The ocular phenotype of stiff-skin syndrome.

PURPOSE Stiff skin syndrome (SSS; MIM#184900) is a rare autosomal dominantly inherited Mendelian disorder characterised by thickened and stone-hard indurations of the skin, mild hypertrichosis, and limitation of joint mobility with flexion contractures. It is autosomal dominant with high penetrance and results from mutations in the fibrillin 1 (FBN1; MIM*134797) gene. Here we present the associated ocular phenotype in a two generation nonconsanguineous Northern Irish family.METHODS The affected patients underwent complete ophthalmic and orthoptic assessment and genetic testing.RESULTS All three patients had ophthalmoplegia of varying degrees. Direct sequencing of the FBN1 gene detected a heterozygous pathogenic mutation (c.4710G>C; p.Trp1570Cys) in all affected patients.CONCLUSIONS This is the first report of ophthalmoplegia in association with SSS.

Challenges in management of primary hypoparathyroidism associated with autoimmune polyglandular syndrome type 1.

We report a case of autoimmune polyglandular syndrome type 1 (APS1) complicated by severe vascular insufficiency due to diffuse vascular calcification. APS1 is characterised clinically by multiple autoimmune conditions and development of at least two components of the triad of mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency. We highlight the problems in current serum calcium monitoring methods and suggest that fluctuations in serum calcium concentrations due to difficulties treating hypoparathyroidism may have contributed to the vascular calcification seen in this case.

Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome.

The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance.

Pattern recognition receptor expression is not impaired in patients with chronic mucocutanous candidiasis with or without autoimmune polyendocrinopathy candidiasis ectodermal dystrophy.

Patients with chronic mucocutaneous candidiasis (CMC) have an unknown primary immune defect and are unable to clear infections with the yeast Candida. CMC includes patients with AIRE gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, suggesting that defective expression of pattern recognition receptors (PRRs) may underlie disease pathogenesis. In 29 patients with CMC (13 with APECED) and controls, we assessed dendritic cell (DC) subsets and monocyte Toll-like receptor (TLR) expression in blood. We generated and stimulated monocyte-derived (mo)DCs with Candida albicans, TLR-2/6 ligand and lipopolysaccharide and assessed PRR mRNA expression by polymerase chain reaction [TLR-1-10, Dectin-1 and -2, spleen tyrosine kinase (Syk) and caspase recruitment domain (CARD) 9] in immature and mature moDCs. We demonstrate for the first time that CMC patients, with or without APECED, have normal blood levels of plasmocytoid and myeloid DCs and monocyte TLR-2/TLR-6 expression. We showed that in immature moDCs, expression levels of all PRRs involved in anti-Candida responses (TLR-1, -2, -4, -6, Dectin-1, Syk, CARD9) were comparable to controls, implying that defects in PRR expression are not responsible for the increased susceptibility to Candida infections seen in CMC patients. However, as opposed to healthy controls, both groups of CMC patients failed to down-regulate PRR mRNA expression in response to Candida, consistent with defective DC maturation, as we reported recently. Thus, impaired DC maturation and consequent altered regulation of PRR signalling pathways rather than defects in PRR expression may be responsible for inadequate Candida handling in CMC patients.

Impaired dendritic cell maturation and cytokine production in patients with chronic mucocutanous candidiasis with or without APECED.

Patients with chronic mucocutaneous candidiasis (CMC) suffer persistent infections with the yeast Candida. CMC includes patients with autoimmune regulator (AIRE) gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, and dendritic cells (DCs), as central orchestrators, may underlie pathogenic disease mechanisms. In 29 patients with CMC (13 with APECED) and controls, we generated monocyte-derived DCs, stimulated them with Candida albicans, Toll-like receptor-2/6 ligand and lipopolysaccharide to assess cytokine production [interleukin (IL)-12p70, IL-23, interferon (IFN)-gamma, IL-2, tumour necrosis factor (TNF)-alpha, IL-6, transforming growth factor-beta, IL-10, IL-5, IL-13] and cell-surface maturation marker expression (CD83, CD86, human leucocyte antigen D-related). In both APECED and non-APECED CMC patients, we demonstrate impairment of DC function as evidenced by altered cytokine expression profiles and DC maturation/activation: (1) both groups over-produce IL-2, IFN-gamma, TNF-alpha and IL-13 and demonstrate impaired DC maturation. (2) Only non-APECED patients showed markedly decreased Candida-stimulated production of IL-23 and markedly increased production of IL-6, suggesting impairment of the IL-6/IL-23/T helper type 17 axis. (3) In contrast, only APECED patients showed DC hyperactivation, which may underlie altered T cell responsiveness, autoimmunity and impaired response to Candida. We demonstrate different pathogenic mechanisms on the same immune response pathway underlying increased susceptibility to Candida infection in these patients.

Mosaic monosomy 14: clinical features and recognizable facies.

A 1-year-old child with clinical features of monosomy 14 is reported. She has dysmorphic facial features including ocular colobomata, dolichocephaly and microcephaly, retinal pigmentation, severe seizures, fair curly hair and tapering fingers. There was severe mental retardation. This is the first reported case of severe mosaic monosomy 14, with up to 30% mosaicism. A recognizable facial gestalt is present in children with 14q deletions or partial monosomy 14, as well as susceptibility to infection, feeding difficulties, seizures and retinal pigmentation.

An Irish three-generation family of Cornelia de Lange syndrome displaying autosomal dominant inheritance.

The existence of familial de Lange syndrome has been documented in sibs and in parent-child families, but the inheritance pattern continues to be the cause of much debate. We describe a classically affected neonate with de Lange syndrome, an affected mother and probably affected maternal grandmother. These cases show evidence for a dominantly inherited syndrome with a de Lange phenotype.

Antimicrobial intermediates of the general phenylpropanoid and lignin specific pathways.

The minimum inhibitory concentration (MIC) of the major intermediates of the general phenylpropanoid and lignin specific pathways of plants were determined employing a range of yeasts and bacteria. Of the three main classes of compounds tested, the hydroxycinnamaldehydes were the most effective, possessing notable antifungal and antibacterial activity. Determination of the minimum killing concentration (MKC) of the hydroxycinnamaldehydes revealed MIC/MKC ratios suggesting these compounds to be fungicidal, but not bactericidal, in their mode of action. In contrast, the hydroxycinnamic acids and hydroxycinnamyl alcohols possessed little antimicrobial activity, with the exception of the hydroxycinnamic acids, which were antibacterial.

Costs, emissions reductions, and vehicle repair: evidence from Arizona.

The Arizona inspection and maintenance (I/M) program provides one of the first opportunities to examine the costs and effectiveness of vehicle emission repair. This paper examines various aspects of emission reductions, fuel economy improvements, and repair costs, drawing data from over 80,000 vehicles that failed the I/M test in Arizona between 1995 and the first half of 1996. We summarize the wealth of data on repair from the Arizona program and highlight its limitations. Because missing or incomplete cost information has been a serious shortcoming for the evaluation of I/M programs, we develop a method for estimating repair costs when they are not reported. We find surprising evidence that almost one quarter of all vehicles that take the I/M test are never observed to pass the test. Using a statistical analysis, we provide some information about the differences between the vehicles that pass and those that do not. Older, more polluting vehicles are much more likely never to pass the I/M test, and their expected repair costs are much higher than those for newer cars. This paper summarizes the evidence on costs and emission reductions in the Arizona program, comparing costs and emissions reductions between cars and trucks. Finally, we examine the potential for more cost-effective repair, first through an analysis of tightening I/M cut points and then by calculating the cost savings of achieving different emission reduction goals when the most cost-effective repairs are made first.