonographic, antenatal MR and postnatal examination findings of a fetus with Pena-Shokeir syndrome. CONCLUSION: Pena-Shokeir syndrome is a potentially lethal condition and most cases are diagnosed prenatally by ultrasound. Fetal MR can be performed to look associated neurological malformation.

Van neck disease: osteochondrosis of the ischiopubic synchondrosis.

BACKGROUND: Van Neck disease (VND) is a benign skeletal abnormality of children involving a hyperostosis of the ischiopubic synchondrosis (IPS) seen on radiographs. Patients typically complain of vague groin or buttock pain. Few descriptions of this disorder exist and it easily can be mistaken for other entities, particularly osteomyelitis or tumor. It is often considered a diagnosis of exclusion as laboratory values are usually normal and routine radiographic workup may be nonspecific. We present a series of patients with VND and we compare them with a similar cohort of patients with acute hematogenous ischiopubic osteomyelitis (IPOM). We also draw attention to a new magnetic resonance imaging (MRI) finding that seems to support the theory that VND results from an excessive pull of the hamstring tendon on the ischial tuberosity. METHODS: All patients presenting to our institution for the evaluation of groin or buttock pain during an 8-year period (August 2001 to May 2009) were retrospectively identified. Twenty-five patients demonstrated enhancement of the ischiopubic area on MRI. Five patients were excluded for lack of sufficient laboratory data. Ten patients were diagnosed and treated with culture proven IPOM and 10 patients were diagnosed with VND and treated with observation. History, physical examination, laboratory values, plain films, and MRI were compared to identify the diagnostic differences between these 2 entities. RESULTS: The age range for both groups was between 4 and 12 years old. The mean age was 7 years for the VND group and 7.6 years for the IPOM group. The VND group tended to have more distinct hyperostosis of the IPS on radiographs. The factors that were characteristic of IPOM were: fever, limp, pain with rotation of the hip, elevated erythrocyte sedimentation rate, elevated C-reactive protein (CRP), and positive blood culture. MRI showed obvious myositis, abscess, and free fluid surrounding the IPS in all patients with IPOM, but not in the VND patients. Enhancement was seen in the ischial tuberosity, near the hamstring origin, in nearly all Van Neck patients; this pattern of edema may support stress reaction and callus formation as a mechanism for IPS hypertrophy. CONCLUSIONS: VND is a little-known entity characterized by enlargement of the IPS and should be in the differential of groin or buttock pain in children from the age of 4 to 12 years. IPOM may present similar to VND. Absence of fever, limp, pain with rotation of the hip, elevated C-reactive protein/erythrocyte sedimentation rate, and negative blood culture can help to differentiate VND from IPOM. Presence of marrow edema around the IPS and in the ischial tuberosity, along with absence of surrounding myositis, abscess, and free fluid on MRI are reliable findings that can confirm the diagnosis of VND. The absence of these characteristics can eliminate the need for admission, aspiration, or biopsy. The treatment for VND is observation and the symptoms should abate over time with expectant management. LEVEL OF EVIDENCE: Comparative Diagnostic, Level IV.

Acromelic dysplasias: how rare musculoskeletal disorders reveal biological functions of extracellular matrix proteins.

Acromelic dysplasias are a group of rare musculoskeletal disorders that collectively present with short stature, pseudomuscular build, stiff joints, and tight skin. Acromelic dysplasias are caused by mutations in genes (FBN1, ADAMTSL2, ADAMTS10, ADAMTS17, LTBP2, and LTBP3) that encode secreted extracellular matrix proteins, and in SMAD4, an intracellular coregulator of transforming growth factor-ß (TGF-ß) signaling. The shared musculoskeletal presentations in acromelic dysplasias suggest that these proteins cooperate in a biological pathway, but also fulfill distinct roles in specific tissues that are affected in individual disorders of the acromelic dysplasia group. In addition, most of the affected proteins directly interact with fibrillin microfibrils in the extracellular matrix and have been linked to the regulation of TGF-ß signaling. Together with recently developed knockout mouse models targeting the affected genes, novel insights into molecular mechanisms of how these proteins regulate musculoskeletal development and homeostasis have emerged. Here, we summarize the current knowledge highlighting pathogenic mechanisms of the different disorders that compose acromelic dysplasias and provide an overview of the emerging biological roles of the individual proteins that are compromised. Finally, we develop a conceptual model of how these proteins may interact and form an "acromelic dysplasia complex" on fibrillin microfibrils in connective tissues of the musculoskeletal system.

Lack of the mesodermal homeodomain protein MEOX1 disrupts sclerotome polarity and leads to a remodeling of the cranio-cervical joints of the axial skeleton.

Meox1 and Meox2 are two related homeodomain transcription factor genes that together are essential for the development of all somite compartments. Here we show that mice homozygous for Meox1 mutations alone have abnormalities that are restricted to the sclerotome and its derivatives. A prominent and consistent phenotype of these mutations is a remodeling of the cranio-cervical joints whose major feature is the assimilation of the atlas into the basioccipital bone so that the skull rests on the axis. These abnormalities can be traced back to changes in the relative rates of cell proliferation in the rostral and caudal sclerotome compartments, and they are associated with alterations in the expression of at least three transcription factor genes, Tbx18, Uncx, and Bapx1. As previously observed for Bapx1, MEOX1 protein occupies evolutionarily conserved promoter regions of Tbx18 and Uncx, suggesting that Meox1 regulates these genes at least in part directly. Hence, Meox1 is part of a regulatory circuit that serves an essential, non-redundant function in the maintenance of rostro-caudal sclerotome polarity and axial skeleton formation.

A new Ehlers-Danlos syndrome with craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations.

We previously described two unrelated patients showing characteristic facial and skeletal features, overlapping with the kyphoscoliosis type Ehlers-Danlos syndrome (EDS) but without lysyl hydroxylase deficiency [Kosho et al. (2005) Am J Med Genet Part A 138A:282-287]. After observations of them over time and encounter with four additional unrelated patients, we have concluded that they represent a new clinically recognizable type of EDS with distinct craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations. The patients exhibited strikingly similar features according to their age: craniofacial, large fontanelle, hypertelorism, short and downslanting palpebral fissures, blue sclerae, short nose with hypoplastic columella, low-set and rotated ears, high palate, long philtrum, thin vermilion of the upper lip, small mouth, and micro-retrognathia in infancy; slender and asymmetric face with protruding jaw from adolescence; skeletal, congenital contractures of fingers, wrists, and hips, and talipes equinovarus with anomalous insertions of flexor muscles; progressive joint laxity with recurrent dislocations; slender and/or cylindrical fingers and progressive talipes valgus and cavum or planus, with diaphyseal narrowing of phalanges, metacarpals, and metatarsals; pectus deformities; scoliosis or kyphoscoliosis with decreased physiological curvatures of thoracic spines and tall vertebrae; cutaneous, progressive hyperextensibility, bruisability, and fragility with atrophic scars; fine palmar creases in childhood to acrogeria-like prominent wrinkles in adulthood, recurrent subcutaneous infections with fistula formation; cardiovascular, cardiac valve abnormalities, recurrent large subcutaneous hematomas from childhood; gastrointestinal, constipation, diverticula perforation; respiratory, (hemo)pneumothorax; and ophthalmological, strabismus, glaucoma, refractive errors.

Prevalence of multiple congenital contractures including arthrogryposis multiplex congenita in Alberta, Canada, and a strategy for classification and coding.

BACKGROUND: The population prevalence of multiple congenital contractures, many of which have either arthrogryposis multiplex congenita or amyoplasia congenita, ranges from 1/3300 to 1/56,000. Three other studies report a range of 1/4500 to 1/12,500. Classification and coding of these disorders in the International Classification of Diseases, tenth edition, (ICD-10) is less than satisfactory, even when augmented by the Royal College of Pediatrics and Child Health (RCPCH). expansion. METHODS: The database of the Alberta Congenital Anomalies Surveillance System (ACASS) was used to review all cases (1980-2007) of the previously named disorders with special emphasis on the 1997-2007 cohort. The latter period was chosen because more complete ascertainment was likely due to the addition of terminations of pregnancy data beginning in 1997. This cohort was further analyzed into the three practical groups: I, limb only; II, limb plus non-central nervous system anomalies; and III, limb plus lethality, central nervous system anomalies, or both, with further syndrome identification in groups II and III. The ICD-10-RCPCH classification and codes were reviewed. RESULTS: The prevalence for multiple congenital contractures in Alberta is 1/8700 for 1980-1996 and 1/4300 for 1997-2007. Rates for the three groups were calculated. Specific diagnostic categories were found in groups II and III of 43% and 65%, respectively. Mortality is high, especially in the first month of life (45% total losses). New classification and coding systems are proposed.

Advantages and drawbacks of proximal interphalangeal joint fusion versus flexor tendon transfer in the correction of hammer and claw toe deformity. A finite-element study.

Correction of claw or hammer toe deformity can be achieved using various techniques, including proximal interphalangeal joint arthrodesis (PIPJA), flexor digitorum longus tendon transfer (FDLT), and flexor digitorum brevis transfer. PIPJA is the oldest technique, but is associated with significant complications (infection, fracture, delayed union, and nonunion). FDLT eliminates the deformity, but leads to loss of stability during gait. Flexor digitorum brevis tendon transfer (FDBT) seems to be the best surgical alternative, but it is a recent technique with still limited results. In this work, these three techniques have been analyzed by means of the finite-element method and a comparative analysis was done with the aim of extracting advantages and drawbacks. The results show that the best technique for reducing dorsal displacement of the proximal phalanx is PIPJA (2.28 mm versus 2.73 mm for FDLT, and 3.31 mm for FDBT). However, the best technique for reducing stresses on phalanges is FDLT or FDBT (a reduction of approximately 35% regarding the pathologic case versus the increase of 7% for the PIPJA in tensile stresses, and a reduction of approximately 40% versus 25% for the PIPJA in compression stresses). Moreover, the distribution of stresses in the entire phalanx is different for the PIPJA case. These facts could cause problems for patients, in particular, those with pain in the surgical toe.

Exome reports A de novo GNB2 variant associated with global developmental delay, intellectual disability, and dysmorphic features.

Heterotrimeric G proteins are composed of α, ß, and γ subunits and are involved in integrating signals between receptors and effector proteins. The 5 human Gß proteins (encoded by GNB1, GNB2, GNB3, GNB4, and GNB5) are highly similar. Variants in GNB1 were identified as a genetic cause of developmental delay. De novo variant in GNB2 has recently been reported as a cause of sinus node dysfunction and atrioventricular block but not as a cause of developmental delay. Trio-based whole-exome sequencing was performed on an individual with global developmental delay, muscle hypotonia, multiple congenital joint contractures and dysmorphism such as brachycephalus, thick eyebrows, thin upper lip, micrognathia, prominent chin, and bilateral tapered fingers. We identified a de novo GNB2 variant c.229G>A, p.(Gly77Arg). Notably, pathogenic substitutions of the homologous Gly77 residue including an identical variant (p.Gly77Arg, p.Gly77Val, p.Gly77Ser, p.Gly77Ala) of GNB1, a paralog of GNB2, was reported in individuals with global developmental delay and hypotonia. Clinical features of our case overlap with those of GNB1 variants. Our study suggests that a GNB2 variant may be associated with syndromic global developmental delay.

Mice with targeted disruption of the fatty acid transport protein 4 (Fatp 4, Slc27a4) gene show features of lethal restrictive dermopathy.

The fatty acid transport protein family is a group of evolutionarily conserved proteins that are involved in the cellular uptake and metabolism of long and very long chain fatty acids. However, little is known about their respective physiological roles. To analyze the functional significance of fatty acid transport protein 4 (Fatp4, Slc27a4), we generated mice with a targeted disruption of the Fatp4 gene. Fatp4-null mice displayed features of a neonatally lethal restrictive dermopathy. Their skin was characterized by hyperproliferative hyperkeratosis with a disturbed epidermal barrier, a flat dermal-epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis. The rigid skin consistency resulted in an altered body shape with facial dysmorphia, generalized joint flexion contractures, and impaired movement including suckling and breathing deficiencies. Lipid analysis demonstrated a disturbed fatty acid composition of epidermal ceramides, in particular a decrease in the C26:0 and C26:0-OH fatty acid substitutes. These findings reveal a previously unknown, essential function of Fatp4 in the formation of the epidermal barrier.