Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 
  • Users Online: 99
  • Home
  • Print this page
  • Email this page


 
 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 5  |  Issue : 1  |  Page : 1-6

Dermatopathologic emergencies part ii: Dermatopathologic and situational


Dermatology and Pathology, Rutgers University New Jersey Medical School, Newark, New Jersey, USA

Date of Web Publication22-May-2018

Correspondence Address:
Dr. W Clark Lambert
Department of Dermatology and Pathology, Room H576 Medical Science Building, Rutgers University New Jersey Medical School, 185 South Orange Avenue, Newark 07103, New Jersey
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdpdd.ijdpdd_26_17

Rights and Permissions
  Abstract 


In dermatopathology, there are several conditions which must be addressed emergently. While some conditions necessitate emergent intervention because of the pathology of the cutaneous manifestations, others require recognition of the underlying serious systemic conditions represented by the cutaneous signs and symptoms. In this part, we address rickettsial infections and eczema herpeticum as diseases which should be addressed immediately on presentation because of the seriousness and rapidity of progression of their pathology. Moreover, porphyria cutanea tarda, Birt–Hogg–Dubé syndrome, Muir–Torre syndrome, and acquired ochronosis may exemplify conditions where the cutaneous signs serve as warnings for severe systemic disease that may not be emergencies in isolation but can indicate rapid occult development of destructive and sometimes deadly noncutaneous pathology. The literature review was conducted using searches in PubMed and references to textbooks on the subjects.

Keywords: Carcinoma, dermatopathologic, emergency, erythema


How to cite this article:
Atmatzidis DH, Weiss AR, Hoegler K, Lambert W C. Dermatopathologic emergencies part ii: Dermatopathologic and situational. Indian J Dermatopathol Diagn Dermatol 2018;5:1-6

How to cite this URL:
Atmatzidis DH, Weiss AR, Hoegler K, Lambert W C. Dermatopathologic emergencies part ii: Dermatopathologic and situational. Indian J Dermatopathol Diagn Dermatol [serial online] 2018 [cited 2018 Oct 21];5:1-6. Available from: http://www.ijdpdd.com/text.asp?2018/5/1/1/232954




  Rickettsial Infection Top


Rocky Mountain spotted fever (RMSF) is a potentially life-threatening disease caused by Rickettsia rickettsii, an obligate, intracellular bacterium that is spread to human beings by infected ticks. The disease is the most common tick-borne rickettsial disease in the United States and can be fatal.[1]R. rickettsii is a fastidious, small, pleomorphic Gram-negative coccobacillus that primarily infects vascular endothelial cells.[1],[2] In the United States, multiple tick species are vectors for R. rickettsii transmission. The tick species that is most frequently associated with R. rickettsii transmission is the American dog tick found in the eastern, central, and Pacific Coastal United States and is active from spring through autumn, with peak activity during late spring through early summer.[2] Consequently, 90% of RMSF cases occur between April and September and 40% occur in May and June.[3]

Initial clinical signs and symptoms are similar to those observed in other tick-borne rickettsial diseases; thus, diagnosing the disease in the early phase is difficult.[1] Symptoms typically appear 3 to 12 days after the bite of an infected tick.[2] Initial symptoms include sudden onset of fever, headache, chills, malaise, and myalgia, nausea, vomiting, abdominal pain, and anorexia.[3] A rash typically appears 2–4 days after the onset of fever; however, most patients seek health care before a rash develops and a rash may not develop in approximately 9% of cases.[1],[2] During the first 3 days, the classic clinical triad of fever, headache, and rash is observed in a minority of patients, but the triad is observed in approximately 60% of patients within 2 weeks.[1],[4] The rash classically begins as small, blanching, pink macules on the ankles, wrists, or forearms that spread to the palms, soles, arms, legs, and trunk. The face is spared. Over several days, the rash typically becomes maculopapular, sometimes with central petechiae.[1],[2] Vasculitis may result in damage of the brain, heart, kidney, and spleen.[3] Severe late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, acute respiratory distress syndrome, cutaneous necrosis, arrhythmia, and seizure.[2]

In the U.S., RMSF is the most frequently fatal rickettsial illness. Delays in diagnosis and treatment are the most important factor associated with increased likelihood of fatality.[2] Without treatment, RMSF progresses rapidly, and the fatality rate is approximately 25%.[5] With treatment, the fatality rate drops to 5%–10% depending on when the antibiotics were initiated.[6] Infections treated after the 5th day are more likely to be fatal than those treated earlier.[2],[4] Additional risk factors for fatality include advanced age, male gender, and alcohol abuse.[6] Glucose-6-phosphate dehydrogenase deficiency is a risk factor for fulminant RMSF, with death occurring in about 5 days.[2],[6] Although children are affected more commonly than adults, RMSF is more fatal in the elderly population.[3]

The diagnosis of RMSF is based on physical examination of the patient and epidemiological data. Rapid diagnosis can be achieved through frozen section of a punch biopsy. Making a clinical diagnosis is difficult because the initial signs and symptoms are usually nonspecific.[1] The indirect immunofluorescence assay is >90% sensitive and is the most commonly employed serological test for evaluation of R. rickettsii infection. However, antibodies may not be present until after 10–14 days of the illness.[3] Because fatal cases of RMSF are often associated with delayed diagnosis and treatment, the decision to treat should never be delayed by laboratory confirmation.[1] Biopsy of cutaneous lesions reveals leukocytoclastic vasculitis of varying severity, i.e., lymphohistiocytic and occasionally neutrophilic infiltration into the walls of capillaries and postcapillary venules with scattered karyorrhectic nuclear debris.[7]


  Eczema Herpeticum Top


Eczema herpeticum (EH) is a rare, secondary infection of a chronic skin disease with herpes simplex virus (HSV). It is most commonly found in patients with atopic dermatitis (AD).[8],[9],[10],[11],[12] EH presents as an eruption of rapidly spreading disseminated vesicles that are monomorphic and dome-shaped and associated with cutaneous pain.[9],[13] The rash starts in areas affected by the underlying dermatitis, and it can spread to involve normal skin in three to 10 days.[13],[14] Systemic symptoms are often present and include fever, malaise, and lymphadenopathy.[10],[13] Three to six percent of patients with AD develop EH.[9],[12],[13] EH is a difficult clinical diagnosis, and it is commonly misdiagnosed as a flare of the underlying chronic skin condition.[9],[13]

Skin biopsy of EH shows viral inclusions and multinuclear epidermal cells.[9],[15] Viral stains for HSV are positive.[9] Heavy neutrophil infiltrate and early breakdown of the vesicles are usually seen. The diagnosis is mostly clinical.[15]

Risk factors in patients with AD that predispose them to EH include severe AD, early-onset AD, prior Staphylococcus aureus skin infection, high total serum IgE/peripheral eosinophils, and the presence of other allergic diseases.[8],[10] EH is often caused or exacerbated by immunosuppressive agents being used to treat the primary dermatitis.[9] Staphylococcal colonization of the skin may be associated with EH.[8],[9],[16] In some cases, EH becomes secondarily infected with S. aureus, which can lead to septic shock.[9] In other cases, it appears that S. aureus can predispose a patient to develop EH or increase its severity. It has been shown that S. aureus toxins modulate the host response to HSV in normal human keratinocytes, and staphylococcal alpha-toxin increases viral loads of HSV in keratinocytes by forming pores and promoting viral entry into epithelial cells.[16]

The pathogenesis of EH is related to the balance of CD4+ and CD8+ T cells.[8],[9],[16] There is a subset of patients with AD who are susceptible to disseminated viral infections from secondarily infected AD.[8],[10],[11] Susceptibility has been linked to genes in peripheral blood mononuclear cells that have been shown to cause a different immune response following HSV exposure when compared to atopics who do not develop EH after HSV exposure.[11] In a study of 792 genes, interferon genes were the most downregulated in EH patients, as well as several interferon regulatory genes.[11] Skin barrier defects associated with mutations of the FLG gene, claudin-1, and tight junction proteins are also associated with the EH subset of patients with AD.[8],[10]

EH is a life-threatening disease that initially presents with seemingly benign dermatological findings.[9] If untreated, EH can lead to a systemic viral infection involving multiple organ systems. Sequelae of viremia include fever, keratoconjunctivitis, encephalitis, meningitis, multiorgan failure, and septic shock.[8],[9],[17] Six to ten percent of EH cases in immunocompetent and up to 50% of cases in immunocompromised patients are fatal.[9] The cause of death is usually related to viremia, multiorgan involvement, and bacterial superinfection and septic shock. In children, disseminated HSV can be accompanied by bone marrow suppression and disseminated intravascular coagulation. If EH is misdiagnosed as an exacerbation of the underlying dermatitis and corticosteroids are administered, the viral infection can worsen.[13]


  Situational Emergencies Top


Porphyria cutanea tarda

Porphyria cutanea tarda (PCT) is the most common cutaneous porphyria in most populations and results from inhibition of the fifth enzyme in the heme synthesis pathway and uroporphyrinogen decarboxylase (UROD).[18] UROD catalyzes the decarboxylation of uroporphyrinogen III to coproporphyrinogen III.[19] PCT is predominantly a disease of adulthood with an estimated prevalence of one per 25,000. The three major forms of PCT are sporadic, familial, and toxic. PCT occurs as an acquired sporadic condition in 75% of patients, usually in association with liver disease and alcohol abuse, occurring in midlife. The remaining 25% inherit PCT as an autosomal dominant condition with low penetrance;[18] its onset is usually earlier than that of the sporadic form.[20] Conditions associated with UROD inhibition include hepatitis C infection, excessive alcohol intake, prescribed estrogen, HIV infection, and iron overload. Decreased UROD activity increases production of symptom-causing carboxylic porphyrins.[21] The toxic form of PCT results from exposure to polychlorinated aromatic hydrocarbons.[22],[23]

Cutaneous findings include skin fragility, bullae [Figure 1], erosions, vesicles, crusts, milia, hypo and hyperpigmentation, and hypertrichosis. Minor trauma results in skin erosions and blisters, which can become secondarily infected, forming crusts and scarring.[21] Hepatomegaly is common in PCT, and cirrhosis is found in 30%–40% of patients. Urine is often discolored with a red-brown tinge.[21] Following treatment, most patients remain in remission. However, approximately 30% of PCT cases can relapse during long-term follow up, especially if they continue to be exposed to risk factors. PCT is easily treatable and nonfatal. Life expectancy in PCT is normal in the absence of comorbidities, such as advanced liver disease.
Figure 1: Bullous lesion of porphyria cutanea tarda. Note the splitting of the epidermis from the stratum basale (H and E, ×320)

Click here to view


Patients with PCT remain at risk for development of liver disease including hepatocellular carcinoma, irrespective of associated susceptibility factors.[24] The incidence of hepatocellular carcinoma is approximately 3.5 times higher in PCT compared with matched chronic liver disease controls.[18] Emphasis on discontinuing exposure to environmental triggers and counseling patients regarding the treatment plan is of utmost importance.

Birt–Hogg–Dubé Syndrome

An autosomal dominant genodermatosis, Birt–Hogg–Dubé syndrome (BHD), is characterized by cutaneous fibrofolliculomas [25] and an increased propensity for developing renal tumors,[26] multiple pulmonary cysts,[27] and spontaneous pneumothorax.[28],[29] Mutations in the FLCN (BHD) gene on chromosome 17p11.2, which encodes the protein folliculin, is responsible for the syndrome.[30] Folliculin is expressed in the kidneys, lung, and skin.[31] Although fibrofolliculomas, trichodiscomas, and acrochordons were initially described as the three distinct cutaneous tumors of BHD; these three lesions are now believed to represent only one of these tumors, the fibrofolliculoma.[32] Similarly, the perifollicular fibroma is also considered a fibrofolliculoma.[29] Some or all patients with Hornstein–Knickenberg syndrome, which features perifollicular fibromas, may actually have BHD.[32],[33],[34]

Fibrofolliculomas and trichodiscomas are clinically indistinguishable, as both are hair follicle hamartomas, appearing as small, white, dome-shaped papules on the upper trunk, neck, and face.[35] Histologically, fibrofolliculomas consist of strands of epithelial cells, two to four cells wide, emanating from a follicular structure with infundibular features [Figure 2]. The strands may rejoin the infundibulum at many points, and the infundibulum may be filled with keratin and dilated. Within the epithelial cords may be one or more sebocytes, possibly forming tiny lobules. Sebaceous ducts may also be identified. A well-circumscribed proliferation of loose connective tissue, made of fine fibers with some intervening mucin, may be detected around the epithelial cords. Elastic fibers may be sparse or absent.[29] On the other hand, trichodiscomas also radiate from hair follicles and are typically nonencapsulated and well-demarcated tumors.[29],[36] They are fibrous tumors made of thin-walled blood vessels and often have peripherally situated sebaceous lobules.[36] Other cutaneous lesions which may be found in patients with BHD include lipomas, facial angiofibromas, oral mucosal fibromas, and angiolipomas.[37]
Figure 2: Fibrofolliculoma (H and E, ×185)

Click here to view


Patients with BHD are 7 times more likely to develop renal tumors compared to unaffected siblings. The tumors are diagnosed at a mean age of 50 years and are often bilateral or multifocal.[38],[39] Colorectal polyps, colorectal cancer, parotid gland tumors, breast cancer, and melanoma have also been documented in patients with BHD.[31],[39] Over 80% of adult patients with BHD have multiple lung cysts, often in the lung bases. As a result, they have a 50-fold increased risk of spontaneous pneumothorax compared to an unaffected sibling.[31] Therefore, the diagnosis of BHD requires educating the patient about the risk of developing the associated conditions and seeking screening to avoid progression of possible occult malignancies.

Muir–Torre Syndrome

Muir–Torre syndrome (MTS) is an autosomal dominant genodermatosis characterized by the development of sebaceous tumors, often multiple, and in association with visceral neoplasms. The visceral neoplasms tend to be gastrointestinal carcinomas.[29] Colonic polyps, epidermal cysts, and keratoacanthomas may also be present.[40] Although the sebaceous tumors may be difficult to classify, they mostly resemble sebaceomas and sebaceous adenomas and occasionally carcinomas [Figure 3].[29] Despite sebaceous hyperplasia possibly being present, it is not considered an indicator of MTS.[41] Multiple sebaceous tumors, especially when they occur before the age of 50 years, are strongly indicative of MTS.[42]
Figure 3: Sebaceous carcinoma (H and E, ×114.5)

Click here to view


Tumors tend to be in the gastrointestinal tract, especially polyps or adenocarcinomas of the colon. In addition, tumors may also be found in the larynx, ovary, uterus, and in the genitourinary system of men. Lymphoma has also been reported.[29] The tumors may display microsatellite instability. MTS is considered an allelic variant of Lynch syndrome and represents about 9% of individual cases of Lynch syndrome.[43] Immunosuppression may reveal latent MTS, especially in transplant patients.[29],[44] A recent study suggests that solid organ transplant recipients mainly develop sebaceous carcinomas in an extraorbital distribution and that both wide local excision and Mohs micrographic surgery are equally effective treatment options. There were no recurrences after either procedure.[45]

The sebaceous tumors of MTS may demonstrate sheets of basaloid cells in lobules or an intermingling of these cells with sebaceous cells in no particular order. These atypical features of the sebaceous tumors of MTS may be predictive of malignant transformation if not completely excised.[46] Occasionally, the tumors may resemble basal cell carcinomas with focal sebaceous differentiation. Cystic areas and mucin may be detected. Some tumors may join with the surface and possess a central debris-filled crater, almost resembling a keratoacanthoma.[29] All sebaceous tumors should be screened for MLH-1, PMS-2, MSH-2, and MSH-6 and their respective gene products. MTS is diagnosed when nuclear staining for the designated gene product is absent in the tumors.[47] False-negative and false-positive results are uncommon.[48] Alternatively, immunohistochemical or both immunohistochemical and genetic testing of neoplasms may be used to confirm the diagnosis of MTS.[49]

The diagnosis of MTS is made when there is at least one sebaceous neoplasm and at least one internal organ cancer at some point in the patient's life, excluding contributing factors such as AIDS or radiotherapy. The diagnosis is also suggested in a patient with a family history of MTS and a personal history of multiple keratoacanthomas or keratoacanthomas in areas not exposed to sunlight.[49] Similar to BHD, cancer surveillance of patients with BHD should be conducted to prevent the progression of occult malignancy and includes annual examination of the testicles and prostate in men, examination of the breast and pelvis in women, colonoscopy starting as early as age 18 years depending on the genetic subtype of MTS, measurement of tumor markers, complete blood cell count, fecal occult blood test, and urinalysis.[49]

Ochronosis

Alkaptonuria is the endogenous form of ochronosis and results from dysfunction of homogentisate 1,2-dioxygenase (HGD) leading to the accumulation of homogentisic acid (HGA) in connective tissue.[50] Exogenous ochronosis results in a similar clinical picture but results from the topical application of agents such as hydroquinone, phenol, resorcinol, mercury, and picric acid. It can also result after oral or parenteral administration of antimalarial drugs.[51],[52],[53] Like alkaptonuria, exogenous ochronosis causes the inhibition of HGD and accumulation of HGA.[54]

HGA is partially excreted in the urine and partially accumulated in the body.[50] Accumulation of HGA due to HGD defects can be identified because HGA undergoes spontaneous oxidation to benzoquinone-2-acetic acid (BQA). BQA forms an unknown melanin-like polymer that turns the urine black. The blackening of urine is a pathognomonic sign of the disease.[50],[55] The HGA that accumulates in the body also undergoes oxidation into BQA and subsequent polymerization into the melanin-like compound [Figure 4]. The oxidation and polymerization occurs in nonmineralized connective tissues of the skeletal, integumentary, ocular, and cardiovascular systems, leading to a pathological bluish-black discoloration.[50] This phenomenon is known as “ochronosis.”
Figure 4: Ochronotic pigmentation (H and E, ×320)

Click here to view


The development of ochronotic arthropathy is the result of deposition of the unknown melanin-like polymer within hyaline articular cartilage. Pigmentation is widespread, with all tissues of the joint affected. The affected tissues often become weak, brittle, and prone to chipping, fracturing, and cracking, causing rapid joint degeneration.[55] Ligaments and tendons can also rupture.[56] Consequently, patients can be left profoundly disabled.[57] Patients with ochronotic arthropathy usually present with lumbar pain as the initial joint manifestation. Larger weight-bearing joints tend to be affected later in the progression of the condition.[55]


  Conclusion Top


Dermatologic emergencies, although uncommon, may present in a number of ways. It is incumbent on physicians to be vigilant for both the clinical and pathologic signs of these diseases to avoid serious, and sometimes deadly, consequences. We herein describe several such conditions which warrant emergent intervention. This list is not exhaustive but is meant to describe some of the more common pathologies, how to diagnose them, and an overview of appropriate management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Dantas-Torres F. Rocky mountain spotted fever. Lancet Infect Dis 2007;7:724-32.  Back to cited text no. 1
[PUBMED]    
2.
Biggs HM, Behravesh CB, Bradley KK, Dahlgren FS, Drexler NA, Dumler JS, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis-United States. MMWR Recomm Rep 2016;65:1-44.  Back to cited text no. 2
    
3.
Dana AN. Diagnosis and treatment of tick infestation and tick-borne diseases with cutaneous manifestations. Dermatol Ther 2009;22:293-326.  Back to cited text no. 3
[PUBMED]    
4.
Traeger MS, Regan JJ, Humpherys D, Mahoney DL, Martinez M, Emerson GL, et al. Rocky mountain spotted fever characterization and comparison to similar illnesses in a highly endemic area-Arizona, 2002-2011. Clin Infect Dis 2015;60:1650-8.  Back to cited text no. 4
[PUBMED]    
5.
Parola P, Paddock CD, Raoult D. Tick-borne rickettsioses around the world: Emerging diseases challenging old concepts. Clin Microbiol Rev 2005;18:719-56.  Back to cited text no. 5
[PUBMED]    
6.
Chapman AS, Bakken JS, Folk SM, Paddock CD, Bloch KC, Krusell A, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky mountain spotted fever, ehrlichioses, and anaplasmosis – United States: A practical guide for physicians and other health-care and public health professionals. MMWR Recomm Rep 2006;55:1-27.  Back to cited text no. 6
    
7.
Kao GF, Evancho CD, Ioffe O, Lowitt MH, Dumler JS. Cutaneous histopathology of rocky mountain spotted fever. J Cutan Pathol 1997;24:604-10.  Back to cited text no. 7
[PUBMED]    
8.
Ong PY, Leung DY. Bacterial and viral infections in atopic dermatitis: A comprehensive review. Clin Rev Allergy Immunol 2016;51:329-37.  Back to cited text no. 8
    
9.
Tupe CL, Weiler BA, Verceles AC, McCurdy MT. A fatal case of eczema herpeticum with septic shock due to methicillin-resistant Staphylococcus aureus. Am J Crit Care 2016;25:379-82.  Back to cited text no. 9
[PUBMED]    
10.
Sun D, Ong PY. Infectious complications in atopic dermatitis. Immunol Allergy Clin North Am 2017;37:75-93.  Back to cited text no. 10
[PUBMED]    
11.
Bin L, Edwards MG, Heiser R, Streib JE, Richers B, Hall CF, et al. Identification of novel gene signatures in patients with atopic dermatitis complicated by eczema herpeticum. J Allergy Clin Immunol 2014;134:848-55.  Back to cited text no. 11
[PUBMED]    
12.
Luca NJ, Lara-Corrales I, Pope E. Eczema herpeticum in children: Clinical features and factors predictive of hospitalization. J Pediatr 2012;161:671-5.  Back to cited text no. 12
[PUBMED]    
13.
Zhuang K, Wu Q, Ran X, Ran Y, Ding L, Xu X, et al. Oral treatment with valacyclovir for HSV-2-associated eczema herpeticum in a 9-month-old infant: A case report. Medicine (Baltimore) 2016;95:e4284.  Back to cited text no. 13
[PUBMED]    
14.
Rahnama-Moghadam S, Brown ME, Meffert JJ. Vesicular eruption in a 2-year-old boy. J Fam Pract 2016;65:E1-3.  Back to cited text no. 14
    
15.
Patterson J. Viral diseases. In: Weedon's Skin Pathology. 4th ed. London: Churchill Livingstone Elsevier; 2016. p. 717-46.e715.  Back to cited text no. 15
    
16.
Bin L, Kim BE, Brauweiler A, Goleva E, Streib J, Ji Y, et al. Staphylococcus aureus α-toxin modulates skin host response to viral infection. J Allergy Clin Immunol 2012;130:683-9100.  Back to cited text no. 16
[PUBMED]    
17.
Mackool BT, Goverman J, Nazarian RM. Case records of the massachusetts general hospital. Case 14-2012. A 43-year-old woman with fever and a generalized rash. N Engl J Med 2012;366:1825-34.  Back to cited text no. 17
    
18.
Schulenburg-Brand D, Katugampola R, Anstey AV, Badminton MN. The cutaneous porphyrias. Dermatol Clin 2014;32:369-84, ix.  Back to cited text no. 18
[PUBMED]    
19.
Szlendak U, Bykowska K, Lipniacka A. Clinical, biochemical and molecular characteristics of the main types of porphyria. Adv Clin Exp Med 2016;25:361-8.  Back to cited text no. 19
    
20.
Grossman ME, Bickers DR, Poh-Fitzpatrick MB, Deleo VA, Harber LC. Porphyria cutanea tarda. Clinical features and laboratory findings in 40 patients. Am J Med 1979;67:277-86.  Back to cited text no. 20
[PUBMED]    
21.
Horner ME, Alikhan A, Tintle S, Tortorelli S, Davis DM, Hand JL, et al. Cutaneous porphyrias part I: Epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int J Dermatol 2013;52:1464-80.  Back to cited text no. 21
    
22.
Kim JJ, Lim HW. Hexachlorobenzene and porphyria cutanea tarda. Arch Dermatol 1999;135:459-60.  Back to cited text no. 22
[PUBMED]    
23.
Cripps DJ, Peters HA, Gocmen A, Dogramici I. Porphyria turcica due to hexachlorobenzene: A 20 to 30 year follow-up study on 204 patients. Br J Dermatol 1984;111:413-22.  Back to cited text no. 23
[PUBMED]    
24.
Arora S, Young S, Kodali S, Singal AK. Hepatic porphyria: A narrative review. Indian J Gastroenterol 2016;35:405-18.  Back to cited text no. 24
    
25.
Lindor NM, Hand J, Burch PA, Gibson LE. Birt-hogg-dube syndrome: An autosomal dominant disorder with predisposition to cancers of the kidney, fibrofolliculomas, and focal cutaneous mucinosis. Int J Dermatol 2001;40:653-6.  Back to cited text no. 25
[PUBMED]    
26.
Leter EM, Koopmans AK, Gille JJ, van Os TA, Vittoz GG, David EF, et al. Birt-hogg-dubé syndrome: Clinical and genetic studies of 20 families. J Invest Dermatol 2008;128:45-9.  Back to cited text no. 26
[PUBMED]    
27.
Gunji Y, Akiyoshi T, Sato T, Kurihara M, Tominaga S, Takahashi K, et al. Mutations of the birt hogg dube gene in patients with multiple lung cysts and recurrent pneumothorax. J Med Genet 2007;44:588-93.  Back to cited text no. 27
[PUBMED]    
28.
Butnor KJ, Guinee DG Jr. Pleuropulmonary pathology of Birt-Hogg-Dubé syndrome. Am J Surg Pathol 2006;30:395-9.  Back to cited text no. 28
[PUBMED]    
29.
Patterson J. Tumors of cutaneous appendages. In: Weedon's Skin Pathology. 4th ed. London: Churchill Livingstone Elsevier; 2016. p. 903-65.e924.  Back to cited text no. 29
    
30.
Kawasaki H, Sawamura D, Nakazawa H, Hattori N, Goto M, Sato-Matsumura KC, et al. Detection of 1733insC mutations in an Asian family with Birt-Hogg-Dubé syndrome. Br J Dermatol 2005;152:142-5.  Back to cited text no. 30
[PUBMED]    
31.
Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, et al. BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: A new series of 50 families and a review of published reports. J Med Genet 2008;45:321-31.  Back to cited text no. 31
[PUBMED]    
32.
Vincent A, Farley M, Chan E, James WD. Birt-Hogg-Dubé syndrome: A review of the literature and the differential diagnosis of firm facial papules. J Am Acad Dermatol 2003;49:698-705.  Back to cited text no. 32
[PUBMED]    
33.
Schulz T, Hartschuh W. Characteristics of the Birt-Hogg-Dubé/Hornstein-Knickenberg syndrome. Am J Dermatopathol 2000;22:293-4.  Back to cited text no. 33
[PUBMED]    
34.
Adley BP, Smith ND, Nayar R, Yang XJ. Birt-Hogg-Dubé syndrome: Clinicopathologic findings and genetic alterations. Arch Pathol Lab Med 2006;130:1865-70.  Back to cited text no. 34
[PUBMED]    
35.
Aivaz O, Berkman S, Middelton L, Linehan WM, DiGiovanna JJ, Cowen EW, et al. Comedonal and cystic fibrofolliculomas in Birt-Hogg-Dube syndrome. JAMA Dermatol 2015;151:770-4.  Back to cited text no. 35
    
36.
Misago N, Kimura T, Narisawa Y. Fibrofolliculoma/trichodiscoma and fibrous papule (perifollicular fibroma/angiofibroma): A revaluation of the histopathological and immunohistochemical features. J Cutan Pathol 2009;36:943-51.  Back to cited text no. 36
[PUBMED]    
37.
Menko FH, van Steensel MA, Giraud S, Friis-Hansen L, Richard S, Ungari S, et al. Birt-Hogg-Dubé syndrome: Diagnosis and management. Lancet Oncol 2009;10:1199-206.  Back to cited text no. 37
[PUBMED]    
38.
Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell 2002;2:157-64.  Back to cited text no. 38
[PUBMED]    
39.
Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev 2002;11:393-400.  Back to cited text no. 39
[PUBMED]    
40.
Ponti G, Losi L, Di Gregorio C, Roncucci L, Pedroni M, Scarselli A, et al. Identification of muir-torre syndrome among patients with sebaceous tumors and keratoacanthomas: Role of clinical features, microsatellite instability, and immunohistochemistry. Cancer 2005;103:1018-25.  Back to cited text no. 40
[PUBMED]    
41.
Yanaba K, Nakagawa H, Takeda Y, Koyama N, Sugano K. Muir-Torre syndrome caused by partial duplication of MSH2 gene by alu-mediated nonhomologous recombination. Br J Dermatol 2008;158:150-6.  Back to cited text no. 41
[PUBMED]    
42.
Curry ML, Eng W, Lund K, Paek D, Cockerell CJ. Muir-Torre syndrome: Role of the dermatopathologist in diagnosis. Am J Dermatopathol 2004;26:217-21.  Back to cited text no. 42
[PUBMED]    
43.
South CD, Hampel H, Comeras I, Westman JA, Frankel WL, de la Chapelle A, et al. The frequency of Muir-Torre syndrome among lynch syndrome families. J Natl Cancer Inst 2008;100:277-81.  Back to cited text no. 43
    
44.
Landis MN, Davis CL, Bellus GA, Wolverton SE. Immunosuppression and sebaceous tumors: A confirmed diagnosis of muir-torre syndrome unmasked by immunosuppressive therapy. J Am Acad Dermatol 2011;65:1054-80.  Back to cited text no. 44
[PUBMED]    
45.
Hoss E, Nelson SA, Sharma A. Sebaceous carcinoma in solid organ transplant recipients. Int J Dermatol 2017;56:746-9.  Back to cited text no. 45
[PUBMED]    
46.
Misago N, Narisawa Y. Sebaceous neoplasms in Muir-Torre syndrome. Am J Dermatopathol 2000;22:155-61.  Back to cited text no. 46
[PUBMED]    
47.
Southey MC, Young MA, Whitty J, Mifsud S, Keilar M, Mead L, et al. Molecular pathologic analysis enhances the diagnosis and management of Muir-Torre syndrome and gives insight into its underlying molecular pathogenesis. Am J Surg Pathol 2001;25:936-41.  Back to cited text no. 47
[PUBMED]    
48.
Mathiak M, Rütten A, Mangold E, Fischer HP, Ruzicka T, Friedl W, et al. Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations: Establishment of immunohistochemical analysis as a screening test. Am J Surg Pathol 2002;26:338-43.  Back to cited text no. 48
    
49.
John AM, Schwartz RA. Muir-Torre syndrome (MTS): An update and approach to diagnosis and management. J Am Acad Dermatol 2016;74:558-66.  Back to cited text no. 49
[PUBMED]    
50.
Braconi D, Millucci L, Bernardini G, Santucci A. Oxidative stress and mechanisms of ochronosis in alkaptonuria. Free Radic Biol Med 2015;88:70-80.  Back to cited text no. 50
[PUBMED]    
51.
Katsambas AD, Stratigos AJ. Depigmenting and bleaching agents: Coping with hyperpigmentation. Clin Dermatol 2001;19:483-8.  Back to cited text no. 51
[PUBMED]    
52.
Bruce S, Tschen JA, Chow D. Exogenous ochronosis resulting from quinine injections. J Am Acad Dermatol 1986;15:357-61.  Back to cited text no. 52
[PUBMED]    
53.
Mahler R, Sissons W, Watters K. Pigmentation induced by quinidine therapy. Arch Dermatol 1986;122:1062-4.  Back to cited text no. 53
[PUBMED]    
54.
Singh A, Ramesh V. Exogenous ochronosis. Indian J Med Res 2014;139:327.  Back to cited text no. 54
[PUBMED]  [Full text]  
55.
Mistry JB, Bukhari M, Taylor AM. Alkaptonuria. Rare Dis 2013;1:e27475.  Back to cited text no. 55
[PUBMED]    
56.
Laxon S, Ranganath L, Timmis O. Living with alkaptonuria. BMJ 2011;343:d5155.  Back to cited text no. 56
[PUBMED]    
57.
Keller JM, Macaulay W, Nercessian OA, Jaffe IA. New developments in ochronosis: Review of the literature. Rheumatol Int 2005;25:81-5.  Back to cited text no. 57
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Rickettsial Infe...
Eczema Herpeticum
Situational Emer...
Conclusion
References
Article Figures

 Article Access Statistics
    Viewed715    
    Printed66    
    Emailed0    
    PDF Downloaded103    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]