Progressive hyperpigmentation in a Taiwanese child due to an inborn error of vitamin B12 metabolism (cblJ).

The physiology of human skin pigmentation is varied and complex, with an extensive melanogenic paracrine network involving mesenchymal and epithelial cells, contributing to the regulation of melanocyte survival and proliferation and melanogenesis. Mutations in several genes, involving predominantly the KIT ligand/c-Kit and Ras/mitogen-activated protein kinase signalling pathways, have been implicated in a spectrum of diseases in which there is hyperpigmentation, hypopigmentation or both. Here, we report on a 12-year-old girl from Taiwan with a 6-year history of diffuse progressive skin hyperpigmentation resulting from a different aetiology: an inborn metabolic disorder of vitamin B12 (cobalamin), designated cblJ. Using whole-exome sequencing we identified a homozygous mutation in ABCD4 (c.423C>G; p.Asn141Lys), which encodes an ATP-binding cassette transporter with a role in the intracellular processing of cobalamin. The patient had biochemical and haematological evidence of cobalamin deficiency but no other clinical abnormalities apart from a slight lightening of her previously black hair. Of note, she had no neurological symptoms or signs. Treatment with oral cobalamin (3 mg daily) led to metabolic correction and some reduction in the skin hyperpigmentation at the 3-month follow-up. This case demonstrates that defects or deficiencies of cobalamin should be remembered in the differential diagnosis of diffuse hyperpigmentary skin disorders.

Cutaneous sarcoidosis in southern Taiwan: clinicopathologic study of a series with high proportions of lesions confined to the face and angiolupoid variant.

BACKGROUND: Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology. Our clinical experience suggests that facial involvement and the angiolupoid variant appear more common in our patients compared with series reported from the western countries. OBJECTIVE: To characterize the clinicopathologic features of cutaneous sarcoidosis diagnosed in our department and to compare our data with those in the literature. METHODS: We conducted a clinicopathologic review of biopsy-proved cases of cutaneous sarcoidosis diagnosed during January 2002-December 2010. RESULTS: Our study consisted of 37 patients, ages 26-84 years (mean 54.3 years), of whom 84% were females. Systemic involvement was detected in 73%, affecting the lung in 57%, lymph nodes in 65% and eyes in 43%. Most skin lesions were the papulonodular type (70%) and confined to the face (54%). The angiolupoid variant, while rare in Europe and America, was the most common variant (38%) in our series and often associated with eye involvement. The histology was characterized by infiltration of naked sarcoidal granulomas, mostly (86%) mixed with variable amounts of tuberculoid granulomas in the dermis and/or the subcutis. Other findings included fibrinoid necrosis (23%), foreign bodies (16%), osteoclast-like cells (14%) and granuloma annulare-like and necrobiosis lipoidica-like features. CONCLUSION: The present series of cutaneous sarcoidosis was characterized by a marked female predominance and by high proportions of facial involvement and the angiolupoid variant. Angiolupoid sarcoidosis was often associated with eye involvement. A complete dermatologic examination and biopsy of suspicious skin lesions should be routinely performed to facilitate early diagnosis of sarcoidosis.

Analysis of Taiwanese ichthyosis vulgaris families further demonstrates differences in FLG mutations between European and Asian populations.

BACKGROUND: Mutations in the gene encoding filaggrin (FLG) were identified to underlie ichthyosis vulgaris (IV) and also shown to predispose to atopic eczema. Until now, no FLG mutations have been described in the Taiwanese population. OBJECTIVES: To elucidate filaggrin mutations in the Taiwanese population and further to clarify the population genetics of filaggrin gene mutations in the Asian populations. METHODS: In the present study, 12 individuals from four unrelated Taiwanese IV families were examined for FLG mutations. We carried out comprehensive sequencing of the entire FLG coding region using an overlapping polymerase chain reaction strategy. RESULTS: We identified three FLG mutations in the Taiwanese IV families. One mutation E1795X was a previously unidentified FLG mutation, which might be specific to the Taiwanese. Interestingly, another FLG mutation 3321delA is prevalent in the Japanese population and the other mutation Q2417X was found in the Singaporean Chinese population. No FLG mutation identified in the white European population was found in the Taiwanese population. CONCLUSIONS: The present findings suggest that the Taiwanese population, as an East Asian group, share FLG mutations with both the Japanese and the Singaporean Chinese population. In addition, these results exemplify differences in the population genetics of filaggrin between Europe and Asia.

A novel splicing mutation of the CYLD gene in a Taiwanese family with multiple familial trichoepithelioma.

Multiple familial trichoepithelioma (MFT) is an autosomal dominant disease characterized by numerous skin-coloured papules on the central face. Mutations in the CYLD gene, which is also the gene responsible for familial cylindromatosis, have been reported recently. Recent studies indicate that CYLD is a tumour-suppressor gene. The CYLD protein is a negative regulator of the activation of transcription factor nuclear factor-kappaB, and loss of CYLD contributes to oncogenesis. We report a novel splicing mutation (IVS12 + 1 G-->A) in the CYLD gene in a Taiwanese pedigree with MFT, and discuss new developments in treatment options.

Interleukin-19 upregulates keratinocyte growth factor and is associated with psoriasis.

BACKGROUND: Interleukin (IL)-19, a member of the IL-10 family, signals through the IL-20R1/IL-20R2 heterodimer, which is shown to be involved in abnormal keratinocyte differentiation and proliferation. Little is known about its in vitro biological functions or its role in psoriasis. OBJECTIVES: To investigate the role of IL-19 in the psoriatic process. METHODS: The expression of keratinocyte growth factor (KGF) transcripts was measured by polymerase chain reaction in CD8+ T cells treated with IL-19. Next, we developed monoclonal and polyclonal antibodies to measure the levels of IL-19 in the sera of patients with psoriasis and healthy volunteers using an enzyme-linked immunosorbent assay. In addition, we performed immunohistochemical staining on psoriatic skin and normal controls. RESULTS: We found that IL-19 upregulated KGF transcripts on CD8+ T cells. Patients with psoriasis had a lower level of IL-19 in serum than healthy volunteers. The difference between these two groups was statistically significant (P < 0.05). IL-19 expression was seen in basal and suprabasal keratinocytes in a continuous pattern, and was increased in psoriatic epidermis. CONCLUSIONS: These results suggest that IL-19 plays a role in the complex pathological cytokine network in psoriasis.

Capillary morphogenesis gene-2 mutation in infantile systemic hyalinosis: ultrastructural study and mutation analysis in a Taiwanese infant.

Infantile systemic hyalinosis (ISH) is a very rare infantile stiff-skin syndrome characterized by extensive deposits of hyaline material in various organs, especially the skin and gingiva. Recent studies identified pathogenic mutations in the capillary morphogenesis gene 2 (CMG2) in both ISH and juvenile hyaline fibromatosis (JHF). Capillary morphogenesis protein-2 is an integrin-like cell surface receptor for laminins and type IV collagen, and may play a key role in cell-matrix or cell-cell interactions. We report a case of ISH in a 13-month-old Taiwanese girl who manifested progressive joint contractures, recurrent chest infections, chronic diarrhoea with severe hypoalbuminemia and ascites, gum hypertrophy, and violaceous papules and nodules over the occipital area, neck, lumbosacral and anogenital areas since birth. Skin biopsy revealed a thickened and hyalinized papillary dermis. Electron microscopy showed abundant extracellular fibrillogranular material and active fibroblasts with conspicuous Golgi complex filled with fibrillar material. Mutation analysis identified a homozygous 1073-1074insC mutation of CMG2 which had been reported in four other families and may represent a mutation hot spot.

Netherton syndrome: report of two Taiwanese siblings with staphylococcal scalded skin syndrome and mutation of SPINK5.

Netherton syndrome (NS) is a severe autosomal recessive ichthyosis. It is characterized by congenital ichthyosiform erythroderma, trichorrhexis invaginata, ichthyosis linearis circumflexa, atopic diathesis and frequent bacterial infections. Pathogenic mutations in SPINK5 have recently been identified in NS. SPINK5 encodes lymphoepithelial Kazal-type-related inhibitor (LEKTI), a new type of serine protease inhibitor involved in the regulation of skin barrier formation and immunity. We report two Taiwanese brothers with NS. The patients had typical manifestations of NS with an atopic diathesis and recurrent staphylococcal infections, including staphylococcal scalded skin syndrome (SSSS) since birth. Horny layers were obtained by skin surface biopsy for electron microscopy from lesional skin of both patients and from normal controls. All 33 exons and flanking intron boundaries of SPINK5 were amplified for direct sequencing. The ultrastructure of the stratum corneum (SC) was characterized by premature degradation of corneodesmosomes (CDs) with separation of corneocytes. A homozygous 2260A --> T (K754X) mutation of SPINK5 was found in both patients. Staphylococcal exfoliative toxin A (ETA) is a serine protease capable of cleaving desmoglein 1, an important adhesive molecule of CDs, and can cause separation of the SC, resulting in SSSS. The premature degradation of CDs found in our patients may be attributable to insufficient LEKTI, and possibly also to colonization/infection of ETA-producing Staphylococcus aureus. Mechanisms involved in the pathogenesis of the skin barrier defect in NS are proposed. Further study is needed to prove this hypothesis.

Depigmented extramammary Paget's disease.

BACKGROUND: Depigmented extramammary Paget's disease (EMPD) has been reported in a few cases. Depigmented macules or patches may be the only presenting sign or may coexist with the classical erythematous lesions. OBJECTIVES: To investigate the occurrence rate and clinical presentation of depigmentation in EMPD. METHODS: All pathology-proven cases of EMPD diagnosed in our department during 1990-2003 were retrieved. The clinical photographs were reviewed for evidence of local depigmentation. The pathological diagnosis of EMPD in the whitish lesions was confirmed by positive expression of cytokeratin 7 or carcinoembryonic antigen, and/or the presence of intracytoplasmic mucin. RESULTS: Of 19 cases of EMPD, six (30%) manifested depigmented lesions which were confirmed to be EMPD pathologically. In two patients, the hypopigmentation was associated with erythematous lesions at the initial presentation. In four others, the depigmentation developed later as local recurrence after excision, cryotherapy, photodynamic therapy or radiotherapy. The progressive enlargement of the depigmentation and the appearance of separate new white lesions in these four cases suggested that the localized depigmentation was unlikely to be simple postinflammatory hypopigmentation. CONCLUSIONS: Our study suggests that depigmented EMPD may not be rare. Localized depigmentation in the genital area can be an early sign of EMPD and its local recurrence. In patients with an established diagnosis of EMPD, appearance of new white lesions and continuous enlargement of depigmented patches should not be dismissed as simple treatment-induced postinflammatory hypopigmentation or another type of hypopigmented lesion without biopsy confirmation.