Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a rare hereditary disorder of cornification. Mutations in the transglutaminase-1 (TGM1) gene, which encodes for the epidermal enzyme transglutaminase-1 (TGase-1), are one of the causes of ARCI. METHODS: The TGM1 mutation spectrum was characterised and genotype-phenotype correlations investigated in 104 patients with ARCI ascertained through the National Registry for Ichthyosis and Related Disorders in the USA. Methods: Germline mutations in TGM1 were identified in 55% (57/104) of patients with ARCI. Arginine residues in TGase-1 were mutated in 39% (22/57) of patients overall and 54% (20/37) of those with missense mutations. In total, 55% (12/22) of missense mutations were within CpG dinucleotides and 92% (11/12) of these mutations were C-->T or G-->A transitions. The genotype-phenotype investigation found that ARCI with TGM1 mutations was significantly associated with presence of collodion membrane at birth (p = 0.006), ectropion (p = 0.001), plate-like scales (p = 0.005) and alopecia (p = 0.001). Patients who had at least one mutation predicted to truncate TGase-1 were more likely to have more severe hypohidrosis (p = 0.001) and overheating (p = 0.0007) at onset of symptoms than were those with exclusively TGM1 missense mutations. A logistic model was developed, which predicted that individuals with collodion membrane, alopecia and/or eye problems are about four times more likely to have TGM1 mutations than patients without these findings. CONCLUSION: This is the largest investigation of patients with ARCI to date. It expands the TGM1 mutation spectrum and confirms that despite genetic and phenotypic heterogeneity in ARCI, TGM1 is the main causative gene for this disorder. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of CpG dinucleotides.

BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant predisposition to the development of follicular hamartomas (fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney neoplasms. Germline mutations in BHD are associated with the susceptibility for BHDS. We previously described 51 BHDS families with BHD germline mutations. OBJECTIVE: To characterise the BHD mutation spectrum, novel mutations and new clinical features of one previously reported and 50 new families with BHDS. METHODS: Direct bidirectional DNA sequencing was used to screen for mutations in the BHD gene, and insertion and deletion mutations were confirmed by subcloning. We analysed evolutionary conservation of folliculin by comparing human against the orthologous sequences. RESULTS: The BHD mutation detection rate was 88% (51/58). Of the 23 different germline mutations identified, 13 were novel consisting of: four splice site, three deletions, two insertions, two nonsense, one deletion/insertion, and one missense mutation. We report the first germline missense mutation in BHD c.1978A>G (K508R) in a patient who presented with bilateral multifocal renal oncocytomas. This mutation occurs in a highly conserved amino acid in folliculin. 10% (5/51) of the families had individuals without histologically confirmed fibrofolliculomas. Of 44 families ascertained on the basis of skin lesions, 18 (41%) had kidney tumours. Patients with a germline BHD mutation and family history of kidney cancer had a statistically significantly increased probability of developing renal tumours compared to patients without a positive family history (p = 0.0032). Similarly, patients with a BHD germline mutation and family history of spontaneous pneumothorax had a significantly increased greater probability of having spontaneous pneumothorax than BHDS patients without a family history of spontaneous pneumothorax (p = 0.011). A comprehensive review of published reports of cases with BHD germline mutation is discussed. CONCLUSION: BHDS is characterised by a spectrum of mutations, and clinical heterogeneity both among and within families.

Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is the autosomal dominant heritable syndrome with predisposition to development of renal cell carcinoma and smooth muscle tumours of the skin and uterus. OBJECTIVE: To measure the fumarate hydratase (FH) enzyme activity in lymphoblastoid cell lines and fibroblast cell lines of individuals with HLRCC and other familial renal cancer syndromes. METHODS: FH enzyme activity was determined in the whole cell, cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations. RESULTS: Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with HLRCC had lower FH enzyme activity than cells from normal controls (p<0.05). The enzyme activity in lymphoblastoid cell lines from three individuals with mutations in R190 was not significantly different from individuals with other missense mutations. The cytosolic and mitochondrial FH activity of cell lines from individuals with HLRCC was reduced compared with those from control cell lines (p<0.05). There was no significant difference in enzyme activity between control cell lines (n = 4) and cell lines from affected individuals with other hereditary renal cancer syndromes (n = 22). CONCLUSIONS: FH enzyme activity testing provides a useful diagnostic method for confirmation of clinical diagnosis and screening of at-risk family members.

Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839) is the predisposition to develop smooth muscle tumours of the skin and uterus and/or renal cancer and is associated with mutations in the fumarate hydratase gene (FH). Here we characterise the clinical and genetic features of 21 new families and present the first report of two African-American families with HLRCC. METHODS: Using direct sequencing analysis we identified FH germline mutations in 100% (21/21) of new families with HLRCC. RESULTS: We identified 14 germline FH mutations (10 missense, one insertion, two nonsense, and one splice site) located along the entire length of the coding region. Nine of these were novel, with six missense (L89S, R117G, R190C, A342D, S376P, Q396P), one nonsense (S102X), one insertion (111insA), and one splice site (138+1G>C) mutation. Four unrelated families had the R58X mutation and five unrelated families the R190H mutation. Of families with HLRCC, 62% (13/21) had renal cancer and 76% (16/21) cutaneous leiomyomas. Of women FH mutation carriers from 16 families, 100% (22/22) had uterine fibroids. Our study shows that expression of cutaneous manifestations in HLRCC ranges from absent to mild to severe cutaneous leiomyomas. FH mutations were associated with a spectrum of renal tumours. No genotype-phenotype correlations were identified. CONCLUSIONS: In combination with our previous report, we identify 31 different germline FH mutations in 56 families with HLRCC (20 missense, eight frameshifts, two nonsense, and one splice site). Our FH mutation detection rate is 93% (52/56) in families suspected of HLRCC.

Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency.

Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non-Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G-->A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G-->A mutation and for either an 1831+2T-->G or a 2621-2A-->G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G-->A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G-->C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS.

Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2.

Birt-Hogg-Dubé syndrome (BHD), an inherited autosomal genodermatosis characterized by benign tumors of the hair follicle, has been associated with renal neoplasia, lung cysts, and spontaneous pneumothorax. To identify the BHD locus, we recruited families with cutaneous lesions and associated phenotypic features of the BHD syndrome. We performed a genomewide scan in one large kindred with BHD and, by linkage analysis, localized the gene locus to the pericentromeric region of chromosome 17p, with a LOD score of 4.98 at D17S740 (recombination fraction 0). Two-point linkage analysis of eight additional families with BHD produced a maximum LOD score of 16.06 at D17S2196. Haplotype analysis identified critical recombinants and defined the minimal region of nonrecombination as being within a <4-cM distance between D17S1857 and D17S805. One additional family, which had histologically proved fibrofolliculomas, did not show evidence of linkage to chromosome 17p, suggesting genetic heterogeneity for BHD. The BHD locus lies within chromosomal band 17p11.2, a genomic region that, because of the presence of low-copy-number repeat elements, is unstable and that is associated with a number of diseases. Identification of the gene for BHD may reveal a new genetic locus responsible for renal neoplasia and for lung and hair-follicle developmental defects.

Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies. Lysosomal ceroid lipofuscinosis, pulmonary fibrosis and granulomatous colitis are occasional manifestations of the disease. HPS occurs with a frequency of one in 1800 in north-west Puerto Rico due to a founder effect. Several non-Puerto Rican patients also have mutations in HPS1, which produces a protein of unknown function. Another gene, ADTB3A, causes HPS in the pearl mouse and in two brothers with HPS-2 (refs. 11,12). ADTB3A encodes a coat protein involved in vesicle formation, implicating HPS as a disorder of membrane trafficking. We sought to identify other HPS-causing genes. Using homozygosity mapping on pooled DNA of 6 families from central Puerto Rico, we localized a new HPS susceptibility gene to a 1.6-cM interval on chromosome 3q24. The gene, HPS3, has 17 exons, and a putative 113.7-kD product expected to reveal how new vesicles form in specialized cells. The homozygous, disease-causing mutation is a large deletion and represents the second example of a founder mutation causing HPS on the small island of Puerto Rico. We also present an allele-specific assay for diagnosing individuals heterozygous or homozygous for this mutation.

Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations.

BACKGROUND: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an inflammatory disorder characterized by prolonged episodes of periodic fever and localized inflammation and dominantly inherited mutations in TNFRSF1A, the gene encoding the 55-kDa tumor necrosis factor receptor. To our knowledge, the cutaneous pathologic characteristics of TRAPS have not been described previously. OBJECTIVES: To characterize the dermatologic manifestations of TRAPS by clinical, microscopic, and molecular methods, and to investigate its immunophenotype. DESIGN, SETTING, AND PATIENTS: At the National Institutes of Health Clinical Center, Bethesda, Md, a tertiary care referral center, 25 patients with a clinical and molecular diagnosis of TRAPS were evaluated clinically and 10 biopsy specimens of lesional skin were examined by light microscopy and immunohistochemistry. Patients were screened for mutations in TNFRSF1A, the gene coding for the p55 tumor necrosis factor receptor. MAIN OUTCOME MEASURES: Clinical, light microscopic, and immunohistochemical features. RESULTS: The skin eruption usually lasted 4 to 21 days (mean, 13 days). Of 25 patients, 21 (84%) presented with migratory erythematous macules and patches and 10 (40%) had edematous dermal plaques. Conjunctivitis, characterized by pain and redness and/or periorbital edema, was present in 11 patients (44%). Most patients had their first skin eruption during the first 2 years of life. All patients had fever associated with the skin eruption. Most patients had associated abdominal pain (22 [88%]) and myalgia (20 [80%]). Other symptoms included arthralgia (13 [52%]), pleuritic chest pain (10 [40%]), and headache (17 [68%]). Microscopic examination of 10 biopsy specimens of lesional skin showed a superficial and deep perivascular and interstitial infiltrate of lymphocytes and monocytes. None of the biopsy specimens showed multinucleated macrophages or granulomatous or leukocytoclastic vasculitis. The results of immunohistochemistry showed a perivascular infiltrate of CD3+, CD4+, CD8+, CD68+, CD79a-, and CD20- cells. All the mutations were missense mutations in exons 2 through 4 of TNFRSF1A, directly affecting the extracellular domain of the protein. CONCLUSIONS: TRAPS is characterized by a spectrum of dermatologic findings, including migratory patches, edematous plaques, periorbital edema, and/or conjunctivitis. TRAPS is characterized by a perivascular dermal infiltrate of lymphocytes and monocytes.

Detection of type 1 cytokines in discoid lupus erythematosus.

BACKGROUND: Although multiple studies suggest a dysregulated T-cell cytokine production in systemic lupus erythematosus, the cytokine profile in discoid lupus erythematosus (DLE) lesions is unknown. OBJECTIVES: To characterize the cytokine profile in DLE by immunohistochemical and molecular methods, and to investigate the role of cytokines in the pathogenesis of DLE. DESIGN: Patients were evaluated clinically, and biopsy specimens of lesional skin were examined by light microscopy. Reverse transcriptase-polymerase chain reaction and immunohistochemical analysis were performed on 11 biopsy specimens. We investigated the presence of interleukin (IL) 2, interferon gamma (IFN-gamma), IL-4, tumor necrosis factor alpha, (TNF-alpha), and IL-1beta messenger RNA (mRNA) in 8 biopsy specimens of DLE and compared it with 3 biopsy specimens of normal skin. SETTING: Academic referral research hospital. PATIENTS: Eight consecutive patients with a clinical and histologic diagnosis of DLE. RESULTS: Localized DLE was found in 7 patients and widespread in 1. During the 4 years of the investigation, none of the patients developed systemic lupus erythematosus. We found significantly elevated levels of IL-2 and IFN-gamma mRNA in all 8 biopsy specimens of DLE; in contrast, no transcripts of IL-2 or IFN-gamma were detected in 3 biopsy specimens of normal skin (P<.01). Similarly, elevated levels of TNF-alpha mRNA were detected in 8 DLE biopsy specimens, while no TNF-alpha mRNA was detected in 3 biopsy specimens of normal skin (P<.01). No IL-4 or IL-1 beta mRNA was detected in 8 biopsy specimens of DLE lesional skin and 3 biopsy specimens of normal patient skin. Immunohistochemical analysis showed increased staining for IL-2 and IFN-gamma receptors, while no detectable IL-4 receptor was found. No cytokine mRNA or cytokine receptor protein was detected in biopsy specimens of normal skin. CONCLUSIONS: These findings suggest that DLE is associated with type 1 cytokines characterized by the expression of IL-2 and IFN-gamma. Type 1 cytokines may be critical for induction, development, and maintenance of DLE.

gamma delta T-cell lymphoma of the skin: a clinical, microscopic, and molecular study.

BACKGROUND: Only a few cases of primary gamma delta cutaneous T-cell lymphoma (CTCL) have been reported. We encountered 3 cases of this rare condition. OBJECTIVES: To characterize gamma delta CTCL by clinical, microscopic, and molecular methods and to investigate the role of Epstein-Barr virus (EBV) infection in its pathogenesis. DESIGN: Patients were evaluated by clinical examination, and biopsy specimens of lesional skin were examined by light microscopy and immunohistochemistry. Polymerase chain reaction amplification for T-cell receptor gamma gene rearrangements and in situ hybridization for EBV were performed on 3 biopsy specimens. SETTING: National Institutes of Health, a tertiary referral center. PATIENTS: Individuals with a clinical and histologic diagnosis of primary gamma delta CTCL. OUTCOME MEASURES: Clinical, light microscopic, and immunohistochemical features, and the presence of T-cell rearrangement and EBV RNA in biopsy specimens. RESULTS: Patients exhibited multiple plaques, tumors, and/or subcutaneous nodules primarily distributed over the extremities. Individuals exhibited an aggressive clinical course with resistance to multiagent chemotherapy and radiation. Microscopic examination revealed epidermotropism in 2 cases, a dermal infiltrate in all 3 cases, and subcutaneous involvement in 1 case. Immunohistochemical studies showed the presence of CD3(+)TCR delta(+) in 3 patients, CD8(+)in 1, and CD4(+), CD20(+), CD56(+), and beta F1(+) in none. All 3 cases exhibited an activated cytotoxic T-cell phenotype positive for T-cell intracellular antigen 1, perforin, and granzyme B. A clonal T-cell receptor gamma chain gene rearrangement was detected in all 3 cases by polymerase chain reaction. In situ hybridization was negative for EBV sequences in all 3 cases. CONCLUSION: gamma delta Cutaneous T-cell lymphomas are EBV-negative lymphomas that express a mature cytotoxic phenotype and have an aggressive clinical behavior. Arch Dermatol. 2000;136:1024-1032

Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies.

Lamellar ichthyosis (LI, OMIM no. 242300) is a severe autosomal recessive genodermatosis with an estimated prevalence of 1:200,000. LI represents one end of the spectrum of congenital recessive ichthyosis (CRI). Mutations in the gene for transglutaminase-1 (TGM1) are responsible for many cases of LI and occur throughout the coding sequence of the gene. Our analyses of patients with CRI revealed a common TGM1 mutation involving loss of the intron 5 splice acceptor site leading to alternative splicing of the message. We found families in which the splice acceptor site mutation was homozygous, and families where the patients were compound heterozygotes for the splice acceptor site mutation and another TGM1 mutation. A mutation at this same site occurs in the majority of Norwegian patients as a founder effect. In our ethnically diverse patient population, none of whom have known Norwegian ancestry, haplotype analysis of the TGM1 chromosomal region also suggested the existence of a founder effect. Comparison of the common haplotype in our data with the Norwegian data showed that 2/7 of our splice acceptor site mutation chromosomes had the full reported Norwegian haplotype, and the remaining five chromosomes exhibited recombination at the most distal marker studied. History, family origins, and haplotype analysis suggested that the mutation originally arose on a German background and was introduced into Norway around 800-1000 AD. We also found a limited correlation between genotype and phenotype in our study, with the four homozygous patients having less severe disease than many of the heterozygotes, and no patient with a splice acceptor site mutation having erythroderma or a congenital ichthyosiform erythroderma phenotype.

Granuloma annulare and human immunodeficiency virus infection.

OBJECTIVES: To characterize human immunodeficiency virus (HIV)-associated granuloma annulare (GA) by clinical, microscopic, and molecular methods and to investigate the role of Epstein-Barr virus infection in the pathogenesis of GA. DESIGN: Patients were evaluated clinically, and biopsy specimens of lesional skin were examined by light microscopy. Polymerase chain reaction and in situ hybridization for Epstein-Barr virus were performed on 4 and 12 biopsy specimens, respectively. SETTING: Academic referral center. PATIENTS: Thirty-four consecutive HIV-positive patients who have a clinical and histological diagnosis of GA. OUTCOME MEASURES: Clinical distribution of lesions, light-microscopic features, and the presence of Epstein-Barr virus DNA and RNA in biopsy specimens. RESULTS: Granuloma annulare was generalized in 20 patients and localized in 14. Twenty patients (59%) presented with acquired immunodeficiency syndrome. Unusual features were the presence of oral lesions in 1 patient, perforating lesions in 2 patients, and the coexistence of GA and Kaposi sarcoma in 1 biopsy specimen. Microscopic examination of 34 biopsy specimens showed a granulomatous pattern that was interstitial in 8, palisaded in 18, perforating in 2, and mixed interstitial and palisaded in 6. Special staining of all specimens was negative for organisms. Epstein-Barr virus infection was not detected by either polymerase chain reaction or in situ hybridization. CONCLUSIONS: Generalized GA is the most common clinical pattern in HIV infection. Granuloma annulare associated with HIV can present at all stages of HIV infection, but it is slightly more common in patients with acquired immunodeficiency syndrome. Epstein-Barr virus is an unlikely causative agent of HIV-associated GA. Granuloma annulare may be a manifestation of increasing immune dysregulation.

Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a dominantly inherited predisposition for development of fibrofolliculomas, trichodiscomas, and acrochordons. Concurrent internal tumors, such as colonic polyps and renal carcinoma, have been described in patients with BHD. OBJECTIVE: To evaluate kindreds with familial renal tumors for cutaneous manifestations of BHD. DESIGN: One hundred fifty-two patients from 49 families underwent complete oral and skin examination. Skin lesions were identified by their clinical appearance, and the diagnosis was confirmed by results of histologic examination. Individuals underwent screening for familial renal neoplasms. SETTING: A tertiary referral research hospital. PATIENTS: Individuals with familial renal tumors and their asymptomatic at-risk relatives. MAIN OUTCOME MEASURE: We determined whether any form of renal cancer is associated BHD. RESULTS: We identified 3 extended kindreds in whom renal neoplasms and BHD appeared to segregate together. Two kindreds had renal oncocytomas and a third had a variant of papillary renal cell carcinoma. Thirteen patients exhibited BHD. Seven individuals, including a set of identical twins, had renal neoplasms and BHD. An additional 4 patients (3 deceased and not examined) in these families had renal neoplasms but not BHD. Birt-Hogg-Dubé syndrome without renal neoplasms was present in 6 individuals. Thirteen patients with fibrofolliculomas and trichodiscomas presented clinically with multiple smooth skin-colored to grayish-white papules located on the face, auricles, neck, and upper trunk. Oral papules were present in 9 of 28 and achrochordons in 11 of 28 patients. Features of BHD not previously appreciated included deforming lipomas in 5, collagenomas in 4, and pulmonary cysts in 4 of 28 patients. Families with BHD did not display germline mutations in the von Hippel-Lindau gene or in the tyrosine kinase domain of the MET proto-oncogene. CONCLUSIONS: Birt-Hogg-Dubé syndrome may be associated with familial renal tumors. Birt-Hogg-Dubé and renal tumors segregate together in an autosomal dominant fashion. Patients with BHD and their relatives are at risk for development of renal tumors. Therefore, patients with BHD and their relatives should undergo abdominal computed tomography and renal ultrasound screening for renal tumors.

Prognostic factors and evaluation of mycosis fungoides and Sézary syndrome.

BACKGROUND: Staging evaluations of patients with mycosis fungoides (MF) and Sézary syndrome (SS) are performed to individualize therapy and to predict survival. OBJECTIVE: Our purpose was to determine the prognostic factors in patients with MF and SS. METHODS: A retrospective study of 101 patients was performed. For inclusion in the study, patients had to have been evaluated for MF or SS within 6 months of the initial definitive histologic diagnosis. The evaluation included physical examination, chest radiograph, peripheral blood smear, lymph node biopsy, bone marrow biopsy, gallium 67 scan, liver-spleen scan and computed tomography (CT) of the chest, abdomen, and pelvis. RESULTS: The type of skin disease present at initial diagnosis was a good prognostic indicator of survival and clinical outcome. Univariate adverse prognostic features included hepatosplenomegaly or adenopathy by CT scan, abnormal liver-spleen scan, abnormal gallium scan, adenopathy, and peripheral blood, bone marrow, and lymph node involvement. Independent prognostic factors in multivariate analysis were the type of skin involvement as well as peripheral blood and visceral involvement. CONCLUSION: Our study confirms previous reports that type of skin and peripheral blood and visceral involvement are important prognostic factors in patients with MF or SS. Our results support the finding that patients with T1 stage disease have an excellent survival outlook and clinical outcome.

Persistent pigmented purpuric dermatitis and mycosis fungoides: simulant, precursor, or both? A study by light microscopy and molecular methods.

Mycosis fungoides (MF) can present with purpuric lesions, and rare patients who seemed to have persistent pigmented purpuric dermatitis (PPPD) have developed MF. We recently encountered two patients referred to our cutaneous lymphoma clinic who had PPPD rather than MF and two others who appeared to have both conditions, leading us to explore the histologic similarities of these diseases. We examined specimens from 56 patients with PPPD to determine the frequency of MF-like histologic configurations, namely, the psoriasiform lichenoid, psoriasiform spongiotic lichenoid, and atrophic lichenoid patterns. We also noted the degree of spongiosis, epidermotropism, papillary dermal fibrosis, lymphocytic atypia, and epidermal hyperplasia, the number of extravasated erythrocytes and siderophages, and the distribution of lymphocytic infiltrate within the epidermis. In 29 of 56 patients, there were patterns typically seen in MF. PPPD can feature lymphocytes aligned along the epidermal side of the dermoepidermal junction, with few necrotic keratinocytes, as can MF. Papillary dermal edema occurred frequently in PPPD but not in MF, while lymphocytes in MF but not PPPD had markedly atypical nuclei and had ascended into the upper spinous layer. Given these similarities, we tested for clonality of the T-cell population using a polymerase chain reaction assay for gamma-chain rearrangements. Clonal populations were present in three of three and one of two specimens from patients with both PPPD and MF, but also in 8 of 12 specimens typical of lichenoid patterns of PPPD. These findings raise the possibility that the lichenoid variants of PPPD are biologically related to MF.

Receptor specific for certain nucleotides stimulates inositol phosphate metabolism and Ca2+ fluxes in A431 cells.

We have recently reported that extracellular ATP induces a transient rise in cytosolic free Ca2+ [( Ca2+]i) in individual human epidermoid carcinoma A431 cells (Gonzalez et al: Journal of Cellular Physiology 135:269-276, 1988). We have now studied nucleotide specificity and desensitization for several early responses. Extracellular ATP (5-100 microM) caused the rapid formation of inositol trisphosphate and later its metabolites, inositol bisphosphate and inositol monophosphate. ATP also induced the efflux of 45Ca2+ from pre-loaded cells. In addition, an increase in the rate of influx of 45Ca2+ stimulated by extracellular ATP was detected. Based on measurements of 45Ca2+ efflux and influx, desensitization studies, and chlortetracycline fluorimetry, we conclude that ATP mobilizes Ca2+ from internal stores and also stimulates entry across the plasma membrane. These effects were also displayed by UTP and to a lesser extent by ITP, while other nucleoside triphosphates as well as ADP, AMP, and adenosine, were inactive. Furthermore, desensitization of the response to ATP and UTP was seen after prolonged exposure to either nucleotide. This was specific for the nucleotide receptor since a response to bradykinin was not affected by the ATP pretreatment, although pretreatment with phorbol ester inhibited responses to both the nucleotides and bradykinin. Quantitative data on rate of recovery from the desensitized state and the response of desensitized cells to greatly elevated levels of ATP are presented. Extracellular ATP stimulated another early change previously reported for epidermal growth factor, namely, the phosphorylation of an 81-kDa cytoskeletal protein. The stimulation of these events involves an ATP receptor whose properties differ from other ATP receptors that have been described.