Naoko Hosomi

Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population

Summary Background Nethertons syndrome (NS) is an autosomal recessive disorder characterized by trichorrhexis invaginata (‘bamboo hair’), congenital ichthyosiform erythroderma and an atopic diathesis. NS has recently been shown to be due to a defect in the SPINK5 gene, encoding LEKTI, a 15‐domain serine protease inhibitor. SPINK5 maps to chromosome 5q31–q32, and has been suggested to be a locus predisposing to atopy in general. Recently, coding polymorphisms in SPINK5 exons 13 and 14 have been reported to be associated with atopy, asthma and atopic dermatitis (AD).

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.

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.

A novel P gene missense mutation in a Japanese patient with oculocutaneous albinism type II (OCA2).

BACKGROUND Oculocutaneous albinism type II (OCA2) is an autosomal recessively inherited disorder, characterized by white hair and skin, and loss of pigment in the eyes. Mutations in P gene have been shown to result in OCA2. So far, two cases have been reported from Japan. OBJECTIVE We had an opportunity to examine a case of albinism, and screened the mutations of tyrosinase and P gene. METHODS Genomic DNA was prepared from peripheral leukocytes. All of the exons and flanking introns of tyrosinase and P gene were PCR-direct-sequenced. RESULTS Although no mutations were found in tyrosinase, we found two missense substitutions, A481T and Q799H in P gene. The A481T has previously been shown to result in partial function of the P protein. CONCLUSION The Q799H mutation is not a common polymorphism among normal Japanese, seems most likely to be a pathological OCA2 mutation among Japanese with this form of albinism.

No association between atopic dermatitis and the SLC9A3R1-NAT9 RUNX1 binding site polymorphism in Japanese patients.

observed as cutaneous adverse reactions. Oral or leg ulcers, alopecia, acral erythema, allergic vasculitis and fixed drug eruptions have also been documented, although less frequently. In 1975, Kennedy et al. first reported a patient with chronic myelogenous leukaemia (CML) who developed palmoplantar erythema and linear atrophic lesions on the dorsa of the hands, after taking HU for 3 years. In 1995, Senet et al. described a dermatomyositis-like eruption developing on the dorsa of the hands in six MPD patients on long-term HU therapy. This cutaneous presentation caused by HU has since been reported under different names, such as lichenoid drug reaction, hydroxyurea dermopathy, and pseudo-dermatomyositis. According to Vassallo et al. mucocutaneous changes were seen in 21 out of 158 (13%) CML patients receiving HU for 7–120 months, and dermatomyositis-like change was seen in seven out of these 21 patients. The average duration between initiating HU and the onset of the eruption was 39 months. Dermatomyositis-like eruption or change and pseudo-dermatomyositis are rather confusing terms as they seem to include the miscellaneous eruptions in dermatomyositis rather than just Gottron’s papules. Additionally, these terms may suggest an association with the systemic symptoms of dermatomyositis. More precise terminology would better depict the characteristic appearance similar to Gottron’s papules without implying any of the other changes found in dermatomyositis. In fact, all previously reported cases have described eruptions indistinguishable from Gottron’s papules. We prefer the more specific term Gottron-like papules. Gottron-like papules are considered to be the most characteristic eruption induced by HU because of their unique appearance and the late onset in the course of treatment. The pathophysiology of cutaneous changes induced by long-term HU therapy remains unknown, but may be related to a toxic effect of HU in inhibiting DNA synthesis and repair. HU may interfere with basal cell epidermal proliferation over a prolonged period, which may be responsible for the vacuolar degeneration, cytoid bodies and epidermal atrophy. Further investigation into the mechanism of Gottronlike papules might reveal the pathogenesis of not only the effects of HU on the skin but also the development of Gottron’s papules in dermatomyositis.

Fluorescence in situ hybridization analysis is useful for the diagnosis of the carrier state of X-linked ichthyosis

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Guttate morphoea in human T-cell lymphoma/lymphotrophic virus type-1 (HTLV-1) infection

Summary A 62‐year‐old Japanese man presented with multiple small atrophic macules on the trunk and extremities. The lesions were discrete, oval in shape and enclosed by lilac ring. They were distributed in a Christmas tree distribution, reminiscent of pityriasis rosea. Skin biopsy showed increased collagen fibres in the dermis and invading subcutaneous tissue. The clinico‐pathological features were consistent with guttate morphoea, a rare variant of localized scleroderma. Serological tests revealed a positive reaction to human T‐cell lymphoma/lymphotropic virus type‐1 infection.

Vascular type of Ehlers–Danlos syndrome associated with mild haemophilia A

A 21-year-old man was referred for evaluation of possible vascular-type Ehlers–Danlos syndrome (EDS), formerly known as type IV EDS. His father had died of aortic rupture at the age of 49 years, and his maternal grandmother had also been diagnosed with vascular-type EDS. The patient had experienced repeated episodes of subcutaneous haemorrhage, and severe bleeding had occurred when he underwent neurosurgery for a Rathke s cleft cyst at the age of 18 years. Physical examination revealed thin skin, and the finger joints were more flexible than normal. However, these changes were not as clear as in the classic type of EDS, and the joint hypermobility did not meet Beighton s criteria. Chest X-ray revealed mild pulmonary haemorrhage. The platelet count was normal. The bleeding time was prolonged to 8 min (normal < 5 min). In platelet aggregation tests, the responses to collagen and adenosine diphosphate (ADP) were slightly raised at 86% (normal range 45–75%) and 82% (35–75%), respectively. Coagulation screening tests, including prothrombin time and activated partial thromboplastin time, were normal. Factor IX and von Willebrand factor were normal. Notably, factor VIII activity was reduced to 32% of control levels, indicating mild haemophilia A. This patient had thin skin, translucent veins on the forearms, and hypermobile joints of the fingers, although the possibility that all of these findings were within the range of normal variation could not be fully excluded. We therefore performed Western blotting of the proteins secreted into the media of cultured skin fibroblasts from the patient. The fibroblasts produced a limited amount of type III collagen, approximately one-tenth that of control fibroblasts, although production of type I collagen was preserved. The diagnosis of vascular type EDS was thus confirmed by biochemical analysis. We prepared type III collagen cDNA from cultured fibroblasts to perform a mutation study. We sequenced the cDNA but failed to detect any mutations; the genomic DNA of the patient was not examined. Several months later, the patient died from sudden and severe pulmonary bleeding. Two cases of association of EDS and factor VIII deficiency have been reported previously. However, the type of EDS was not determined in either of those cases. To our knowledge, this is the first case in which confirmed vascular-type EDS was noted to be associated with haemophilia A. Anstey et al. 4 examined platelet and coagulation activities in 51 cases of EDS, seven of which were found to be type IV (vascular type). One of these seven patients exhibited a platelet release defect. Of the other six cases, three had a prolonged bleeding time, and four had reduced platelet aggregation to ristocetin. Results of platelet aggregation tests with collagen, ADP and arachidonate were all normal. As this patient s haemophilia A was mild, the fatal pulmonary haemorrhage was probably due to the vasculartype EDS. Clotting factor deficiencies in EDS may be more common than previously thought. EDS should be considered as a diagnosis in clinical situations such as pulmonary or intestinal bleeding, even if abnormalities are observed on clotting studies or in coagulation factors, which indicate other disorders.