Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.

Dysregulated transforming growth factor TGF-ß signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-ß-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-ß signaling, ipo8-/- zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8-/- zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-ß signaling during development and reinforces the existing link between TGF-ß signaling and connective tissue defects.

Dermatological manifestations in Costello syndrome: A prospective multicentric study of 31 HRAS-positive variant patients.

BACKGROUND: Data on dermatological manifestations of Costello syndrome (CS) remain heterogeneous and lack in validated description. OBJECTIVES: To describe the dermatological manifestations of CS; compare them with the literature findings; assess those discriminating CS from other RASopathies, including cardiofaciocutaneous syndrome (CFCS) and the main types of Noonan syndrome (NS); and test for dermatological phenotype-genotype correlations. METHODS: We performed a 10-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Thirty-one patients were enrolled. Hair abnormalities were ubiquitous, including wavy or curly hair and excessive eyebrows, respectively in 68% and 56%. Acral excessive skin (AES), papillomas and keratotic papules (PKP), acanthosis nigricans (AN), palmoplantar hyperkeratosis (PPHK) and 'cobblestone' papillomatous papules of the upper lip (CPPUL), were noted respectively in 84%, 61%, 65%, 55% and 32%. Excessive eyebrows, PKP, AN, CCPUL and AES best differentiated CS from CFCS and NS. Multiple melanocytic naevi (>50) may constitute a new marker of attenuated CS associated with intragenic duplication in HRAS. Oral acitretin may be highly beneficial for therapeutic management of PPHK. No significant dermatological phenotype-genotype correlation was determined between patients with and without HRAS c.34G>A (p.G12S). CONCLUSIONS AND RELEVANCE: This validated phenotypic characterization of a large number of patients with CS will allow future researchers to make a positive diagnosis, and to differentiate CS from CFCS and NS.

Metameric pruritus as the sole manifestation of an intramedullary tumor in a toddler.

An 18-month-old child presented with persistent pruritus and excoriation involving the right T9 and T10 dermatomes. She did not exhibit any other dermatological or neurological anomalies. Based on magnetic resonance imaging investigation of the spine, T8 ganglioglioma was diagnosed and surgically removed resulting in resolution of the pruritus within a few days. This observation underlines the importance of neuroimaging in patients presenting with metameric pruritus without specific skin lesions, especially in young children.

A Plasma Pyrophosphate Cutoff Value for Diagnosing Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE) is a rare inherited systemic disease responsible for a juvenile peripheral arterial calcification disease. The clinical diagnosis of PXE is only based on a complex multi-organ phenotypic score and/or genetical analysis. Reduced plasma inorganic pyrophosphate concentration [PPi]p has been linked to PXE. In this study, we used a novel and accurate method to measure [PPi]p in one of the largest cohorts of PXE patients, and we reported the valuable contribution of a cutoff value to PXE diagnosis. Plasma samples and clinical records from two French reference centers for PXE (PXE Consultation Center, Angers, and FAVA-MULTI South Competent Center, Nice) were assessed. Plasma PPi were measured in 153 PXE and 46 non-PXE patients. The PPi concentrations in the plasma samples were determined by a new method combining enzymatic and ion chromatography approaches. The best match between the sensitivity and specificity (Youden index) for diagnosing PXE was determined by ROC analysis. [PPi]p were lower in PXE patients (0.92 ± 0.30 µmol/L) than in non-PXE patients (1.61 ± 0.33 µmol/L, p < 0.0001), corresponding to a mean reduction of 43 ± 19% (SD). The PPi cutoff value for diagnosing PXE in all patients was 1.2 µmol/L, with a sensitivity of 83.3% and a specificity of 91.1% (AUC = 0.93), without sex differences. In patients aged <50 years (i.e., the age period for PXE diagnosis), the cutoff PPi was 1.2 µmol/L (sensitivity, specificity, and AUC of 93%, 96%, and 0.97, respectively). The [PPi]p shows high accuracy for diagnosing PXE; thus, quantifying plasma PPi represents the first blood assay for diagnosing PXE.

Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.

Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.

Low risk of embryonic and other cancers in PIK3CA-related overgrowth spectrum: Impact on screening recommendations.

The PIK3CA-related overgrowth spectrum (PROS) encompasses various conditions caused by mosaic activating PIK3CA variants. PIK3CA somatic variants are also involved in various cancer types. Some generalized overgrowth syndromes are associated with an increased risk of Wilms tumor (WT). In PROS, abdominal ultrasound surveillance has been advocated to detect WT. We aimed to determine the risk of embryonic and other types of tumors in patients with PROS in order to evaluate surveillance relevance. We searched the clinical charts from 267 PROS patients for the diagnosis of cancer, and reviewed the medical literature for the risk of cancer. In our cohort, six patients developed a cancer (2.2%), and Kaplan Meier analyses estimated cumulative probabilities of cancer occurrence at 45 years of age was 5.6% (95% CI = 1.35%-21.8%). The presence of the PIK3CA variant was only confirmed in two out of four tumor samples. In the literature and our cohort, six cases of Wilms tumor/nephrogenic rests (0.12%) and four cases of other cancers have been reported out of 483 proven PIK3CA patients, in particular the p.(His1047Leu/Arg) variant. The risk of WT in PROS being lower than 5%, this is insufficient evidence to recommend routine abdominal imaging. Long-term follow-up studies are needed to evaluate the risk of other cancer types, as well as the relationship with the extent of tissue mosaicism and the presence or not of the variant in the tumor samples.

Accurate diagnosis of acute hemorrhagic edema of infancy: a French multicenter observational study.

The purpose of the study is to highlight clinical signs that are either suggestive of or against the diagnosis of AHEI to improve diagnosis and management. The medical records of children under 3 years old diagnosed with AHEI were retrospectively reviewed. Clinical data and photographs were reviewed by three independent experts, and the cases were classified as probable, doubtful, or unclear AHEI. Of the 69 cases of children diagnosed with AHEI included in 22 centers, 40 were classified as probable, 22 as doubtful, and 7 as unclear. The median age of patients with probable AHEI was 11 months [IQR 9-15], and they were in overall good condition (n = 33/40, 82.5%). The morphology of the purpura was targetoid in 75% of cases (n = 30/40) and ecchymotic in 70% of cases (n = 28/40) and affected mostly the legs (n = 39/40, 97%), the arms (n = 34/40, 85%), and the face (n = 33/40, 82.5%). Edema was observed in 95% of cases and affected mostly the hands (n = 36/38, 95%) and feet (n = 28/38, 74%). Pruritus was absent in all patients with probable AHEI and described for 6/21 with doubtful AHEI (29%). AHEI was the original diagnosis in only 24 patients (n = 24/40, 60%). The major differential diagnoses were purpura fulminans and urticaria multiforme.  Conclusion: AHEI, which the diagnosis is made on clinical findings, is often misdiagnosed. Purpuric lesions localized on the face/ears, arms/forearms, and thighs/legs with edema of the hands without pruritus in a young child with a good overall condition are highly suggestive of AHEI. What is Known: •Acute hemorrhagic edema of infancy (AHEI) is a cutaneous leukocytoclastic vasculitis affecting children under 3 years old. •Appropriate diagnosis is important to distinguish this benign disease from more serious diseases to avoid investigations and treatments, iatrogenic harm and unnecessary follow-up. What is New: •AHEI is an uncommon disorder often misdiagnosed by pediatricians and dermatologists. •Purpuric lesions localized on the face/ears, arms/forearms, and thighs/legs with edema of the hands without pruritus in an infant with a good overall condition are highly suggestive of AHEI.

Risk of melanoma in congenital melanocytic nevi of all sizes: A systematic review.

Congenital melanocytic nevi (CMN) are commonly encountered benign skin lesions in newborns. Larger CMN is associated with a higher lifetime risk of developing melanoma. However, the level of risk is unclear when CMN are small or medium-sized. Our objective was to assess melanoma risk in patients with CMN of all size categories. A literature review with meta-analysis was performed. Prevalence and incidence densities of melanoma at onset were calculated in the entire study population and according to CMN size, type of treatment and location of the CMN. A total of 91 melanomas were reported in 7915 patients (1.15%, 95% CI, 0.93-1.41). The overall incidence density was 0.057% person-years (95% CI, 0.044-0.071). The risk ratio of melanoma incidence densities was 21.9 (95% CI, 8.55-56.3) in large to giant CMN compared with small to medium CMN at 15 years of age. The incidence density was higher in CMN located on the trunk and as well as in those which were untreated or partially treated versus complete excision. Our review suggests patients with CMN of medium, large and giant size are at risk of melanoma, whereas the risk remains unknown for small CMN.

Objective structured clinical examination versus traditional written examinations: a prospective observational study.

BACKGROUND: Recently, Objective Structured Clinical Examinations (OSCE) became an official evaluation modality for 6-year medical students in France. Before, standard examination modalities were: written progressive clinical cases (PCC), written critical reading of scientific articles (CRA), and internship evaluation (IE). The aim of this study was to assess the performances of 6-year medical students in their final faculty tests by comparing OSCE-exams with standard examination modalities. METHODS: This was a prospective observational study. We included all 6-year medical students in our university from 2020 to 2021. The endpoints were the scores obtained at the following final faculty tests during the 6th year of medical studies: OSCE-training, OSCE-exams, written PCC, written CRA, and IE. All scores were compared in a paired-analysis. RESULTS: A total of 400 students were included in the study. No student was excluded in the final analysis. The mean scores obtained at the OSCE-exams were significantly different from those obtained at OSCE-training, PCC, CRA, and IE (12.6 ± 1.7, 11.7 ± 1.7, 13.4 ± 1.4, 13.2 ± 1.5, 14.7 ± 0.9, respectively; p < 0.001). OSCE-exams scores were moderately and significantly correlated with OSCE-training and PCC (Spearman rho coefficient = 0.4, p < 0.001); OSCE examination scores were lowly but significantly correlated with CRA and IE (Spearman rho coefficient = 0.3, p < 0.001). OSCE-scores significantly increased after an OSCE training session. CONCLUSION: In our faculty, 6-year medical students obtained lower scores at OSCE exams compared to other standard evaluation modalities. The correlation was weak to moderate but significant. These results suggest that OSCE are not redundant with the other evaluation modalities. Interestingly, a single OSCE training session led to an improvement in OSCE scores underlining the importance of a specific training.

The pathogenic c.1171A>G (p.Arg391Gly) and c.2359G>A (p.Val787Ile) ABCC6 variants display incomplete penetrance causing pseudoxanthoma elasticum in a subset of individuals.

ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequency alterations, we identified two incomplete penetrant pathogenic variants, c.2359G>A (p.Val787Ile) and c.1171A>G (p.Arg391Gly), with 6.5% and 2% penetrance, respectively. However, when penetrant, the c.1171A>G (p.Arg391Gly) manifested a clinically unaltered severity. After applying in silico and in vitro characterization, we suggest that incomplete penetrant variants are only deleterious if a yet unknown interacting partner of ABCC6 is mutated simultaneously. The low penetrance of these variants should be contemplated in genetic counseling.

NOX1 and NOX2: Two enzymes that promote endothelial-to-mesenchymal transition induced by melanoma conditioned media.

Tumor microenvironment plays an important role in melanoma progression. Recent studies reported endothelial cells (EC) are involved in endothelial-to-mesenchymal transition (EndMT). During this phenotypic switch, EC progressively lose their endothelial markers and acquire mesenchymal properties. Depending on their concentration, reactive oxygen species (ROS) can control tumor growth. In EC, ROS are mainly produced by NAPDH oxidases (NOX) such as NOX1 and NOX2. The aim of the present study was to determine the role of these enzymes in EndMT induced by conditioned media (CM) from SK-MEL 28 melanoma cells. The capacity of CM to induce EndMT in HUVEC after 24 h, 48 h or 72 h has been evaluated by following endothelial HUVECs proliferation, migration and their capacity to form capillary on ECMgel®. Furthermore, EndMT was confirmed by western blot and flow cytometry. To determine the role of NOX in EndMT, specific NOX1 and/or NOX2 inhibitors has been tested. TGF-ß2 + /- IL-1ß was used as positive control. ROS production was determined through DCFDA assay. An altered endothelial phenotype was found in CM-treated HUVECs. This phenotypic modification was correlated with a decrease in both capillary formation on ECMgel® and cell proliferation and an increase in cell migration. Exposure to CM for 48 h significantly enhanced intracellular HUVECs ROS production and this increase was prevented by the dual pharmacological inhibition of NOX1 and NOX2. Furthermore, inhibition of NOX1/2 also leads to a partial reversion of CM-induced EndMT. These data confirmed the role of NOX1 and NOX2 in EndMT induced by melanoma cancer cell secretome.

Biologics combined with conventional systemic agents for the treatment of children with severe psoriasis. Real-life data from the BiPe cohorts and a practice survey among French and Italian pediatric dermatologists.

Combined therapies involve the use of multiple drugs to increase efficacy and reduce the toxicity of individual treatments. We evaluated the use of combinations of conventional systemic therapies and biologics in children with psoriasis in daily practice. This two-part study used data from the 170 children in the Franco-Italian BiPe cohorts to evaluate the use, efficacy, and safety of combined conventional systemic-biologic therapies, and from a survey carried out among French and Italian dermatologists to better understand the reasons for using or avoiding these combinations. In total, 33 children (19.4%) from 13 dermatology centers received 48 combined conventional systemic-biologic therapies (cumulative duration: 43.6 years), including three triple combination therapies (acitretin-methotrexate, with a TNF-alpha inhibitor). A total of 14 different combinations were used, most frequently etanercept-acitretin (n = 10), adalimumab-acitretin (n = 7), adalimumab-methotrexate (n = 5), and ustekinumab-methotrexate (n = 5). The combined therapies were started at biologic initiation in 41 cases (85.4%), and after a period of biologic monotherapy in the remaining 7 cases. Mean PGA and PASI scores decreased between baseline and M3 with all the combinations used. Four serious adverse events were reported, all with favorable outcomes. The survey was completed by 61 dermatologists: 39 (63.9%) had previously used or planned to use the combined therapies, most commonly TNF-alpha inhibitors with acitretin or methotrexate. The main reason for using these treatments was to improve the outcome of biologic therapies in cases of partial efficacy or loss of efficacy. Combined therapies have been used frequently in the treatment of childhood psoriasis, in a range of clinical situations and in variable drug combinations, without significant toxicity. Although the use of these combined therapies needs to be clarified in future management guidelines, these combined therapies should be considered for the treatment of children with severe psoriasis, psoriatic arthritis, and recalcitrant disease.

Benefits of semiology taught using near-peer tutoring are sustainable.

BACKGROUND: Near-peer tutoring appears to be an efficient approach for teaching clinical skills. However, the clinical experience gained in the form of student medical internships may offset any interest in such tutoring programme. We then investigated the long-term benefits of this programme. METHODS: This study was conducted in a medical school that experimented in near-peer tutoring for semiology intended for undergraduate medical students. Objective Structured Clinical Examinations and a written semiology test were used to assess students' clinical skills immediately on its conclusion and repeated one and 2 years after the tutoring was completed. RESULTS: 116 students were evaluated initially (80 tutored and 36 untutored), 38 at 1 year (16 tutored and 22 untutored), 42 at 2 years (21 tutored and 21 untutored). In the global score for Objective Structured Clinical Examinations: at 1 year, the tutored group scored 14.0 ± 1.05 and the untutored group scored 11.3 ± 2.3 (p < 0.001), at 2 years, the tutored group scored 15.1 ± 1.5 and the untutored group scored 12.4 ± 2.2 (p < 0.001). We found a similar but smaller difference for the written semiology test. The difference for Objective Structured Clinical Examinations between tutored and untutored students vanished over time for cross-cutting skills. CONCLUSIONS: Near-peer tutoring in semiology for undergraduate medical students led to better results that remained with the passing of time. Though internships do allow an improvement in the clinical skills of untutored students, they did not reach the level of tutored students.

Vitamin D and Calcium Supplementation Accelerate Vascular Calcification in a Model of Pseudoxanthoma Elasticum.

Arterial calcification is a common feature of pseudoxanthoma elasticum (PXE), a disease characterized by ABCC6 mutations, inducing a deficiency in pyrophosphate, a key inhibitor of calcium phosphate crystallization in arteries. METHODS: we analyzed whether long-term exposure of Abcc6-/- mice (a murine model of PXE) to a mild vitamin D supplementation, with or without calcium, would impact the development of vascular calcification. Eight groups of mice (including Abcc6-/- and wild-type) received vitamin D supplementation every 2 weeks, a calcium-enriched diet alone (calcium in drinking water), both vitamin D supplementation and calcium-enriched diet, or a standard diet (controls) for 6 months. Aorta and kidney artery calcification was assessed by 3D-micro-computed tomography, Optical PhotoThermal IR (OPTIR) spectroscopy, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS) and Yasue staining. RESULTS: at 6 months, although vitamin D and/or calcium did not significantly increase serum calcium levels, vitamin D and calcium supplementation significantly worsened aorta and renal artery calcification in Abcc6-/- mice. CONCLUSIONS: vitamin D and/or calcium supplementation accelerate vascular calcification in a murine model of PXE. These results sound a warning regarding the use of these supplementations in PXE patients and, to a larger extent, patients with low systemic pyrophosphate levels.

Reassessment of causality of ABCC6 missense variants associated with pseudoxanthoma elasticum based on Sherloc.

PURPOSE: Pseudoxanthoma elasticum (PXE) is a heritable disorder affecting elastic fibers in the skin, eyes, and cardiovascular system. It is caused by biallelic pathogenic variants in the ABCC6 gene. To date, over 300 ABCC6 variants are associated with PXE, more than half being missense variants. Correct variant interpretation is essential for establishing a direct link between the variant and the patient's phenotype and has important implications for diagnosis and treatment. METHODS: We used a systematic approach for interpretation of 271 previously reported and 15 novel ABCC6 missense variants, based on the semiquantitative classification system Sherloc. RESULTS: Only 35% of variants were very likely to contribute directly to disease, in contrast to reported interpretations in ClinVar, while 59% of variants are currently of uncertain significance (VUS). Subclasses were created to distinguish VUS that are leaning toward likely benign or pathogenic, increasing the number of (likely) pathogenic ABCC6 missense variants to 47%. CONCLUSION: Besides highlighting discrepancies between the Sherloc, American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP), ClinVar, and Leiden Open Variation Database (LOVD) classification, our results emphasize the need for segregation analysis, functional assays, and detailed evidence sharing in variant databases to reach a confident interpretation of ABCC6 missense variants and subsequent appropriate genetic and preconceptual counseling.

Quantitative analysis of the natural history of prolidase deficiency: description of 17 families and systematic review of published cases.

PURPOSE: Prolidase deficiency is a rare inborn error of metabolism causing ulcers and other skin disorders, splenomegaly, developmental delay, and recurrent infections. Most of the literature is constituted of isolated case reports. We aim to provide a quantitative description of the natural history of the condition by describing 19 affected individuals and reviewing the literature. METHODS: Nineteen patients were phenotyped per local institutional procedures. A systematic review following PRISMA criteria identified 132 articles describing 161 patients. Main outcome analyses were performed for manifestation frequency, diagnostic delay, overall survival, symptom-free survival, and ulcer-free survival. RESULTS: Our cohort presented a wide variability of severity. Autoimmune disorders were found in 6/19, including Crohn disease, systemic lupus erythematosus, and arthritis. Another immune finding was hemophagocytic lymphohistiocytosis (HLH). Half of published patients were symptomatic by age 4 and had a delayed diagnosis (mean delay 11.6 years). Ulcers were present initially in only 30% of cases, with a median age of onset at 12 years old. CONCLUSION: Prolidase deficiency has a broad range of manifestations. Symptoms at onset may be nonspecific, likely contributing to the diagnostic delay. Testing for this disorder should be considered in any child with unexplained autoimmunity, lower extremity ulcers, splenomegaly, or HLH.

Disruption of AtHAK/KT/KUP9 enhances plant cesium accumulation under low potassium supply.

Understanding the molecular mechanisms that underlie cesium (Cs+ ) transport in plants is important to limit the entry of its radioisotopes from contaminated areas into the food chain. The potentially toxic element Cs+ , which is not involved in any biological process, is chemically closed to the macronutrient potassium (K+ ). Among the multiple K+ carriers, the high-affinity K+ transporters family HAK/KT/KUP is thought to be relevant in mediating opportunistic Cs+ transport. Of the 13 KUP identified in A. thaliana, only HAK5, the major contributor to root K+ acquisition under low K+ supply, has been functionally demonstrated to be involved in Cs+ uptake in planta. In the present study, we showed that accumulation of Cs+ increased by up to 30% in two A. thaliana mutant lines lacking KUP9 and grown under low K+ supply. Since further experiments revealed that Cs+ release from contaminated plants to the external medium is proportionally lower in the two kup9 mutant alleles, we proposed that KUP9 disruption could impair Cs+ efflux. By contrast, K+ status in kup9 mutants is not affected, suggesting that KUP9 disruption does not alter substantially K+ transport in experimental conditions used. The putative primary role of KUP9 in plants is further discussed.

Transient abdominal telangiectasia of the newborn.

We report 20 newborns who developed, at a median age of 7 days, large abdominal patches of radially arranged purplish telangiectasia in a bilateral and symmetrical pattern in relation to the midline, creating a "butterfly wing" pattern. Clinical examination was normal in 13 newborns, six newborns had abdominal distention, and one newborn had poor weight gain due to inadequate breastfeeding. Most lesions spontaneously resolved within 3 months and did not reoccur for 19 newborns. Transient abdominal telangiectasia of the newborn (TATN) appears to be a distinctive entity that has not been previously described.

ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions.

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the "PXE gene" and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

Constitutively-active FGFR3 disrupts primary cilium length and IFT20 trafficking in various chondrocyte models of achondroplasia.

Fibroblast growth factor receptor 3 (FGFR3) gain-of-function mutations cause dwarfisms, including achondroplasia (ACH) and thanatophoric dysplasia (TD). The constitutive activation of FGFR3 disrupts the normal process of skeletal growth. Bone-growth anomalies have been identified in skeletal ciliopathies, in which primary cilia (PC) function is disrupted. In human ACH and TD, the impact of FGFR3 mutations on PC in growth plate cartilage remains unknown. Here we showed that in chondrocytes from human (ACH, TD) and mouse Fgfr3Y367C/+ cartilage, the constitutively active FGFR3 perturbed PC length and the sorting and trafficking of intraflagellar transport (IFT) 20 to the PC. We demonstrated that inhibiting FGFR3 with FGFR inhibitor, PD173074, rescued both PC length and IFT20 trafficking. We also studied the impact of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) pathway. Interestingly, mTOR inhibition also rescued PC length and IFT20 trafficking. Together, we provide evidence that the growth plate defects ascribed to FGFR3-related dwarfisms are potentially due to loss of PC function, and these dwarfisms may represent a novel type of skeletal disorders with defective ciliogenesis.