Understanding irritant napkin dermatitis.

Irritant napkin dermatitis (IND, often referred to as irritant diaper dermatitis) is an exceedingly common problem in the first 2 years of life. It is now established that a number of factors are considered important in the etiology of IND. The principal irritants are fecal enzymes, which damage infant skin and are further amplified by a number of factors, including skin maceration and friction, high pH, the presence of urine, and the duration of contact with feces. In recent years, the decreasing incidence and severity of IND reflects improvements in the design and performance of diapers, diaper skin care products, and overall awareness about maintaining infant skin health.

Mosaic Activating Mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis.

Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11(R183C) and GNA11(Q209L) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11(R183C) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.

Germline melanocortin-1-receptor genotype is associated with severity of cutaneous phenotype in congenital melanocytic nevi: a role for MC1R in human fetal development.

Congenital melanocytic nevi (CMN) are pigmented birthmarks that affect up to 80% of the skin surface area. The increased frequency of CMN in families of severely affected individuals is suggestive of a predisposing germline genotype. We noted a high prevalence of red hair in affected families, and considered a role for MC1R in this condition. A cohort of 166 CMN subjects underwent pigmentary phenotyping, with MC1R genotyping in 113. Results were compared with a local control group of 60 unrelated children and with 300 UK children without CMN. CMN subjects had higher prevalences of red hair and a red-haired parent than local controls and had a higher rate of compound heterozygosity and homozygosity for MC1R variants. The presence of a V92M or R allele (D84E, R151C, R160W, D294H) was associated with increasing size of the CMN, implying a growth-promoting effect of these alleles. Unexpectedly, the V92M and R151C alleles were also strongly associated with birth weight in the CMN cohort, a finding confirmed in the control group. The effect of germline MC1R genotype on development and severity of CMN led us to investigate potential broader effects on growth, revealing a role for MC1R in normal fetal development.

Congenital anetoderma in a preterm infant.

Isolated, small lesions of anetoderma presenting at birth have been reported in twins born at 25 weeks of gestational age. We report the first case of widespread congenital anetoderma occurring in an infant born at 24 weeks of gestation weighing 640 g and discuss the potential factors in its etiology.

Clinical resolution of a neonatally eroded giant congenital melanocytic nevus.

We report an unusual occurrence of spontaneous pigmentary regression with a desmoplastic reaction in a neonatally eroded giant congenital melanocytic nevus. This process has been documented with photographs and skin biopsy specimens. Neonatal histology demonstrated connective tissue proliferation. Histology at age 5 years also demonstrated a very high proportion of amelanotic dermal nevus cells. Regression of pigmentation in our patient may be due to a decrease in melanin production by dermal nevus cells rather than a decrease in their number.

Infantile haemangiomas.

Infantile haemangiomas are the commonest tumours occurring in infants, but regress spontaneously without causing major problems in the great majority of cases. However, in some infants they can cause life-threatening complications. Fortunately, if the decision to treat is made promptly, and the most appropriate form of treatment selected, these complications can usually be prevented.

Complete maternal isodisomy of chromosome 3 in a child with recessive dystrophic epidermolysis bullosa but no other phenotypic abnormalities.

The mechanobullous disease Hallopeau-Siemens recessive dystrophic epidermolysis bullosa (HS-RDEB) results from mutations in the type VII collagen gene (COL7A1) on chromosome 3p21.31. Typically, there are frameshift, splice site, or nonsense mutations on both alleles. In this report, we describe a patient with HS-RDEB, who was homozygous for a new frameshift mutation, 345insG, in exon 3 of COL7A1. However, sequencing of parental DNA showed that although the patient's mother was a heterozygous carrier of this mutation, the father's DNA contained only wild-type sequence. Microsatellite marker analysis confirmed paternity and genotyping of 28 microsatellites spanning chromosome 3 revealed that the affected child was homozygous for every marker tested with all alleles originating from a single maternal chromosome 3. Thus, the HS-RDEB phenotype in this patient is due to complete maternal isodisomy of chromosome 3 and reduction to homozygosity of the mutant COL7A1 gene locus. To our knowledge, there are no published reports of uniparental disomy (UPD) in HS-RDEB; moreover, this case represents only the third example of UPD of chromosome 3 to be reported. The severity of the HS-RDEB in this case was similar to other affected individuals and no additional phenotypic abnormalities were observed, suggesting an absence of maternally imprinted genes on chromosome 3.

Successful treatment of laryngeal stenosis in laryngo-onycho-cutaneous syndrome with topical mitomycin C.

Laryngo-onycho-cutaneous syndrome is a very rare entity found in Punjabi families. It affects the skin, nails, and larynx. Laryngeal involvement may cause lethal airway obstruction, and has in the past proved very difficult to treat. Mitomycin C is an antibiotic that acts as an alkylating agent, inhibiting DNA synthesis. It reduces fibroblast proliferation, and has previously been used to treat choanal atresia and laryngeal stenosis. We report an 18-year-old man with complete transglottic laryngeal stenosis secondary to laryngo-onycho-cutaneous syndrome. An airway was established by dissection with a bougie and sickle knife, and was initially maintained by the upper limb of a Montgomery T-tube. Laryngeal granulation tissue present on removal of the T-tube was treated with topical mitomycin C (2 mg/mL) applied for 4 minutes on two occasions with an interval of 1 month. A year later, the airway remained patent, with no granulation tissue.

Mycosis fungoides with a CD56+ immunophenotype.

We report 3 cases of mycosis fungoides (MF) with a CD56+ cytotoxic immunophenotype. Each patient presented with a different clinical phenotype: one exhibited limited poikilodermatous patches (skin stage T1); one, widespread hypopigmented lesions (skin stage T2); and one, poikiloderma with a single cutaneous tumor (skin stage T3). MF was confirmed both histologically and by the presence of a T-cell receptor clone in lesional skin in all cases. CD56 and T-cell intracellular antigen-1 were expressed by the malignant lymphocytes in all patients and two expressed CD8. No sample demonstrated loss of the pan T-cell markers CD2 or CD3. None of the 3 developed systemic disease and T-cell receptor gene analysis of peripheral blood was polyclonal in all cases. Only 3 cases of CD56+ MF have been reported previously, none of which exhibited tumor-stage disease. Currently, the disease in our patients appears to be behaving in a manner similar to that predicted for MF with a normal immunophenotype but the prognosis has to be guarded in view of the rarity of this subtype.

A review of the pathophysiology, prevention and treatment of irritant diaper dermatitis.

Irritant diaper dermatitis (IDD) is a form of contact dermatitis occurring in the diaper area as a consequence of disruption of the barrier function of the skin through prolonged contact with faeces and urine. Despite advances in diaper technology, it is a condition that still occurs regularly in young children. To combat this, barrier preparations can be used to protect the skin by coating the surface of the skin and/or by supplying lipids that can penetrate the intercellular spaces of the stratum corneum. In this review, the pathophysiology of IDD is outlined and its prevention and treatment are discussed, with particular reference to the role of emollients.

Recurrent mutations in kindlin-1, a novel keratinocyte focal contact protein, in the autosomal recessive skin fragility and photosensitivity disorder, Kindler syndrome.

Kindler syndrome (OMIM 173650) is a rare autosomal recessive disorder characterized by trauma-induced blister formation (especially in childhood) and photosensitivity. Other features include mucocutaneous scarring and progressive poikiloderma. There is also an increased risk of skin and mucous membrane malignancy. The disorder was recently mapped to 20p12.3 and pathogenic mutations were identified in a new gene, KIND1. This gene encodes a 677 amino acid protein, kindlin-1, a component of focal contacts in keratinocytes. In this study, we identified four new recurrent mutations in KIND1 in 16 individuals with Kindler syndrome from 13 families of Pakistani (676insC), UK Caucasian (E304X), Omani (W616X), or Italian (958-1G > A) origins. Haplotype analysis demonstrated common ancestral mutant alleles for each mutation, apart from one of the six Pakistani families in which the mutation 676insC (which occurs in a repeat of seven cytosines) was present on a different genetic background. All mutations were homozygous, apart from the three UK Caucasian cases that were all compound heterozygotes (second allele mutations: L302X, 1161delA, 1909delA). All mutations were associated with markedly reduced or absent skin immunostaining with an antikindlin-1 antibody. These loss-of-function KIND1 mutations demonstrate the importance of kindlin-1 in maintaining epithelial integrity, although the mechanism linking this mutant protein to photosensitivity and poikiloderma remains to be determined. Delineation of these recurrent mutations is also relevant to optimizing mutation detection strategies in Kindler syndrome patients from particular ethnic backgrounds.

Azathioprine as a treatment for severe atopic eczema in children with a partial thiopurine methyl transferase (TPMT) deficiency.

Azathioprine is a valuable agent in the treatment of severe childhood atopic eczema. Thiopurine methyl transferase (TPMT) exhibits autosomal codominant polymorphism and plays an important role in the metabolism of azathioprine. In most large population groups studied to date, approximately 10% of the population had intermediate activity due to heterozygosity at the TPMT locus, and about 0.33% were TPMT deficient. TPMT deficiency results in the accumulation of thioguanine nucleotides and cytotoxic 6-mercaptopurine metabolites. Previously it was considered unsafe to treat this group with azathioprine because of what was considered to be an unacceptably high risk of toxicity (profound myelosuppression). Better understanding of the pharmacogenetics of purine metabolism has changed this, and with appropriate dose adjustments, individuals who have a partial TPMT deficiency (heterozygotes) can now be treated with thiopurines. It seems probable that these individuals are more likely to have a therapeutic response while being at lower risk of developing dose-related hepatotoxicity because of the reduced doses required to effect a therapeutic response. Two patients with severe refractory atopic eczema, both of whom had a partial TPMT deficiency, have had an excellent response to treatment with azathioprine. They were treated with half-standard doses and response to treatment occurred within 2 weeks.

Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive conditions characterized by multiple subcutaneous skin nodules, gingival hypertrophy, joint contractures, and hyaline deposition. We previously mapped the gene for JHF to chromosome 4q21. We now report the identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 (CMG2) in 17 families with JHF or ISH. CMG2 is a transmembrane protein that is induced during capillary morphogenesis and that binds laminin and collagen IV via a von Willebrand factor type A (vWA) domain. Of interest, CMG2 also functions as a cellular receptor for anthrax toxin. Preliminary genotype-phenotype analyses suggest that abrogation of binding by the vWA domain results in severe disease typical of ISH, whereas in-frame mutations affecting a novel, highly conserved cytoplasmic domain result in a milder phenotype. These data (1) demonstrate that JHF and ISH are allelic conditions and (2) implicate perturbation of basement-membrane matrix assembly as the cause of the characteristic perivascular hyaline deposition seen in these conditions.

An unusual N-terminal deletion of the laminin alpha3a isoform leads to the chronic granulation tissue disorder laryngo-onycho-cutaneous syndrome.

Laryngo-onycho-cutaneous (LOC or Shabbir) syndrome (OMIM 245660) is an autosomal recessive epithelial disorder confined to the Punjabi Muslim population. The condition is characterized by cutaneous erosions, nail dystrophy and exuberant vascular granulation tissue in certain epithelia, especially conjunctiva and larynx. Genome-wide homozygosity mapping localized the gene to a 2 Mb region on chromosome 18q11.2 with an LOD score of 19.8 at theta=0. This region includes the laminin alpha3 gene (LAMA3), in which loss-of-expression mutations cause the lethal skin blistering disorder Herlitz junctional epidermolysis bullosa. Detailed investigation showed that this gene possesses a further 38 exons (76 exons in total) spanning 318 kb of genomic DNA, and encodes three distinct proteins, designated laminin alpha3a, alpha3b1 and alpha3b2. The causative mutation in 15 families was a frameshift mutation 151insG predicting a stop codon 7 bp downstream in an exon that is specific to laminin alpha3a. This protein is secreted only by the basal keratinocytes of stratified epithelia, implying that LOC is caused by dysfunction of keratinocyte-mesenchymal communication. Surprisingly, the 151insG mutation does not result in nonsense-mediated mRNA decay due to rescue of the transcript by an alternative translation start site 6 exons downstream. The resultant N-terminal deletion of laminin alpha3a was confirmed by immunoprecipitation of secreted proteins from LOC keratinocytes. These studies show that the laminin alpha3a N-terminal domain is a key regulator of the granulation tissue response, with important implications not only in LOC but in a range of other clinical conditions associated with abnormal wound healing.

Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-extracellular-matrix linker protein UNC-112, causes Kindler syndrome.

Kindler syndrome is an autosomal recessive disorder characterized by neonatal blistering, sun sensitivity, atrophy, abnormal pigmentation, and fragility of the skin. Linkage and homozygosity analysis in an isolated Panamanian cohort and in additional inbred families mapped the gene to 20p12.3. Loss-of-function mutations were identified in the FLJ20116 gene (renamed "KIND1" [encoding kindlin-1]). Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage.

Two cases of primarily palmoplantar keratoderma associated with novel mutations in keratin 1.

Mutations in keratin 1 were initially described in the classical form of bullous congenital ichthyosiform erythroderma (also known as epidermolytic hyperkeratosis). More recently the range of phenotypes associated with mutations in this gene has been extended to include annular ichthyosiform erythroderma and mild epidermolytic palmoplantar keratoderma. Here we present two novel mutations in the keratin 1 gene (KRT1): a 5' donor splice site mutation in exon 1 (591 + 2T > A) that predicts a 22 amino acid in-frame deletion in the keratin 1 1A domain; and an in-frame deletion in exon 7 (1376del24) that predicts a foreshortened 2B coiled-coil domain of keratin 1. In each case these mutations are associated with palmoplantar keratoderma and mild ichthyosis, largely limited to the flexural areas. These mutations appear to have a less damaging effect than previously reported mis-sense mutations sited in the helix boundary motifs. This report extends the range of phenotypes associated with mutations in KRT1.