A rare case of invasive melanoma likely arising from passenger melanocytes of a basal cell carcinoma

Neoplasms consisting of different cell lineages within a single skin specimen are rare, yet well documented in the literature. However, to date, there appears to be no report of invasive melanoma arising directly from the passenger melanocytes of a basal cell carcinoma (BCC). We present a case of a 91-year-old male with a suspicious lesion on the ear. Histopathology and immunohistochemical staining revealed BCC closely intertwined with invasive melanoma that exhibited foci of chondroid differentiation. The melanoma appeared to arise from the benign-appearing passenger melanocytes of the BCC and lacked connection to the overlying epidermis or an in situ component. Multiple dermatopathologists reviewed the case and agreed that the most likely explanation for the histopathologic findings was that the invasive melanoma arose from the passenger melanocytes within the BCC.     

Fatal neonatal nephrocutaneous syndrome in 18 Roma children with EGFR deficiency

Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine-kinase signaling activity, involved in many cellular functions including cell growth and differentiation. Germ line loss-of-function mutations in EGFR lead to a severe neonatal skin disorder (Online Mendelian Inheritance in Man #131550). We report 18 premature Roma children from 16 families with birthweights ranging 440–1470 g and multisystem diseases due to the homozygous mutation c.1283G˃A (p.Gly428Asp) in EGFR. They presented with thin, translucent, fragile skin (14/15), skin desquamation (10/17), ichthyosis (9/17), recurrent skin infections and sepsis (9/12), nephromegaly (10/16) and congenital heart defects (7/17). Their prognosis was poor, and all died before the age of 6 months except one 13-year-old boy with a severe skin disorder, dentinogenesis imperfecta, Fanconi-like syndrome and secondary hyperaldosteronism. Management of ion and water imbalances and extremely demanding skin care may improve the unfavorable outcome of such patients.     

The impact of public performance reporting on health plan selection and switching: A systematic review and meta-analysis

The dissemination of public performance reporting (PPR) cards aims to increase utilisation of information on quality of care by consumers when making health plan choices. However, evaluations of PPR cards show that they have little impact on consumer choices. The aim of this study is to undertake a systematic review and meta-analysis of the impact of PPR cards in promoting health plan selection and switching between health plans by consumers. We searched five online databases and eight previous reviews for studies reporting findings on PPR and health plans. We extracted data and conducted quality assessment, systematic critical synthesis and meta-analyses on the included studies. We identified eight relevant health plan articles related to selection (n?=?2), switching (n?=?4), selection/switching (n?=?2). Meta-analyses showed that PPR was associated with an improvement in health plan selection and a very small deterioration in switching health plans though these changes were not statistically significant. Differences were observed between employer-sponsored health insurance and Medicare/Medicaid insurance. Given the small number of studies included in the review, further research examining the impact of PPR on health plan selection and switching in a range of insurance markets is required.     

An essential role of PI(4,5)P2 for maintaining the activity of the transient receptor potential canonical (TRPC)4β

The transient receptor potential canonical 4 (TRPC4) channel is a Ca²⁺-permeable nonselective cation channel in mammalian cells and mediates a number of cellular functions. Many studies show that TRPC channels are activated by stimulation of Gα_q-phospholipase C (PLC)-coupled receptors. However, our previous study showed that the TRPC4 current was inhibited by co-expression of a constitutively active form of Gα_q (Gα_q ^Q209L). A shortage of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] in Gα_q ^Q209L may be responsible for reduced TRPC4 activity. Here, we tested this hypothesis by using a rapamycin-inducible system that regulates PI(4,5)P₂ acutely and specifically. Our results showed that the TRPC4β current was reduced by inducible Gα_q ^Q209L, but not by the mutants with impaired binding ability to PLCβ. Depletion of PI(4,5)P₂ by inducing the inositol polyphosphate 5-phosphatase to HEK293 cells that express TRPC4β led to an irreversible inhibition of TRPC4β currents. In contrast, inducing phosphatidylinositol 4-phosphate 5-kinase or intracellular PI(4,5)P₂ application did not activate the TRPC4β current. Finally, we revealed that PI(4,5)P₂ is important in delaying the desensitization of TRPC4β. Taken together, we suggest that PI(4,5)P₂ is not the activator of TRPC4β activation, but it is still necessary for regulating TRPC4β activation.     

Clinical and laboratory characteristics in septic arthritis patients with and without isolated germs

Background

The management of septic arthritis without bacteriological evidence is not well codified.

An exome sequencing strategy to diagnose lethal autosomal recessive disorders

Rare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There is often limited fetal DNA available for investigation. We investigated a strategy for diagnosing autosomal recessive lethal disorders in non-consanguineous pedigrees with multiple affected fetuses. Exome sequencing was performed to identify genes where each parent is heterozygous for a rare non-synonymous-coding or splicing variant. Putative pathogenic variants were tested for cosegregation in affected fetuses and unaffected siblings. In eight couples of European ancestry, we found on average 1.75 genes (range 0–4) where both parents were heterozygous for rare potentially deleterious variants. A proof-of-principle study detected heterozygous DYNC2H1 variants in a couple whose five fetuses had short-rib polydactyly. Prospective analysis of two couples with multiple pregnancy terminations for fetal akinesia syndrome was performed and a diagnosis was obtained in both the families. The first couple were each heterozygous for a previously reported GLE1 variant, p.Arg569His or p.Val617Met; both were inherited by their two affected fetuses. The second couple were each heterozygous for a novel RYR1 variant, c.14130-2A>G or p.Ser3074Phe; both were inherited by their three affected fetuses but not by their unaffected child. Biallelic GLE1 and RYR1 disease-causing variants have been described in other cases with fetal akinesia syndrome. We conclude that exome sequencing of parental samples can be an effective tool for diagnosing lethal recessive disorders in outbred couples. This permits early prenatal diagnosis in future pregnancies.     

Insights into Severe 5,10‐Methylenetetrahydrofolate Reductase Deficiency: Molecular Genetic and Enzymatic Characterization of 76 Patients

5,10‐Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common inherited disorder of folate metabolism and causes severe hyperhomocysteinaemia. To better understand the relationship between mutation and function, we performed molecular genetic analysis of 76 MTHFR deficient patients, followed by extensive enzymatic characterization of fibroblasts from 72 of these. A deleterious mutation was detected on each of the 152 patient alleles, with one allele harboring two mutations. Sixty five different mutations (42 novel) were detected, including a common splicing mutation (c.1542G>A) found in 21 alleles. Using an enzyme assay in the physiological direction, we found residual activity (1.7%–42% of control) in 42 cell lines, of which 28 showed reduced affinity for nicotinamide adenine dinucleotide phosphate (NADPH), one reduced affinity for methylenetetrahydrofolate, five flavin adenine dinucleotide‐responsiveness, and 24 abnormal kinetics of S‐adenosylmethionine inhibition. Missense mutations causing virtually absent activity were found exclusively in the N‐terminal catalytic domain, whereas missense mutations in the C‐terminal regulatory domain caused decreased NADPH binding and disturbed inhibition by S‐adenosylmethionine. Characterization of patients in this way provides a basis for improved diagnosis using expanded enzymatic criteria, increases understanding of the molecular basis of MTHFR dysfunction, and points to the possible role of cofactor or substrate in the treatment of patients with specific mutations.