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Persistent pruritic subcutaneous nodules have been reported at the site of vaccination (vaccination granulomas) following the use of several aluminium-adsorbed vaccines. An incidence of 0.8–0.9% has been reported in the literature. Contact allergy to aluminium has been strongly associated with the presence of vaccination granulomas. During the aluminium adsorbed diphtheria-tetanus/acellular pertussis vaccine trials, hypersensitivity to aluminium was demonstrated in 77% of those with pruritic nodules. These nodules appear to be long-lasting but little is known regarding prognosis. In this case series, we report twelve children who developed pruritic nodules at injection sites following vaccination and were referred to a tertiary paediatric Dermatology centre for assessment between 2010 and 2018. The median age at onset of symptoms was twelve (IQR: 6 – 19.5) months and the main presenting symptoms were pruritus in eight children (67%) and pain in three children. Six out of the seven children tested in the series for contact allergy for aluminium were positive (86%). One child was found to have developed cutaneous pseudolymphoma on biopsy, a potential adverse effect of vaccines containing aluminium hydroxide as an adjuvant. This is the first case described in a child following vaccination. Four of the eleven children had imaging studies, two of which were reported as venous malformations. Conclusion Although an infrequent occurrence following vaccination with aluminium-adsorbed vaccines, the development of persistent pruritic nodules can cause significant distress and anxiety for parents and children and lead to unnecessary investigations and a delay in subsequent vaccination. Greater awareness among clinicians and primary health care providers of this potential adverse reaction is necessary.

Parry Romberg Syndrome (PRS) - also known as Progressive Hemifacial Atrophy- is a rare disorder primarily affecting the soft tissues on one side of the scalp and face, existing on a spectrum with linear scleroderma and ‘en coup de sabre’ morphoea. Its myriad presenting features, ranging from skin dyspigmentation, thickening or atrophy, hair loss, ophthalmic, dental involvement or even seizures, mean these patients often encounter a variety of specialists before arriving at a diagnosis or commencing on a treatment regimen. Primarily a clinical diagnosis, many children undergo adjunctive blood-based and radiological investigations. Thermographic imaging is also utilised as a non-invasive measure of disease activity, and has been demonstrated to compliment clinical assessment in our cohort. Dermatologists are key in the instigation and monitoring of responses to treatment, which are primarily a regimen of methotrexate and/or pulsed methylprednisolone. Lesions that do not regress with treatment may leave significant facial soft tissue contour defects of the forehead, periocular region, cheek or jaw, which can be socially stigmatising and stressful for these children. Our case series assessed the outcomes for ten children with PRS who underwent facial fat-grafting for these residual sequelae. This included five male and five females, with an age of symptom onset ranging from 3 to 11 years. All completed a single course of immunosuppressant therapy under dermatologic supervision without relapse. After a mean time to stabilisation of 3.5 years, referral to a dedicated Paediatric Plastic and Craniofacial surgeon was made. Thereafter, time to lipofilling ranged from one to twelve months. Patients underwent a mean of 1.3 autologous fat grafting procedures, with very favourable results and no complications. There were no relapses following treatment. To date, this is one of the largest paediatric series reporting outcomes regarding the efficacy of surgery in the management of Parry Romberg Syndrome. It demonstrates a safe, reproducible and well-tolerated procedure for paediatric patients with a condition requiring true multidisciplinary management, and highlights a need for increased awareness across specialties.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

By 2050, two-thirds of the world’s population is expected to reside in cities and urban agglomerations (UN Department of Economic and Social Affairs 2014). Cities have always showcased the best and the worst aspects of humanity – gleaming skyscrapers, art, and inventiveness on the one hand; slums, crime, and abject poverty on the other. Such challenges, which cities already face, will be further amplified by increasing urbanization, and it will be coastal cities in particular that bear the brunt of the global threat of climate change. Not without reason is the quest for “Sustainable Cities and Communities” one of the UN’s explicit sustainable development goals (United Nations 2015).

We describe the cases of 2 autistic children with ophthalmic and systemic manifestations of vitamin A deficiency due to food faddism. Although vitamin A deficiency is common in the developing world, reports in developed societies are rare. Our patients presented over a 1-year period. The patients were 14 and 13 years old at the time of presentation and were both found to have marked features of vitamin A deficiency related to unusual dietary habits. Anterior segment signs of xerophthalmia were present in both patients. In addition, patient 1 showed evidence of a rod-predominant retinopathy, which resolved with vitamin A supplementation. Due to its rare occurrence, hypovitaminosis A must be highlighted and anticipated in this cohort.

Congenital haemangiomas are rare and are estimated to have a combined incidence of less than 3% of all infantile haemangiomas. They are fully grown at birth, having undergone their proliferative phase in utero (1). Congenital hemangiomas can present at birth or in some cases can be detected antenatally on imaging (2,3). In the majority of patients no therapeutic intervention is required. Congenital hemangiomas also differ from infantile hemangiomas by staining negatively with GLUT1 antibody. They fall into two major subtypes: rapidly involuting congenital hemangiomas (RICHs) and noninvoluting congenital hemangiomas (NICHs) (4,5). Here we describe a case of RICH detected antenatally on ultrasound imaging. This lesion caused significant complications in the postnatal period due to the bulk of the lesion and the presence of incipient ulceration with the risk of possible catastrophic hemorrhage. A therapeutic trial of oral corticosteroid was commenced in an effort to accelerate involution due to the significant risk associated with other possible treatment modalities such as embolization or surgical intervention.

PHACE (posterior fossa defects, haemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities) syndrome describes a constellation of abnormalities that can occur in association with segmental craniofacial infantile haemangioma. To report the spectrum of clinical and imaging abnormalities seen in a cohort of children. A retrospective review of the clinical and imaging records of all patients diagnosed with PHACE syndrome between 1998 and 2009 was performed. Information sought included patient demographics, craniofacial segments involved, imaging findings and other extracutaneous abnormalities. Twelve patients were diagnosed with PHACE syndrome over 11 years. All patients had a segmental craniofacial haemangioma. Involved facial segments, in order of frequency, were frontotemporal (12), maxillary (8), mandibular (5) and frontonasal (1). The most common extracutaneous abnormalities were neurovascular anomalies (10), with many patients having multiple anomalies. The spectrum of arterial anomalies ranged from hypoplasia (9) to ectasia (3), anomalous origin/course (2) and persistent fetal anastomosis (2). Other anomalies found included cardiac anomalies (3), coarctation of the aorta (2), posterior fossa malformations (1) and sternal region anomalies (1). Intracranial anomalies are the most common extracutaneous feature of PHACE syndrome. The contribution of the radiologist in the recognition of such anomalies is important for the diagnosis of PHACE syndrome.

Kaposiform hemangioendothelioma is an aggressive vascular tumor, named for its striking histologic resemblance to Kaposi sarcoma and locally invasive growth. Mortality is high, and ranges from 10% to 24% for all kaposiform hemangioendothelioma lesions, with a significantly higher mortality for deep soft-tissue or visceral lesions occurring in infants less than 6 months. Mediastinal and neck kaposiform hemangioendothelioma in particular merit special discussion, as involvement of these critical anatomic locations results in significant site-specific therapeutic challenges due to invasion of vital structures, inherent delays in establishing histopathologic confirmation, and difficulties in monitoring disease status. We report our experience with three cases of mediastinal and neck kaposiform hemangioendothelioma, emphasizing the unique diagnostic and management challenges, variable response to treatment and outcome of this anatomic variant of kaposiform hemangioendothelioma.

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.

Familial cold auto-inflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurologic, cutaneous, articular syndrome are related disorders associated with mutations in the CIAS1 gene. They appear to represent a continuum of one disease characterized by IL-1-mediated inflammation. Until recently, these conditions have been difficult to treat; however, with the advent of IL-1-receptor antagonist therapy, many reports of successful treatment of patients with these autoinflammatory diseases have emerged in the past 2 years. We describe an 8-year-old girl, diagnosed with Familial cold auto-inflammatory syndrome, confirmed by presence of a novel CIAS1 mutation, who was refractory to symptomatic treatment. As frequent attacks of urticaria and associated arthralgia had a debilitating effect on the child's lifestyle, a trial of IL-1-receptor antagonist (anakinra) was instituted. Dramatic sustained clinical improvement was evident within days and serum amyloid and C-reactive protein levels normalized within a month. Although several authors have reported successful use of this agent in children with chronic infantile neurologic, cutaneous, articular syndrome, we believe ours is the first report of successful treatment with anakinra in a young child with familial cold auto-inflammatory syndrome.

Results When HR IgE FHS were categorized by eczema severity, those with severe AD were more likely to have HR IgE to cow’s milk (x2 11.3, P < 0.001), egg (x2 6.5, P < 0.05) and peanut (x2 25.4, P < 0.0001) compared to those with mild to moderate AD. Those ≤ 2 years with severe AD were more likely to have multiple HR IgE FHS compared to those with mild to moderate AD for all combinations: cow’s milk and egg (x2 18.62, P < 0.0001); peanut and egg: (x2 24.72, P < 0.0001); cow’s milk and peanut (x2 16.37, P < 0.0001); cow’s milk, egg and peanut (x2 20.01, P < 0.0001).

Background Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients. Methods Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected. Results Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes. Conclusions HFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics. © 2015 Nature America, Inc. All rights reserved.

The current highly fragmented multitude of information systems supporting tourism greatly increases the tourist’s search costs, and while touring there is almost no information systems support. A more cohesive and integrated approach should enhance the tourist’s experience in the three phases of tourism: planning, touring, and reminiscing. The emergence of u-commerce, the ultimate form of commerce, is the backdrop to identifying a series of information products that will improve the searching, management, delivery, and sharing of tourism data. It is proposed that the six products identified (TourDM, TourML, TourStyle, TourCMS, TourImplement, and TourCommunity) be developed using the open source model and the cooperative efforts of a large number of geographically dispersed students. The Open Tourism Consortium has been created to support this collaborative endeavor.

Rapidly involuting congenital hemangiomas (RICHs) are rare tumors that usually present as well-defined bluish or violaceous plaques or tumors with scattered telangiectasias and central or peripheral pallor. We report two previously unreported cases of RICH with associated pustules.

Summary We report a case of a 6-month-old girl who was referred for evaluation of a congenital melanocytic naevus (CMN) on her right thigh. The lesion was consistent with a medium-sized CMN and was managed conservatively. A halo of depigmentation, which coincided with occlusion of the lesion during a holiday in a sunny climate, was noted soon after her fourth birthday and the CNM regressed completely over a 4-month period. A residual patch of leucoderma still remained at the original CMN site > 2 years after its total involution. The process has been documented with photographs and a skin biopsy during the resolving phase.

A 6-week-old boy was referred with a generalized bullous rash since birth. Examination revealed bullous mastocytosis with initially no evidence of systemic involvement. Hepatosplenomegaly was noted at 6 months, and at 12 months he was found to have generalized lymphadenopathy. He developed bouts of vomiting associated with increased blistering. At 17 months he had sudden collapse following a brief bout of vomiting and was apneic and asystolic on arrival at the emergency department. The cause of death was attributed to massive hypotension secondary to mast cell degranulation. Although childhood mastocytosis has a favorable course in general, the subset of children with congenital bullous mastocytosis is at higher risk of sudden death and a more guarded prognosis should be given.

Neonatal lupus erythematosus (NLE) is a rare acquired autoimmune disease caused by transplacental transfer of maternal immunoglobulin G antibodies to the fetus. NLE has well-recognized cutaneous features and may also manifest in other organs. The majority of cases are associated with Ro/SSA and La/SSB antibodies. Neonatal lupus due to antiribonucleoprotein (RNP) antibodies has rarely been reported. On rare occasions RNP has been found in association with other antibodies. We report a case of NLE occurring solely due to RNP antibodies presenting as varicelliform lesions at birth. We recorded the features in our case and 14 additional cases identified in the literature. It is important to recognize that maternal transfer of RNP antibodies may produce the classic cutaneous features of neonatal lupus. The limited case reports of this condition suggest that manifestations are limited to the skin; specifically, there are no reports of cardiac involvement. The long-term outcome remains unknown. RNP-positive, Ro/La-negative NLE seems to represent a different clinical subset of NLE. The recognition of RNP antibody NLE as a benign condition limited to the skin is helpful in planning antenatal care for subsequent pregnancies.

Background: Filaggrin, coded by FLG, is the main source of several major components of natural moisturizing factor (NMF) in the stratum corneum (SC), including pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA). Loss-offunction mutations in FLG lead to reduced levels of filaggrin degradation products in the SC. It has recently been suggested that expression of filaggrin may additionally be influenced by the atopic inflammatory response. In this study, we investigated the levels of several breakdown products of filaggrin in the SC in healthy controls (CTRL) and patients with atopic dermatitis (AD) in relation to FLG null allele status. We examined the relationship between NMF (defined here as the sum of PCA and UCA) and AD severity. Methods: The SC levels of filaggrin degradation products including PCA, UCA, histidine (HIS) and tyrosine were determined in 24 CTRL and 96 patients with moderate-to-severe AD. All subjects were screened for 11 FLG mutations relevant for the study population. Results: The levels of PCA, UCA and HIS correlated with FLG genotype. Furthermore, these levels were higher in the CTRL when compared to AD patients with no FLG mutations. Multiple regression analysis showed that NMF levels were independently associated with FLG genotype and severity of disease. Conclusion: Decreased NMF is a global feature of moderate-to-severe AD; within AD, FLG genotype is the major determinant of NMF, with disease severity as a secondary modifier. NMF components are reliably determined by a noninvasive and relatively inexpensive tape stripping technique.

We studied 121 patients with systemic lupus erythematosus (SLE), of whom 119 were complement typed. Both black and white patients with SLE were more likely than racially matched controls to have a C4A null allotype. Patients with homozygous C4A deficiency had less proteinuria than other patients (p = 0.02) and both homozygous and heterozygous C4A-deficient patients (p = 0.05) had fewer seizures than other patients. Anti-dsDNA, anti-Sm, anti-Ro, and anticardiolipin antibodies were less common in patients with homozygous C4A deficiency, with heterozygous C4A-deficient patients intermediate in frequency between homozygous C4A-deficient and normal patients with SLE. Both homozygous and heterozygous C4A-deficient patients (p < 0.005) had higher C3 levels than other patients, and heterozygous C4A-deficient patients had higher, not lower, C4 levels (p < 0.002), compared with non-C4A-deficient patients. C4A gene deletion was found in 23.4% of patients. C4A gene deletion was associated with subacute cutaneous lupus erythematosus (p = 0.04) and Sjogren syndrome (p = 0.02) in patients with SLE. Both anti-dsDNA (p = 0.04) and anticardiolipin (p = 0.04) were found less frequently in patients with C4A gene deletion. Patients with C4A gene deletion had lower C4 levels than patients with C4A deficiency from other mechanisms. We conclude that the presence of 1 or 2 C4A null allotypes and the presence of a C4A gene deletion identify subgroups of patients with SLE that differ in clinical, laboratory, and autoantibody characteristics from other patients with SLE.

Figure 1 Dramatic resolution of warts involving the hands over 3 months after initiating cidofovir treatment. Successful treatment of refractory cutaneous warts using topical 3% cidofovir in a child after heart transplant Aoife Cleary, MB, Rosemarie Watson, FRCPI, and Colin J. McMahon, FRCPI From the Departments of Paediatric Cardiology, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland; and the Departments of Dermatology, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland

Advances in the medical care of epidermolysis bullosa (EB) have led to the development of National Service Centers for EB in many countries worldwide. The exemplary model of care to children and adults with EB in the United Kingdom, combined with the knowledge that people with EB were travelling to the United Kingdom for treatment, encouraged the development of the Irish national service. Dystrophic Epidermolysis Bullosa Research Association of Ireland, founded in 1988 played a pivotal role in this development.

The major mucous membrane and cutaneous manifestation of Sjogren's syndrome (SS) is xerosis. Severe dryness of the eyes, mouth, nasal passage, and vagina produce many annoying symptoms, including photophobia, burning and itching of the eyes, alterations in taste and smell, recurring nonallergic bacterial sinusitis rhinitis, and dysparunia. SS patients frequently complain of dryness of lips and soreness and a burning sensation of the tongue and oral mucosa. SS patients also complain of dryness of their hair and note a decrease in luster, and severe dryness of the skin is frequently accompanied by pruritus.

We examined 18 families with infants who had neonatal lupus erythematosus (NLE) syndrome to determine whether abnormalities in C4 phenotypes and genotypes were an additional risk factor for this syndrome. Fifteen of 18 mothers of infants with NLE (83%) had C4 null allotypes compared with 36% of population controls (p = less than .001). This increased frequency was due mainly to the presence of C4A null allotypes (11/18, 61%). C4 gene abnormalities, i.e., deletion or probable duplication, were present in 100% (16/16) of mothers of infants with NLE. The most common molecular genetic abnormality in mothers of infants with NLE in this study was deletion of C4A genes. Duplication of C4A and C4B loci was also commonly seen. Duplication of C4A genes was detected only in mothers of infants with complete congenital heart block (CCHB), and duplication of C4B was detected only in mothers of infants with dermatitis. No significant increase in C4A or C4B null allotypes or protein deficiencies was noted in mothers of infants with neonatal lupus when compared with anti-Ro(SS-A)-positive mothers delivered of clinically normal infants. Fathers of infants with NLE showed a trend toward increase in C4B null allotypes when compared with population controls (75%, 3/4, p = .06). The two infants with CCHB examined were C4B protein-deficient, in contrast to infants with lupus dermatitis, who had frequent C4B null allotypes but no C4B protein deficiency. C4B null allotypes were not seen in unaffected siblings of infants with NLE and in only 1 of 7 anti-Ro(SS-A)-positive mothers who delivered clinically normal infants. We conclude that inheritance of C4A null allotypes is not predictive of increased risk of neonatal lupus when present in anti-Ro(SS-A)-positive women. Examination of paternal and maternal C4 genes of additional infants with NLE, in particular those with CCHB, and of normal infants born to anti-Ro(SS-A)-positive mothers--and of the normal infants' parents--is required to determine if abnormal C4B genes are a critical factor rendering susceptibility to the NLE syndrome.

Background Polymorphisms in the serine protease inhibitor gene serine peptidase inhibitor Kazal type 5 (SPINK5) and the serine protease kallikrein-related peptidase 7 gene (KLK7) appear to confer risk to eczema in some cohorts, but these findings have not been widely replicated. These genes encode proteins thought to be involved in the regulation of posttranslation processing of filaggrin (FLG) , the strongest identified genetic risk factor for eczema to date. Objectives We sought to clarify the individual risk of eczema conferred by the SPINK5 polymorphism rs2303067 (Glu420Lys) and a previously described insertion in the 3′ untranslated region of KLK7 and to examine potential epistatic effects between these variants and FLG mutations. Methods Initially, we examined the effects of these polymorphisms and FLG in 486 unrelated patients from a German family-based study, an additional 287 German patients, and 418 unrelated Irish/English patients with eczema (n for 3 genes studied=1191 vs 4544 control subjects). We then additionally studied the SPINK5 polymorphism and FLG mutations in 1583 patients with eczema from the Avon Longitudinal Study of Parents and Children cohort (sample size for 2 genes studied=2774 vs 10,607 control subjects). Results No association was seen with the SPINK5 or KLK7 variants in the case-control analysis; however, a weaker effect was observed for the SPINK5 variant with maternal transmission in the family-based study. No interactions were seen between the polymorphisms in KLK7 , SPINK5 , and FLG . Conclusion The SPINK5 420LysSer mutation confers a risk of eczema when maternally inherited but is not a major eczema risk factor. The KLK7 insertion appears to confer no risk of eczema. We found no interaction between the SPINK5 risk allele or the putative KLK7 risk allele and FLG mutations.

Eosinophilia-myalgia syndrome (EMS) is a recently described clinical entity that has been ascribed to taking over-the-counter preparations of the amino acid L-tryptophan. We describe 4 patients with EMS, 3 of whom presented with eosinophilic fasciitis, and we review the epidemiology of EMS reported in Maryland and discuss the possible pathophysiology of the disease. EMS should be considered in the differential diagnosis of severe myalgia, eosinophilia, and eosinophilic fasciitis.

Juvenile localised scleroderma (JLS) is a rare connective tissue disorder in childhood. Most lesions are benign and self-limiting, but some progress to cause functional disabilities and cosmetic disfigurement. These lesions require systemic treatment, the mainstay of which is corticosteroids and methotrexate. To report the experience of the use of systemic treatment in children with JLS in our department. We performed a retrospective chart review looking at the patients who received systemic treatment over 14 years and recorded their outcomes. Ten children with aggressive JLS were treated with systemic immunosuppressive therapy. There was an 80% response to treatment. Three of the responders relapsed off treatment, but responded to a further course of therapy. Mean disease duration at diagnosis was 8 months. Treatment was generally well tolerated with few side effects. Early recognition of aggressive localised scleroderma and appropriate referral is imperative for a good outcome.

Nat. Genet. 47 803–808 (2015); published online 25 May 2015; corrected after print 8 July 2015 In the version of this article initially published, there was an error with the affiliations for author Roman Chrast. His correct affiliations are: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Rhombencephalosynapsis is a rare cerebellar malformation that can be associated with anomalies of the cerebral hemispheres and variable degrees of neurodevelopmental delay. A syndromic association, comprising rhombencephalosynapsis, developmental delay, scalp alopecia and trigeminal anaesthesia (Gomez-López-Hernández syndrome) has been described in seven individuals. We report the case of a 2-year-old boy with rhombencephalosynapsis, and review the evidence for a possible diagnosis of Gomez-López-Hernández syndrome. We also discuss other malformations reported in combination with rhombencephalosynapsis, and consider the possibility that a genetic aetiology for syndromic and nonsyndromic forms of rhombencephalosynapsis may be established with more detailed clinical and genetic studies.

Anonychia and hyponychia congenita (OMIM 206800) are rare autosomal recessive conditions in which the only presenting phenotype is the absence or severe hypoplasia of all fingernails and toenails. After determining linkage to chromosome 20p13, we identified homozygous or compound heterozygous mutations in the gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, in eight affected families. Rspo4 expression was specifically localized to developing mouse nail mesenchyme at embryonic day 15.5, suggesting a crucial role in nail morphogenesis.

Mutations in the filament aggregating protein (filaggrin) gene have recently been identified as the cause of the common genetic skin disorder ichthyosis vulgaris (IV), the most prevalent inherited disorder of keratinization. The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris. Here, we have studied six Irish families with IV for mutations in filaggrin. We have identified a new mutation, 3702delG, in addition to further instances of the reported mutations R501X and 2282del4, which are common in people of European origin. A case of a 2282del4 homozygote was also identified. Mutation 3702delG terminates protein translation in filaggrin repeat domain 3, whereas both recurrent mutations occur in repeat 1. These mutations are semidominant: heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity and in some cases fine-scale and/or keratosis pilaris, whereas homozygotes or compound heterozygotes generally have more marked ichthyosis. Interestingly, the phenotypes of individuals homozygous for R501X, 2282del4, or compound heterozygous for R501X and 3702delG, were comparable, suggesting that mutations located centrally in the filaggrin repeats are also pathogenic.

Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

We report a patient with cutis marmorata telangiectatica with the hitherto unreported anomaly of a double aortic arch. The presence of two major vascular anomalies in this patient may be secondary to a developmental defect of the mesoderm during embryogenesis.

We describe a 19-year-old girl who has clinical features of microphthalmia with linear skin defects (MLS) syndrome caused by a microdeletion of Xp22.3. In addition to the classical ocular abnormalities and linear skin defects she has other features not previously described. She was previously reported in this journal in 1990 as poikiloderma congenitale, but her true diagnosis of an Xp22.3 microdeletion was clarified when fluorescent in situ hybridization (FISH) analysis indicated that one of her X chromosomes had a microdeletion including the KAL gene. We describe this patient with an Xp22.3 microdeletion to heighten awareness among dermatologists of this syndrome and to underscore the difficulties in diagnosing MLS syndrome.

Objective To study the clinical and immunopathologic findings of drug-induced, Ro/SSA-positive cutaneous lupus erythematosus (CLE). Design Retrospective medical and laboratory record review. Setting Immunodermatology Division of Johns Hopkins Hospital (Baltimore, Md). Patients Of 120 patients found to have anti-Ro/SSA antibodies by hemagglutination and/or double immunodiffusion, 70 had clinical and immunopathologic confirmation of CLE. Fifteen of these 70 patients had a history of new drug exposure, defined as less than 6 months, associated with disease development. Results The disease-associated drugs included hydrochlorothiazide (5 patients), angiotensin-converting enzyme inhibitors (3 patients), calcium channel blockers (3 patients), interferons (2 patients), and statins (2 patients). The most common presentations were photodistributed diffuse erythema and subacute CLE-type lesions without evidence of significant systemic disease. All specimens revealed interface dermatitis and fine granular IgG deposition along the basement membrane zone and throughout the epidermis. Most patients experienced improvement or resolution of clinical lesions within 8 weeks and decrease of Ro/SSA titers within 8 months after discontinuation of drug treatment. Conclusions Antihypertensive drugs are the most commonly associated with Ro-positive CLE. Clinical and immunopathologic features of this drug-induced variant do not seem to differ from the idiopathic disease. In most cases, the disease improves or resolves on discontinuation of the offending drug treatment. It is not known if these drugs precipitate disease in patients who have subclinical disease. Drug-induced Ro/SSA-positive CLE should be included on the differential diagnosis in patients presenting with photosensitive or subacute CLE-type eruptions.

The anti-Ro(SS-A) antibody is arguably the most important antibody determination except for antinuclear antibodies in evaluation of patients suspected of having lupus erythematosus. During the past 25 years, studies have established the importance of this antibody in the evaluation of patients with atypical lupus erythematosus, who have a photosensitive dermatitis as the presenting sign. The purpose of this review is to demonstrate the utility and the necessity of this antibody determination in the evaluation of all patients with cutaneous manifestations who are suspected of having a connective tissue disease.

Reflex sympathetic dystrophy is characterized by severe pain and autonomic dysfunction in a limb, usually after an injury. We describe a patient with childhood reflex sympathetic dystrophy with unilateral Beau's lines on the nails of the affected hand. Unilateral Beau's lines have not been described previously in this condition to our knowledge, and we discuss their possible pathogenesis.

To explore further the varied clinical expression of anti-Ro(SS-A) antibody positive patients and to determine the outcomes of these patients, we followed 100 anti-Ro(SS-A) antibody positive patients, originally seen at the Johns Hopkins Medical Institutions in 1982 and 1983, over a 10-year period. The results of this study indicate that anti-Ro(SS-A) antibody positive patients have a diverse clinical presentation and that the anti-Ro(SS-A) antibody response generally persists for years. Some of these patients appear to have a static disease process for years. However, 65% (51, including 13 deaths, of 78 patients) of the patients for whom we had follow-up data had a chronic (10 years or greater) progressive disease process. Black patients, in general, have an earlier onset of disease and may have a more severe disease than white patients. At least 25% of our anti-Ro(SS-A) antibody positive patients demonstrated a dynamic change in clinical presentation with the development of Sjogren syndrome and/or a progressive "rheumatoid-like" arthritis. Interstitial pulmonary disease, central nervous system disease, and vasculitic insults occur frequently in these patients. Renal disease occurred in 19 anti-Ro(SS-A) positive patients, and in 47% of these renal disease patients, no anti-DNA antibodies (dsDNA or ssDNA) were detected. Cutaneous manifestations are prominent in anti-Ro(SS-A) antibody positive patients with lupus. Photosensitivity and a malar dermatitis were the most common features. Twenty percent of lupus patients had discoid lesions, and 20% had SCLE lesions. Based on this study, we believe that anti-Ro(SS-A) antibody positive patients should be routinely evaluated for the emergence of systemic features. Since these systemic features are at least in part, if not solely, the result of inflammation, early treatment with steroids and/or immunosuppressive agents may minimize the damage and influence in a positive manner the significant morbidity and mortality observed in some anti-Ro(SS-A) antibody positive patients.

Background: Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD(FLG)) compared with that seen in patients with AD without these mutations (AD(NON-FLG)). Objectives: We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD(FLG) versus patients with AD(NON-FLG). We also sought to examine the same profiles in a murine model of filaggrin deficiency (Flg(ft)/Flg(ft) [Flg(delAPfal)] mice). Methods: One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1 alpha, IL-1 beta, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flg(ft)/Flg(ft) (Flg(delAPfal)) mice, separated from maFlg(ft)/maFlg(ft) (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1 alpha, IL-1 beta, and IL-1RA. Results: SC IL-1 levels were increased in patients with AD(FLG); these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flg(ft)/Flg(ft) mice had upregulated expression of IL-1 beta and IL-1RA mRNA. Conclusions: AD(FLG) is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches. (J Allergy Clin Immunol 2012;129:1031-9.)