Clinical features of atypical presentations of mucocutaneous herpes simplex virus infection observed in immunosuppressed individuals. Part II: the knife-cut sign.

The knife-cut sign is a distinctive manifestation of herpes simplex virus (HSV) type 1 or HSV type 2 infection that has been described in at least 10 immunocompromised patients. It appears as an extremely painful linear erosion or fissure in an intertriginous area such as the body folds beneath the breast, or within the abdomen, or in the inguinal region. Also, concurrent HSV infection at other mucocutaneous sites, or viscera, or both have been observed. The patients had medical conditions (at least 9 patients) and/or immunosuppressive drug therapy (6 patients). The diagnosis of HSV infection was confirmed by viral culture (8 patients), biopsy (4 patients), direct fluorescence antibody testing (3 patients), immunohistochemistry staining (2 patients), polymerase chain reaction (2 patients), or Western blot serologic assay (1 patient). Knife-cut sign-associated HSV infection is potentially fatal; three patients died. However, clinical improvement or complete healing occurred in the patients who received oral valacyclovir (1 patient), or intravenous acyclovir (2 patients), or intravenous acyclovir followed by foscarnet (1 patient). In summary, HSV infection associated with a positive the knife-cut sign is a potentially fatal variant of HSV infection that occurs in the intertriginous areas of immunocompromised patients and usually requires intravenous antiviral therapy.

Clinical features of atypical presentations of mucocutaneous herpes simplex virus infection observed in immunosuppressed individuals. Part I: herpetic geometric glossitis.

Herpetic geometric glossitis is a unique morphologic variant of HSV (herpes simplex virus) type 1 infection on the dorsum of the tongue that presents as an extremely painful linear central lingual fissure with a branched pattern. in the center of the tongue; there is a branched pattern of fissures that extend bilaterally from the central linear fissure. Herpetic geometric glossitis has been reported in 11 patients; 8 of these individuals were immunocompromised. Medical conditions and immunosuppressive medication treatment (7 patients) or only medical disorders (3 patients) or neither (1 patient) were present. HSV type 1 infection was diagnosed by viral culture in (7 patients), Tzanck preparation (2 patients) or clinically (2 patients). Mucocutaneous HSV infection at non-lingual locations--including the lips, labial mucosa, face and chest--were observed in 5 patients. All patients' symptoms and lesions responded to treatment with oral antiviral therapy: acyclovir (9 patients), famciclovir (1 patient) or valacyclovir (1 patient). The lingual pain and dorsal tongue fissures completely resolved completely within two to 14 days. In summary, herpetic geometric glossitis is a unique HSV type 1 infection, usually in immunocompromised patients, that occurs on the dorsal tongue and responds completely after treatment with orally administered antiviral therapy.

Basal cell carcinoma in situ of the skin revisited: case reports of the superficial type and fibroepithelioma type of this in situ cutaneous neoplasm.

Cutaneous basal cell carcinoma in situ is a recently proposed subtype of this skin cancer. It is characterized by either restriction of the tumor cells within the epidermis or the presence of tumor cells contiguous with the overlying epidermis that extend into the underlying dermis, or both. Importantly, cancer invasion-demonstrated by non-contiguous aggregates of basaloid tumor cells in the dermis-is not a feature of in situ basal cell carcinoma of the skin. A 63-year-old woman with cutaneous basal cell carcinoma in situ-superficial type that presented as an erythematous scaly plaque on her abdomen and a 61-year-old man with a cutaneous basal cell carcinoma in situ-fibroepithelioma type that presented as a flesh-colored smooth exophytic nodule on his back are reported. The characteristics of in situ basal cell carcinoma of the skin in these individuals are summarized. In conclusion, similar to other cutaneous malignant neoplasms-such as squamous cell carcinoma, malignant melanoma, and Merkel cell carcinoma-basal cell carcinoma of the skin can also present as an in situ cancer.

Patients with a new-onset cutaneous sebaceous neoplasm following immunosuppression should be evaluated for Muir-Torre syndrome with germline mismatch repair gene mutation analysis: case reports.

Patients with Muir-Torre syndrome may have a systemic malignancy and a sebaceous neoplasm such as an adenoma, epithelioma, and/or carcinoma. The syndrome usually results from a germline mutation in one or more mismatch repair genes. Iatrogenic or acquired immunosuppression can promote the appearance of sebaceous tumors, either as an isolated event or as a feature of Muir-Torre syndrome and may unmask individuals genetically predisposed to the syndrome. Two iatrogenically immunosuppressed men with Muir-Torre syndrome features are described. Similar to these immunocompromised men, Muir-Torre syndrome-associated sebaceous neoplasms have occurred in solid organ transplant recipients, human immunodeficiency virus-infected individuals, and patients with chronic diseases who are treated with immunosuppressive agents. Muir-Torre syndrome-associated sebaceous neoplasms occur more frequently and earlier in kidney recipients, who are receiving more post-transplant immunosuppressive agents, than in liver recipients. The development of sebaceous neoplasms is decreased by replacing cyclosporine or tacrolimus with sirolimus or everolimus. Specific anti-cancer vaccines or checkpoint blockade immunotherapy may merit exploration for immune-interception of Muir-Torre syndrome-associated sebaceous neoplasms and syndrome-related visceral cancers. We suggest germline testing for genomic aberrations of mismatch repair genes should routinely be performed in all patients-both immunocompetent and immunosuppressed-who develop a Muir-Torre syndrome-associated sebaceous neoplasm.

Cutaneous Superficial Basal Cell Carcinoma is a Basal Cell Carcinoma In Situ: Electron Microscopy of a Case Series of Basal Cell Carcinomas.

Basal cell carcinoma (BCC) is the most common skin cancer. Skin cancers may present either as a non-invasive tumor or an invasive malignancy. The terminology of carcinoma in situ is used when the tumor is either just limited to epidermis or not present as single cells or nests in the dermis. However, currently the terminology superficial BCC is inappropriately used instead of BCC in situ when the skin cancer is limited to epidermis. In this study we compare the pathologic changes of superficial, nodular, and infiltrative BCCs using electron microscopy to identify the ultrastructural characteristics and validate the previously proposed terminology. Three cases of BCC (superficial BCC, nodular BCC, and infiltrative BCC) diagnosed by dermatopathologists at our institute were selected for review. Paraffin block tissues from these cases were sent for electron microscopy studies which demonstrated disruption of basal lamina in both nodular and infiltrative type of BCC, while it remains intact in BCC superficial type after extensive examination. Therefore, similar to other in situ skin cancers, there is no invasion of the neoplasm in superficial BCC into the dermis. Hence, the older term superficial BCC should be appropriately replaced with the newer terminology BCC in situ.

An Autobiographical Case Series of Familial Post Ambulatory Swollen Hands (POTASH): Hand Swelling in a Man and His Sister While Participating in a Half Marathon.

Post ambulatory swollen hands (POTASH) is an acquired condition characterized by swelling of the hands, thumbs, and fingers following either walking, hiking, or running; no other body sites are swollen. The asymptomatic hand swelling begins in adulthood and recurs after adequate ambulation. A distinctive feature of POTASH that is often present is a positive fist sign demonstrated by the inability of the affected person to clench their fingers into the palm and form a fist. POTASH usually resolves spontaneously within a few hours after stopping ambulation; however, less frequently, it can persist for one or two days. The pathogenesis of POTASH has not been determined. In this case report, POTASH is described in an adult man and his sister. Neither the man's parents nor two of his other younger sisters had POTASH. However, the man's wife also develops POTASH with prolonged exercise; none of the three biological adult children of the man and his wife had POTASH. Therefore, based on these observations, the possibility that POTASH may have an autosomal recessive mode of inheritance and/or may be sporadic is suggested.

Lichen Planus Pigmentosus Inversus: A Case Report of a Man Presenting With a Pigmented Lichenoid Axillary Inverse Dermatosis (PLAID).

Lichen planus pigmentosus is an uncommon subtype of lichen planus and lichen planus pigmentosus inversus is a rare variant of lichen planus pigmentosus. Lichen planus pigmentosus inversus typically presents as hyperpigmented patches or plaques, particularly in the intertriginous areas such as the axillae, the groin and inguinal folds, and in the submammary region. In some patients with lichen planus pigmentosus inversus, the condition can present as a pigmented lichenoid axillary inverse dermatosis (PLAID) when the lesions are in the axillae. A 49-year-old Hispanic man who had hyperlipidemia and diabetes mellitus developed lichen planus pigmentosus inversus and presented with a PLAID. Skin biopsies established the diagnosis of lichen planus pigmentosus inversus. The clinical differential diagnosis of lichen planus pigmentosus inversus includes inherited disorders, primary cutaneous dermatoses, acquired dyschromias, and reactions to topical or systemic medications. Friction in intertriginous areas has been related to the development of lichen planus pigmentosus inversus. Factors that can precipitate lichen planus pigmentosus inversus include not only topical exposure to almond oil, amala oil, cold and cosmetic creams, henna, and paraphenyldiamine but also either topical contact or consumption of mustard oil and nickel. Lichen planus pigmentosus inversus can be associated with autoimmune conditions (hypothyroidism), endocrinopathies (diabetes mellitus), and hyperlipidemia. The dyschromia found in patients with lichen planus pigmentosus inversus is frequently refractory to treatment. Initial management includes removal of potential disease triggers such as eliminating tight clothing to stop friction with the adjacent skin. Topical corticosteroids do not result in improvement; however, topical calcineurin inhibitors such as tacrolimus have been reported to be efficacious. In conclusion, inverse lichen planus and lichen planus pigmentosus inversus can present with a PLAID; whereas topical corticosteroids may be helpful to resolve inverse lichen planus lesions, topical tacrolimus may be useful to improve the dyschromia in lichen planus pigmentosus inversus.

Myocardial Infarction Simulated From Improper Telemetry (MISFIT): An Autobiographical Case Report.

An electrocardiogram, used to not only assess the rate and rhythm of the heart but also to evaluate for injury to the heart, is performed by attaching 12 leads to the patient's body. A myocardial infarction can be mimicked by the misplacement of the leads. A 58-year-old man with long-distance running-associated bradycardia developed postoperative atrial fibrillation with a rapid ventricular response. He converted to normal sinus rhythm after a single oral dose of 30 milligrams of diltiazem; however, the automated reading of the electrocardiogram performed in the hospital showed new changes suggestive of a postero-lateral myocardial infarction, including Q waves in leads I and aVL, as well as early precordial R wave progression with R waves and positive T waves in V2 and V3, and a dominant R wave (R wave to S wave ratio greater than one) in V2. A cardiac work-up was entirely normal: serial troponin levels, thyroid stimulating hormone, echocardiogram, computerized tomography of the chest, and Doppler studies of the extremities. Lead misplacement during the electrocardiogram was suspected during the subsequent evaluation by an astute cardiologist; the findings were diagnostic for a left arm to right arm limb lead reversal. All the changes in myocardial infarction were absent when the electrocardiogram was repeated in the office. Misplacement of leads during an electrocardiogram is not a rare event; therefore, the clinician needs to consider the possibility of improper placement of the leads when evaluating an electrocardiogram. Indeed, emotional distress, additional diagnostic procedures, and potentially harmful procedures may be experienced by the patient from incorrect diagnoses based on electrode misplacement during an electrocardiogram; in addition, there are often increased costs to the patient and the healthcare system. Therefore, in the setting of an incorrect diagnosis attributed to lead misplacement during the performance of an electrocardiogram, the acronym MISFIT (which uses the first letters of the words "myocardial infarction simulated from improper telemetry") has been introduced. In conclusion, it is important to emphasize that a MISFIT is characterized by an electrocardiogram 'mis'diagnosis of a myocardial infarction that does not 'fit' with the clinical scenario.

Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer.

BACKGROUND: Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions. MAIN BODY: Approximately 0.15-0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS. CONCLUSION: Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.

Injected Drug Addiction-Associated Swollen Hands: A Case Report of Methylamphetamine-Related Unilateral Drug Addiction-Related Puffy Hand Syndrome.

Puffy hand syndrome occurs in addicts who have injected drugs either intravenously, intradermally, or subcutaneously. It usually presents as bilateral reversible pitting edema of the hands; less frequently, it occurs unilaterally. The forearms and arms may also be affected. The onset of puffy hand syndrome can occur while the patient is still injecting drugs; however, it can initially appear several years after injection of the drug has been discontinued. Infection with hepatitis C is a common comorbidity. A 47-year-old man is described who had a 20-year history of injecting methylamphetamine only into his non-dominant left arm, forearm, and hand and experienced his second episode of unilateral puffy hand syndrome four years after discontinuing injecting the drug and three years after his initial episode; he also had hepatitis C infection. He presented with erythema and pitting edema of his left hand and forearm. Cellulitis was initially suspected, and he was admitted to the hospital for intravenous antibiotics; all cultures were negative for pathogens. The erythema and swelling resolved after five days of therapy. Puffy hand syndrome has been associated with various drugs; it has also been observed to occur in women during pregnancy and occasionally associated with acrocyanosis. The diagnosis is often not originally entertained by the clinician; the condition is often initially treated empirically as an infection. Serologic evaluation is typically negative for rheumatologic diseases, such as systemic lupus erythematosus and scleroderma, and cultures of the skin and blood are usually negative for pathogens. Radiologic assessment (such as roentgenograms, ultrasound to rule out venous thrombosis, computed tomography, magnetic resonance imaging, venogram, and lymphangiogram) may be performed, to exclude other conditions. Skin biopsy of the affected edematous hand occasionally demonstrates granulomatous inflammation and foreign bodies (suggestive of starch or injection additives) in the dermis. The edema for some of the patients with puffy hand syndrome was successfully treated with daily bandaging with compression stockings. The pathogenesis of puffy hand syndrome is considered to be multifactorial: damage to the veins, injury to the lymphatic system, and direct toxicity of the injectable drugs to the vascular structures.

Linea Nigra: Case Report of a Woman With a Pregnancy-Associated Linear Streak of Cutaneous Hyperpigmentation on Her Abdomen From the Umbilicus to the Pubic Symphysis.

Linea nigra is a distinctive presentation of asymptomatic cutaneous hyperpigmentation on the abdomen that usually extends from the umbilicus to the pubic symphysis. It is frequently observed as a physiologic change associated with pregnancy. A primigravida 19-year-old woman began to develop skin darkening during week 24 of gestation. She delivered a healthy infant. Three months postpartum, the hyperpigmentation had not resolved. After the benign characteristics of her cutaneous hyperpigmentation were explained, the patient decided to clinically monitor the dark linear streak. Similar to this patient, clinical studies of pregnant women have observed the incidence of pregnancy-associated linea nigra to range from 32% to 92%; in contrast to this woman, partial or complete spontaneous resolution of the skin darkening commonly occurs after delivery of the newborn. During gestation, the development of linea nigra has been postulated to be caused by elevated estrogen, progesterone, and/or melanocyte-stimulating hormone levels. Linea nigra is not restricted to gestational females; it has also been noted in newborns and children. In addition, it has also been observed in men who had either benign prostate hyperplasia or prostate cancer. In summary, linea nigra is often an acquired longitudinal streak of benign cutaneous hyperpigmentation on the abdomen; when linea nigra is pregnancy-associated, the skin darkening often partially or completely resolves, spontaneously after delivery.

ALPK1 mutants causing ROSAH syndrome or Spiradenoma are activated by human nucleotide sugars.

The atypical protein kinase ALPK1 is activated by the bacterial nucleotide sugar ADP-heptose and phosphorylates TIFA to switch on a signaling pathway that combats microbial infection. In contrast, ALPK1 mutations cause two human diseases: the ALPK1[T237M] and ALPK1[Y254C] mutations underlie ROSAH syndrome (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis, and migraine headache), while the ALPK1[V1092A] mutation accounts for 45% of spiradenoma and 30% of spiradenocarcinoma cases studied. In this study, we demonstrate that unlike wild-type (WT) ALPK1, the disease-causing ALPK1 mutants trigger the TIFA-dependent activation of an NF-κB/activator protein 1 reporter gene in the absence of ADP-heptose, which can be suppressed by either of two additional mutations in the ADP-heptose binding site that prevent the activation of WT ALPK1 by ADP-heptose. These observations are explained by our key finding that although ALPK1[T237M] and ALPK1[V1092A] are activated by bacterial ADP-heptose, they can also be activated by nucleotide sugars present in human cells (UDP-mannose, ADP-ribose, and cyclic ADP-ribose) which can be prevented by disruption of the ADP-heptose binding site. The ALPK1[V1092A] mutant was also activated by GDP-mannose, which did not activate ALPK1[T237M]. These are new examples of disease-causing mutations permitting the allosteric activation of an enzyme by endogenous molecules that the WT enzyme does not respond to. We propose that the loss of the specificity of ALPK1 for bacterial ADP-heptose underlies ROSAH syndrome and spiradenoma/spiradenocarcinoma caused by ALPK1 mutation.

Colorimetric Scale for Skin of Color: A Practical Classification Scale for the Clinical Assessment, Dermatology Management, and Forensic Evaluation of Individuals With Skin of Color.

Skin of color refers to individuals whose skin color ranges from very light beige to very dark brown. Anthropologists and sociologists have previously recognized the importance of an objective classification of skin color for individuals with skin of color that does not include race and ethnicity. Since 1975, dermatologists have used the Fitzpatrick classification of sun-reactive skin types to categorize patients with skin of color; this classification was established for psoriasis patients participating in using oral methoxsalen and phototherapy clinical trial to determine the initial ultraviolet A dose. The Fitzpatrick classification merely classifies individuals as white, brown, and black; the individuals with white skin are further divided into four groups based on their burning or tanning capacity. This classification system does not provide reliable information with regard to the risk of skin cancer for individuals with darker skin color and does not aid in the evaluation of medical conditions with cutaneous involvement or assessment of appropriate cosmetic interventions for aesthetic management. Many clinicians, including forensic pathologists, incorporate the patient's race or ethnicity in their medical evaluation to describe the individual's skin color. Established scales for skin of color either include white skin color, or include 10 or more color types, or include both. We introduce a simple and rapidly performed scale that is not based on race or ethnicity to categorize persons with skin of color. The colorimetric scale ranges from very light beige to very dark brown and does not include white skin. The scale has five colors ranging from lightest (skin color type 1) to darkest (skin color type 5): very light beige (skin color type 1), light brown (skin color type 2), medium brown (skin color type 3), dark brown (skin color type 4), and very dark brown (skin color type 5); an individual with white skin would have a skin color type 0 in this classification of patient skin color. In conclusion, a scale that is not based on race or ethnicity is useful for categorizing individuals with skin of color not only for sociologists but also for clinicians who treat these patients. This colorimetric scale will be helpful for dermatologists to categorize persons with skin of color to predict their risk for developing skin cancer and to assessing appropriate cosmetic procedures and devices for these patients. In addition, the colorimetric scale will be useful for not only forensic pathologists but also other clinicians to provide a non-racial and non-ethnic designation of skin color type for their patients.

Editors and Journals: Part II-Relationship between the Editor-in-Chief and the Owner of the Journal: The Consequences When Editorial Independence Dissolves.

A symbiotic relationship between the editor and the owner of a medical journal is important for the journal to fulfill successfully the expectations of its readers and authors. Editorial freedom and transparency by owner of the journal are important qualities that enable the editor to provide valid scientific information in an unbiased manner. Unresolved impedance of editorial freedom or the persistent lack of transparency or both frequently results in untenable consequences for editor and often a substantial defamation of the journal's credibility. Unfortunately, misguided and inappropriate behavior by a medical society or the publication owner repeatedly occurs with the same devastating effect for the editor: prompt, unanticipated, and unjustified termination of the position at the journal. Alternatively, conditions imposed by a journal's owner may lead to the resignation of the editor because of untenable conditions. Because the owner does not have to account for its actions and there is no recourse for the editor, currently there seems to be no effective measures to prevent this tragic sequence of events in the future.

Identifying Human Trafficking Victims: A Potential Role for Forensic Dermatology.

Human trafficking is a worldwide problem that predominantly affects women and children. The victims are recruited by coercion, deception, or force and then exploited for commercial sex acts or labor, or both. Human trafficking results in severe suffering of the victims including not only physical injuries but also psychological consequences. Many of the victims of human trafficking encounter the medical system; however, this chance for potential intervention is often not realized by the clinician treating the individual. Many of the manifestations of injuries to human trafficking victims involve the skin, hair, nails, and mucosa. Hence, there is a paramount opportunity for forensic dermatology in the detection and evaluation of suspected victims of human trafficking. Cutaneous manifestations frequently observed in victims of sex trafficking include branding (with tattoos), rashes, bruising, and sequelae of self-injurious behavior; in addition, mucocutaneous stigmata of sexually transmitted diseases may be present. Skin features more commonly associated with victims of labor trafficking include deep and long cuts, skin injuries (such as bruises and tears), and scars from prior burns and knife cuts. The presence of an uncommon infection affecting the skin, such as new world leishmaniasis, that only occurs in a specific and restricted geographic endemic area can also be a subtle clue to human trafficking. Forensic dermatology has the potential to identify victims of human trafficking; when a healthcare worker entertains the possibility of human trafficking, a comprehensive cutaneous examination may provide objective evidence that the individual who is being evaluated and treated may be a human trafficking victim and therefore prompt the clinician to initiate appropriate intervention.

Tomato Plant-Associated Xanthoderma: Case Report and Review of Exogenous Causes of Yellow Skin.

The skin, hair, and nails can all present with yellow discoloration secondary to exogenous etiologies. Xanthoderma, yellow discoloration of the skin, can occur not only from exogenous sources secondary to topical contact with various substances but also from endogenous causes such as diseases from the liver and kidney, or oral medications. A 64-year-old man developed asymptomatic, yellow staining of his distal left forearm, hand, and fingertips. He was not receiving antimalarials, did not have hepatic or renal dysfunction, and had not applied any sunless tanning solutions to his skin. Prior to the appearance of his xanthoderma, he had been tending to a tomato plant in his yard; the yellow staining appeared on the areas of his left upper extremity that had contacted the stems and leaves of the tomato plant. Within two days, the yellow skin discoloration resolved spontaneously after several washings of the affected areas with soap and water. Tomato plants have trichomes that appear as hair-like structures on the stems and produce an oily substance; the trichomes not only produce the scent of the plant, but also provide protection from cold, drought, disease, and pests. Initially, when the oily substance contacts the skin, the skin appears yellow; subsequently, the skin may become black. The skin that has been stained by a tomato plant is referred to as "tomato skin" (TOMASK). In addition to reviewing the etiology of exogenous xanthoderma, this paper also summarizes the causes of exogenous yellow hair and yellow nails. Exogenous yellowing of the skin can result from various topical causes. Common topical etiologies of xanthoderma include not only contact with tomato plants, but also sunless tanning solutions (that contain dihydroxyacetone) and tobacco (that not only causes yellow staining of the white hair on men's upper lip referred to as "smoker's mustache", but also yellow staining of the nail plate and fingertips used to hold the cigarette or cigar). In summary, tomato plant-associated xanthoderma is a benign exogenous etiology of yellow staining of the skin which eventually resolves after several washings of the affected sites with soap and water.