Kazuyoshi Fukai

Interleukin 4 receptor α chain polymorphism Gln551Arg is associated with adult atopic dermatitis in Japan

Localization of a locus for atopy to chromosome 16p12–p11 and reported associations of Ile50Val and Gln551Arg polymorphisms in interleukin‐4 receptor α chain (IL 4R gene) with atopy prompted us to sequence the gene in 27 adult atopic dermatitis (AD) and 29 non‐atopic (non‐AD) subjects. Among six known polymorphisms, Gln551Arg was significantly associated with AD (P = 0·01). This polymorphism was found to be heterozygous in six of 27 patients with AD but none of the 28 non‐AD controls. Ile50Val, which was previously reported to be associated with atopic asthma in Japan, showed no association with AD in our group. Glu375Ala and Cys406Arg also showed no association with AD. The IL 4R gene should thus be considered a compelling candidate gene for AD.

Angelman syndrome associated with oculocutaneous albinism due to an intragenic deletion of the P gene.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation, speech impairment, ataxia, and happy disposition with frequent smiling. AS results from the loss of expression of a maternal imprinted gene, UBE3A, mapped within 15q11‐q13 region, due to different mechanisms: maternal deletion, paternal UPD, imprinting center mutation, and UBE3A mutation. Deletion AS patients may exhibit hypopigmentation of skin, eye, and hair correlating with deletion of P gene localized in the distal part of Prader‐Willi (PWS)/AS region. Our patient presented developmental delay, severe mental retardation, absence of speech, outbursts of laughter, microcephaly, ataxia, hyperactivity, seizures, white skin, no retinal pigmentation, and gold yellow hair. His parents were of African ancestry. The SNURF‐SNRPN methylation analysis confirmed AS diagnosis and microsatellite studies disclosed deletion with breakpoints in BP2 and BP3. All of the 25 exons and flanking introns of the P gene of the patient, his father, and mother were investigated. The patient is hemizygous for the deleted exon 7 of the P gene derived from his father who is a carrier of the deleted allele. Our patient manifests OCA2 associated with AS due to the loss of the maternal chromosome 15 with the normal P allele, and the paternal deletion in the P gene. As various degrees of hipopygmentation are associated with PWS and AS patients, the study of the P gene in a hemizygous state could contribute to the understanding of its effect on human pigmentation during development and to disclose the presence of modifier pigmentation gene(s) in the PWS/AS region.

Immunohistochemical localization of lysyl oxidase in normal human skin.

Lysyl oxidase (EC 1.4.3.13), a copper‐dependent enzyme which catalyses the formation of aldehyde cross‐links, and acts primarily on collagen and elastin, is known to be increased during wound healing and in fibrotic disorders including liver cirrhosis and atherosclerosis, and to be decreased in some hereditary connective tissue diseases and in malignant cell lines. A recent study showed that lysyl oxidase might possess tumour suppressor activity as an antioncogene for ras. Little is known about the localization of this enzyme in human skin. In this study, we determined immunohistochemically the localization of lysyl oxidase in normal skin of young and elderly subjects obtained from sun‐exposed and unexposed regions of the body. All skin samples tested had similar distributions of lysyl oxidase. The enzyme was present both extracellularly and intracellularly. Extracellularly, a few granular aggregates of immunoreactants were observed along collagen and elastic fibres. These granules were more common in the adventitial portion of the dermis than in the reticular portion. Of all sun‐exposed and unexposed regions studied, the skin of the face displayed the greatest amount of extracellular immunoreactants. Immunopositive granules were observed intracellularly in fibroblasts, vascular endothelial cells, sweat glands, sebaceous glands, arrector pili muscles and some keratinocytes. These findings provide evidence that, as suggested in recent reports, lysyl oxidase may have a variety of intracellular functions.

TIE2 Gain-of-Function Mutation in a Patient with Pancreatic Lymphangioma Associated with Blue Rubber-Bleb Nevus Syndrome: Report of a Case

Abdominal lymphangioma is a rare tumor in adults. The most common location is the mesentery, but this tumor occasionally develops in the pancreas. We report a case of pancreatic lymphangioma associated with blue rubber-bleb nevus syndrome (BRBNS) in a Japanese woman. The pancreatic lymphangioma spread extensively throughout the retroperitoneum without causing any symptoms for more than 4 years after its histological diagnosis by laparoscopic biopsy. Multiple hemangiomas were also seen in the mucous membranes and on the skin. The hemangiomatosis was segregated in the dominant fashion in her family, and a germ-line gain-of-function mutation (Arg849Trp) in TIE2 gene was confirmed. To our knowledge, this is the first report of pancreatic lymphangioma occurring in association with BRBNS in a patient with genetic alteration. We describe the clinical features of this case and discuss a possible correlation between these two uncommon conditions.

Heterozygous HPS1 mutations in a case of Hermansky-Pudlak syndrome with giant melanosomes.

We report a Japanese man with Hermansky–Pudlak syndrome, having oculocutaneous albinism with a bleeding diathesis. Gene analysis of the patients peripheral blood cells revealed that he was a compound heterozygote for HPS1 gene mutations. One of the mutations was a novel frameshift mutation at codon 321 (a G insertion) in exon 11 (≈ 962–963insG), and the other was a 5′ splice‐junction mutation of IVS5 (IVS5 + 5G→A). The content of eumelanin in the patients hairs was significantly reduced. Histological analysis using light and electron microscopy revealed that melanocytes in the patients epidermis contained an appreciable number of giant melanosomes. Cultured melanocytes from the patients skin also contained giant melanosomes. Our finding of mutations in the HPS1 gene in relation to abnormalities in melanosome morphology and melanin production shed light on the role and function of the HPS1 gene product in the synthesis of melanosomes and melanin pigment.

Mild phenotype of familial cylindromatosis associated with an R758X nonsense mutation in the CYLD tumour suppressor gene.

Familial cylindromatosis is a rare dominantly inherited disease characterized by the development of multiple benign tumours of the skin appendages, including cylindromas, trichoepitheliomas and spiradenomas. The gene responsible was positionally cloned recently, and was designated CYLD. We describe a family with cylindromatosis, in which affected individuals have an inherited R758X nonsense mutation of CYLD. Affected members of this family manifest a relatively mild tumour phenotype; the largest tumour was only 30 mm in diameter. Thus far, there is no evident genotype–phenotype relationship in cylindromatosis, although the number of families reported with both phenotypic and genotypic data remains small.

Chédiak‐Higashi Syndrome: Report of a Case and Review of the Japanese Literature

We report the case of a Japanese female infant with Chédiak‐Higashi syndrome born to consanguineous parents. At birth she had fair skin but, when she was three months old, marked hyperpigmentation of the sun‐exposed skin areas developed. Microscopic examination of blood and electron microscopic examination confirmed the diagnosis. She enjoyed good health until she was two years old when she had pneumonia with marked hepatosplenomegaly. It is important for dermatologists and pediatricians to be aware of the skin manifestations of this disease because hyperpigmentation after sun exposure may be a characteristic, initial feature of this condition.

Immunohistochemical localization of type I, III, IV, V, and VI collagens and laminin in neurofibroma and neurofibrosarcoma

By using antibodies to type I, III, IV, V, and VI collagens and laminin, we examined the localization of interstitial collagens and basement membrane components with indirect immunofluorescence and immunoelectron microscopy (IEM). Furthermore, the morphological changes of these collagens in malignant transformation were investigated. In neurofibroma. IEM showed type I, III, and V collagens to be present diffusely on cross-striated collagen fibrils, whereas type VI collagen was present between the fibrils. Type IV collagen and laminin were observed to surround tumor cells. In neurofibrosarcoma, tumor collagen bundles that reacted with antibodies to type I, III, V, and VI collagens were irregularly arranged. Immunofluorescent deposits that reacted with anti-type IV collagen and anti-laminin antibodies were decreased in number, showing a thin and sparse arrangement.

Primary cutaneous adenoid cystic carcinoma: ultrastructural study and immunolocalization of Types I, III, IV, V collagens and laminin

A primary adenoid cystic carcinoma of the skin is reported. Light microscopy revealed pseudocysts. PAS‐positive basement membrane and true glandular lumen, which in aggregates are specific for adenoid cystic carcinoma. Perineural invasion was also observed. Ultrastructural examinations revealed three types of cystic spaces; pseudocysts, true glandular lumens and intercellular spaces. Enzyme histochemical examinations showed positive reactions for eccrine enzymes, including phosphorylase and succinic dehydrogenase and negative for apocrine enzymes. Immunolocalization of collagens and laminin revealed that basement membranes of the pseudocysts involve Type V collagen as well as Type IV collagen and laminin.

Caspase-1 activity of stratum corneum and serum interleukin-18 level are increased in patients with Netherton syndrome

cess or psychological distress during active disease could result in lower serum DHEA-S concentrations in patients with CIU. If so, it might be expected that DHEA-S concentration in blood would be raised upon long-term remission of urticaria. Indeed, in the present study, we observed some relationships between the clinical status (active disease or remission) and DHEA-S concentration. DHEA-S concentration was significantly lower in patients with symptomatic CIU as compared with those with CIU in remission, and as compared with healthy subjects. So far, it is unknown whether the decline in DHEA-S concentration precedes the onset of chronic urticaria, i.e. occurs before the first symptoms of the illness are observed, or appears later in consequence of a chronic illness. The lack of persistence of hormonal alterations, when the disease is clinically inactive, suggests that the mechanisms responsible for such change apply only throughout the active period of the disease and are most probably associated with distress. Undoubtedly, the symptoms of chronic urticaria, e.g intense pruritus, give rise to distress. An unresolved question is whether restored serum DHEA-S concentration results in improved clinical status in urticaria or vice versa. Consequently, a further approach to determine DHEA-S behaviour in the course of urticaria would be a longitudinal study of patients with chronic recurrent urticaria. Such study would comprise multiple assessment of DHEA-S levels upon remission and during active disease as well as throughout the period directly preceding the urticaria symptoms; however, such a study would be difficult to perform and would take a long time. Taken together, these data suggest that lower DHEA-S serum concentration is a transient and reversible phenomenon accompanying CIU, occurring during the active period and disappearing upon spontaneous remission of the disease. Explicit understanding of the changes in the hormonal environment may provide the basis to develop new therapeutic strategies.