10  Cutaneous Manifestations         of Systemic Disease                                                                  ...
Committed to Your Future       For practice exam questions and interactive study         tools, visit the Dermatology In-R...
10.1  CUTANEOUS           MANIFESTATIONS OF HEPATITIS C VIRUSMorphology and Epidemiology   •	 Single-stranded RNA virus, m...
Porphyria Cutanea Tarda (PCT)    •	 Caused by a deficiency in uropoprhyrinogen decarboxylase (UROD); may be inherited,    ...
•	 Behçet’s syndrome      •	 Mooren corneal ulcers      •	 Granuloma annulare      •	 Disseminated superficial actinic por...
   •	  linical manifestations include non-specific signs seen with hyperthyroidism, goiter, pretibial       C       myxed...
Non-specific Manifestations of Hypothyroidism     Skin		   •	 Cool, dry, pale     •	 Xerosis     •	 Hypohidrosis    •	 Ye...
Birt-Hogg-Dube Syndrome (BHDS)       •	 Autosomal dominant, due to defect in the BHD gene that encodes the tumor suppresso...
•	 Patients can present with localized or generalized symptoms. Physical examination of the         skin will often reveal...
•	 Histopathology demonstrates a diffuse fibroblastic proliferation in the dermis with minimal         to slight increase ...
•	 Typical initial symptom is epistaxis. Melena, related to angiomas in the GI tract, is the       presenting sign in 25%....
•	 Constitutional symptoms such as low grade fever, headache and joint aches may preceed       skin eruption. Arthralgias ...
•         The GI polyps are benign, although they may result in protein-losing enteropathy, bleeding,       and a small ri...
•	 There is a high incidence of HLA-B8, DR3 and DQw2 haplotypes      •	 Pathogenesis is unclear. The major problem lies in...
10.5  CUTANEOUS              MANIFESTATIONS OF NEUROLOGIC DISEASENeurofibromatosis 1 (NF1) •	 Autosomal dominant disorder...
•	 Other syndromes with development of multiple BCCs:    	     1.) Bazex syndrome: This is an X-linked dominant disorder c...
•	 By age three, there are telangiectasias of the conjunctiva. Later telangiectasis develop on       the malar face, ears,...
KID Syndrome (Keratitis-Ichthyosis-Deafness) • 	 Inheritance is both autosomal dominant and autosomal recessive. It is ca...
•	 CNS abnormalities include: severe psychomotor retardation, seizures, and growth failure   •	 Diagnosis made by low seru...
•	 Approximately 20% of NLD patients have diabetes or glucose intolerance. Conversely,        up to 3% of diabetics have N...
Candida    •	 Candida infections, usually due to C. albicans, occur with increased frequency and severity       in diabeti...
Homocystinuria   •	his condition is autosomal recessive inheritance in most uTIP       T       cases. Phenotype is relate...
•	 Mortality is related to impaired ventilation secondary to kyphoscoliosis    •	 Brack syndrome = OI plus arthrogryposis ...
Naxos Disease                                                                            MNEMONIC     •	 Autosomal recess...
Table 10-2.  Paraneoplastic Diseases (cont.)                                                                              ...
Table 10-2.  Paraneoplastic Diseases (cont.)                                                                              ...
Table 10-2.  Paraneoplastic Diseases (cont.)                                                                              ...
ETAS_10 cutaneous
ETAS_10 cutaneous
ETAS_10 cutaneous
ETAS_10 cutaneous
ETAS_10 cutaneous
ETAS_10 cutaneous
ETAS_10 cutaneous
ETAS_10 cutaneous
ETAS_10 cutaneous
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ETAS_10 cutaneous

  1. 1. 10  Cutaneous Manifestations of Systemic Disease Dori Rausch, MD Valerie Harvey, MD Anthony Gaspari, MD C o n t e n t s 10.1 Cutaneous Manifestations of Hepatitis C Virus . . 355 10.2 Cutaneous Manifestations of Thyroid Disease . . . 357 10.3 Cutaneous Manifestations of Renal Disease . . . . . 359 10.4 Cutaneous Manifestations of Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . 362 10.5  Cutaneous Manifestations of Neurologic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367 10.6  Cutaneous Manifestations of Diabetes Mellitus . . . . 371 10.7 Cutaneous Manifestations of Cardiac Disease . . . . . 373 10.8 Porphyrias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381 Cutaneous Manifestations of Systemic Disease  353
  2. 2. Committed to Your Future For practice exam questions and interactive study tools, visit the Dermatology In-Review Online Practice Exam and Study System at DermatologyInReview.com/GaldermaSponsored by
  3. 3. 10.1  CUTANEOUS MANIFESTATIONS OF HEPATITIS C VIRUSMorphology and Epidemiology • Single-stranded RNA virus, member of the flaviviridae family • Six major genotypes all with a number of subtypes. Types 1a and 1b account for 75% of infections in the United States • In developed nations the prevalence of HCV antibodies <3% compared with 10-30% in highly endemic areas such as Egypt and Japan • 3.9 million people infected in U.S.Risk Factors • Intravenous drug use accounts for two-thirds of the cases • Transfusion of blood or blood products • Nosocomial infection • Cases from sexual transmission, vertical transmission and breast-feeding are rareDisease Course/Diagnosis • 20-30% of develop symptoms with acute infection • Chronic disease course: 70% of patients will progress to chronic hepatitis; cirrhosis will develop in 20%-30% of the patients with chronic disease and 4-11% of cirrhotic patients will develop hepatocellular cancer • Diagnosis is made by ELISAExtra Hepatic Systemic Manifestations • Autoimmune thyroiditis (most common associated autoimmune disorder) • Pulmonary fibrosis • Aplastic anemia, autoimmune thrombocytopenic purpura, peripheral neuropathies, arthralgias, systemic sclerosis, and lymphocytic sialadenitis. Most of these are believed to be immune mediatedCutaneous Manifestations Cryoglobulinemia u TIP • Systemic vasculitis of small-sized arteries Cryoglobulinemia Immunoglobulin involving multiple organs Type 1 Monoclonal IgG or IgM • Cryoglobulins: Immunoglobulins that Type 2 Polyclonal IgG and monoclonal IgM reversibly precipitate in the cold. There Type 3 Polyclonal IgG and polyclonal IgM are three major types of cryoglobulins. Type 1 is composed of monoclonal immunoglobulins, type 2 is composed of polyclonal IgG and monoclonal IgM (rheumatoid factor activity) and in type 3 there are polyclonal IgG and polyclonal IgM • 80 percent of cases of mixed cryoglobulinemia are associated with HCV infection • Classical clinical presentation includes palpable purpura (most common finding), arthralgias and glomerulonephritis. Livedo reticularis, hemmorhagic bullae, acrocyanosis and urticarial plaques can also be found • Lab abnormalities include an elevation of liver enzymes, positive rheumatoid factor (70- 90%) and depressed C3 levels • Histopathology demonstrates a leukocytoclastic vasculitis • Cutaneous lesions respond to alpha interferon therapy, but there is a high relapse rate after stopping the drug Cutaneous Manifestations of Systemic Disease  355
  4. 4. Porphyria Cutanea Tarda (PCT) • Caused by a deficiency in uropoprhyrinogen decarboxylase (UROD); may be inherited, sporadic or associated with Hepatitis C • Sporadic form may occur in association with HCV; in one study 82% of patients with PCT had HCV-antibodies • Other environmental triggers include alcohol, estrogens, and polyhalogenated hydrocarbons • kin findings include vesicles and bullae on sun-exposed areas, atrophic scarring with milia S formation, facial hypertrichosis, hyper/hypopigmentation, skin fragility and sclerodermoid changes. Path demonstrates a subepidermal bulla lined by well-preserved dermal papillae (festooning), thickening of basement membrane zone and vessels • The pathogenesis of HCV related PCT might be related to decompartmentalization of iron stores resulting in formation of free iron radicals and oxidation of UROD • Treatment includes phlebotomy to decrease iron load, interferon based regimens and avoidance of triggering factors u TIP Lichen Planus a • Incidence of HCV in patients with lichen planus varies from Erosive mucosal variant of LP has the strongest association with HCV 0.1% to 35%, depending on region • The pathogenesis of the skin lesions is unclear but may be secondary to proliferation of the virus within lymphocytes • Treatment with interferon has caused both worsening and improvement of the skin lesions Polyarteritis Nodosa • Multisystem segmental necrotizing vasculitis affecting medium- and small-sized arteries • utaneous lesions occurring in 25-50% of patients include subcutaneous nodules that C course along blood vessels with variable overlying erythema. Nodules may be painful, pulsatile and are most commonly located on the lower legs • In various studies 12-31% of patients were HCV+ • Polyarteritis nodosa is also associated with Hepatitis B Pruritus • Common complaint of patients with chronic HCV infection • Patients will present with excoriations, lichenification and prurigo nodularis lesions • Tends to be generalized and not relieved with scratching • he pathogenesis may be related to elevated bile salt levels that occur in the setting of liver T failure. However, there is not always a direct correlation between serum bile salt level and degree of pruritus • Treatment regimens include cholestyramine, ursodeoxycholic acid, rifampin, naltrexone, thalidomide, and UVA, UVB and interferon alpha Uncommon Associations Most of these are from anecdotal case reports, therefore further epidemiological studies are needed to clarify whether these are true associations. • Erythema nodosum • Erythema multiforme • Unilateral nevoid telangiectasia • Pyoderma gangrenosum • Vitiligo • Psoriasis356  2011/2012 Dermatology In-Review l Committed to Your Future
  5. 5. • Behçet’s syndrome • Mooren corneal ulcers • Granuloma annulare • Disseminated superficial actinic porokeratosis Adverse Skin Reactions Secondary to Treatment u TIP Currently the best management of Hepatitis C is the combina- ahe most frequently reported Ttion of interferon α and ribavirin. The major systemic side effects cutaneous findings with interferonof interferon therapy include a flu-like illness consisting of fatigue, were alopecia, lichenoid eruption, eczema, malar erythema, and localneutropenia, fever, myalgia, anorexia, vomiting, and headaches. A cutaneous necrosissmall study comparing patients treated with interferon/ribavirin tocontrols on interferon alone found that cutaneous reactions weremore common in the group on combination therapy.10.2 CUTANEOUS MANIFESTATIONS OF THYROID DISEASEThyroid-Specific Diseases Thyroglossal Duct Cyst TIP u a alignant degeneration to M • Remnant of embryonic duct papillary adenocarcinoma rare • Most common cystic abnormality of neck • Presents as mobile nontender mass, midline anterior neck • ath: Cyst wall lined by cuboidal, columnar or stratified squamous epithelium. Characteristic P histologic feature is presence of thyroid follicles in cyst wall Thyroid Malignancies • Metastases to the skin from a thyroid malignancy is rare • Most reported cases occur with papillary adenocarcinoma • ultiple endocrine neoplasia (MEN) 2a, Sipple syndrome, is autosomal dominant and is M characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia/adenomas. The gene defect lies in the RET proto-oncogene, which encodes a tyrosine receptor kinase. Skin findings are rare but may include lichen or macular amyloidosis • EN 2b/III is also autosomal dominant and characterized by medullary thyroid carcinoma, M pheochromocytoma, marfanoid features, and gastrointestinal ganglioneuromatosis. The most common skin finding is mucosal neuromas. Other associated cutaneous findings include perioral and acral hypopigmentation, café-au-lait macules, and cirumoral lentigines • owden’s syndrome (multiple hamartoma syndrome) autosomal dominant due to a defect C in the PTEN tumor supressor gene, which encodes a protein phosphatase. This condition is characterized by trichilemmomas, acral keratoses, oral papillomas, acanthosis nigricans, lipomas, facial dysmorphism and bony abnormalities and macrocephaly. In addition, patients may develop thyroid adenomas, thyroid goiter, thyroglossal duct cyst, and are at an increased risk of developing the follicular type of thyroid carcinoma. Patients are also at risk for fibrocystic breast disease, breast cancer and Lhermite Duclos disease (dysplastic gangliocytoma of cerebellum)Cutaneous Manifestations of Hyperthyroidism Graves Disease • A hypermetabolic state characterized by thyrotoxicosis, diffuse goiter, infiltrative opthalmopathy. An infiltrative dermopathy is present in a subset of patients Cutaneous Manifestations of Systemic Disease  357
  6. 6.  • linical manifestations include non-specific signs seen with hyperthyroidism, goiter, pretibial C myxedema (thyroid dermopathy) • hyroid dermopathy: Bilaterally symmetric, non-pitting yellowish-brown to red waxy T papules, nodules and plaques on lower extremities ankles, arms, and shoulders. May progress to resemble elephantiasis verrucosa nostra. Can occur in the euthyroid, hypothyroid, or hyperthyroid state. The clinical findings are due to an increase in hyaluronic acid in dermis. The pathogenesis of how this occurs is unknown. Treatment regimens include high potency topical steroids and intralesional triamcinolone • Cutaneous conditions associated with Grave’s disease include u TIP vitiligo, anetoderma, dermatitis herpetiformis, mid-dermal a hyroid acropachy: clubbing of T elastolysis, herpes gestationis, pemphigus vulgaris, and fingers associated with soft tissue Sweet’s syndrome swelling and periosteal new bone formationNon-specific Manifestations of Hyperthyroidism Skin • Warm, and moist • Localized or generalized hypertrichosis • Palmar erythema • Erythema overlying elbows • Flushing of head/neck, trunk Hair • Soft/fine/straight • Diffuse reversible alopecia Nails • Faster rate of growth • Onycholysis • Plummer nails: concave deformity with distal onycholysis Pigmentation • Focal or generalized hyperpigmentation • VitiligoCutaneous Manifestations of Hypothyroidism • These skin findings result from the inadequate circulation of thyroid hormone, target organ resistance, or an iatrogenic cause • Congenital hypothyroidism: rare in U.S., as it is part of neonatal screening. Clinical findings include cool, dry, pasty skin, and thick, pale protuberant lips, delayed dentition, an enlarged tongue, wide set eyes, a broad flat nose, dwarfism, cutis marmorata, cardiac defects, gastrointestinal and skeletal defects • Potassium Iodide (KI) and Wolff-Chaikoff effect (WCE): The WCE is described as the binding of excess organic iodide in the thyroid gland with resultant inhibition of thyroid hormone synthesis. This can occur in the setting of patients with erythema nodosum (or other inflammatory dermatoses) being treated with potassium iodide358  2011/2012 Dermatology In-Review l Committed to Your Future
  7. 7. Non-specific Manifestations of Hypothyroidism Skin • Cool, dry, pale • Xerosis • Hypohidrosis • Yellowish hue secondary to carotenemia • Generalized myxedema: swollen waxy appearance • Swollen lips, broad nose, macroglossia • Purpura secondary to impaired wound healing Hair • Dry, brittle, coarse • Increase in percentage of telogen hairs • Diffuse alopecia • Loss of lateral third of eyebrow (madarosis)10.3 CUTANEOUS MANIFESTATIONS OF RENAL DISEASE Diseases that either indirectly or directly impair renal function can manifest in the form of cuta-neous pathology. This section will highlight the key clinical, serological and histopathological fea-tures of the acquired and hereditary conditions that have both cutaneous and renal manifestations.Genetic Disorders with Cutaneous and Renal Involvement Tuberous Sclerosis (Bourneville’s Disease) u TIP • Autosomal dominant neurocutaneous disorder a ypopigmented macules are the earliest H classified by seizures, mental retardation, and cutaneous finding. Other characteristic skin lesions include facial angiofibromas characteristic skin findings (adenoma sebaceum), collagenomas  • Due to mutations in the TSC1 and TSC2 genes, which (shagreen patch), periungual fibromas code for the tumor suppressor proteins hamartin (Koenen’s tumors), forehead plaques, (TSC1) and tuberin (TSC2) gingival fibromas, and dental pitting • Renal involvement includes the development of renal angiomyolipomas, polycystic renal disease (associated with TSC2) and rarely renal cell carcinoma Fabry’s Disease  • -linked recessive condition due to a deficiency of alpha-galactosidase-A. Absence X of this enzyme leads to accumulation of glycosphingolipids (globotriaosylceramide, galabiosylcermide) within the vascular endothelium  • lassic cutaneous findings include hypohidrosis, and angiokeratoma corporis diffusum in  C a bathing trunk distribution. Extracutaneous findings include whorl-like corneal/lenticular opacities, acral paresthesias, myocardial infarctions and cerebrovascular disease • Patients can develop proteinuria. Diagnosis is confirmed by decreased levels of alpha- galactosidase in white blood cells, serum, fibroblasts, and amniotic fluid. Treatment with enzyme replacement is available; renal failure is due to accumulation of ceramide trihexoside. Diagnosis is confirmed by decreased levels of alpha-galactosidase in white blood cells, serum, fibroblasts, and amniotic fluid. Treatment with enzyme replacement is available Cutaneous Manifestations of Systemic Disease  359
  8. 8. Birt-Hogg-Dube Syndrome (BHDS) • Autosomal dominant, due to defect in the BHD gene that encodes the tumor suppressor  protein, folliculin. The function of this protein is unknown  • Triad of trichodiscomas, fibrofolliculomas and acrochordons • Clinically patients display numerous firm flesh-colored papules over the head, neck and upper trunk • Strong evidence suggesting that BHDS and bilateral renal tumors, co-segregate in an autosomal dominant fashion. Histologically, these renal tumors are oncocytomas, chromophobe adenomas and papillary renal cell carcinoma • Periodic surveillance of patients and their relatives for renal cell carcinoma is recommended. Patients are also at risk for pulmonary cysts and pneumothorax Nail-Patella Syndrome • Autosomal dominant  • The defect has been identified in the LMX1B gene, which encodes a transcription factor involved in collagen synthesis • atients develop dystrophic nails (thumb nail most commonly involved), triangular lunulae, P hypoplastic or absent patellae, dislocation of themradial head, and posterior iliac horns  • Patients may develop hyperpigmentation of the papillary margin of the iris (Lester iris) • enal involvement includes: glomerulonephritis, hemolytic uremic syndrome and rarely, R renal failure Pseudoxanthoma Elasticum (PXE) • Autosomal recessive • ragmentation and calcification of elastic fibers in the skin, Bruch’s membrane of the eye F (angioid streaks) and vasculature leads to the clinical manifestations • Yellow papules and plaques in the flexural areas give the appearance of “plucked chicken skin.” Patients may also develop claudication, loss of peripheral pulses and angina  • Inactivating mutation in the ABCC6 gene, which encodes the MRP6 protein (functions as efflux pump) expressed in hepatocytes and renal cells • Histopathology: fragmented elastic fibers in the mid and deep reticular dermis • Hypertension frequently develops in these patients secondary to involvement of renal vasculatureEnd Stage Renal Disease (ESRD) and Dialysis There are many dermatological manifestations of ESRD. Many patients develop a chronic ane-mia resulting in skin pallor. Deposition of carotenoids and urochrome gives the skin a yellowishhue. Photo-distributed hyperpigmentation, and ecchymoses (secondary to uremic platelet dys-function) are also commonly seen.  • alf and half (Lindsay’s) nails result from edema of the nail bed and capillary network and H give the proximal half of the nail an opaque white appearance. In contrast, patients with cirrhosis or hypoalbuminemia have whitening of the proximal two thirds, while the distal 1/3 is red (Terry’s nails) Pruritus • The most common cutaneous manifestation of ESRD • Seen in both peritoneal or hemodialysis patients360  2011/2012 Dermatology In-Review l Committed to Your Future
  9. 9. • Patients can present with localized or generalized symptoms. Physical examination of the skin will often reveal excoriations, lichenification and prurigo nodularis • The pathogenesis is not well understood and most likely multifactorial. Proposed theories include hypervitaminosis A, accumulation of toxic substances with excitation of cutaneous nerve endings, and increased number of mast cells within lesional skin. None of these theories have been substantiated in studies yet • The management is challenging, and often unsatisfactory. Treatment regimens include topical steroids, lubricants, keratolytics, oral antihistamines, activated charcoal, and cholestyramine. UVB phototherapy is the most effective form of treatment for patients who are not transplant candidates. Renal transplantation is curative Acquired Perforating Dermatosis of ESRD • Similar to primary perforating disorders in that they are all characterized by transepidermal elimination of altered dermal substances. Share overlapping clinical features of Kyrle’s disease, perforating folliculitis and reactive perforating collagenosis • Etiology is unknown, but may be related to the u TIP dermal accumulation of micro-deposits of calcium a ore commonly seen in darker skin types, M with subsequent evacuation through the epidermis and in patients with ESRD econdary to s diabetic nephropathy • Patients present with flesh-colored or hyperpigmented umbilicated papules/nodules/plaques with a central keratotic core • Treatment possibilities include topical steroids, intralesional corticosteroids, topical/oral retinoids, cryotherapy and UVB Metastatic Calcification • Deposition of calcium within tissue secondary to abnormal calcium and or phosphate metabolism • can manifest in the skin as benign nodular calcifications (calcinosis cutis) or as a more It serious condition (calciphylaxis) with an associated mortality rate between 60-80% • alciphylaxis presents as painful purpuric plaques and retiform pupura with progression C to ulceration and necrosis. Distribution of the lesions may predict prognosis; patients with acral lesions have a better outcome that those with proximally located lesions • istological finding of medial calcification/intimal hyperplasia of small arteries and arteri- H oles points to an abnormality of calcium/phosphate metabolism • anagement of these patients includes total or subtotal parathyroidectomy (if PTH levels M are elevated), wound care, and avoidance or precipitating factors. Mortality is related to Staphylococcal superinfection of ulcers with resultant sepsis Nephrogenic Systemic Fibrosis (NSF) • Nephrogenic fibrosing dermopathy (NFD). It is a newly recognized fibrosing disorder that occurs in the setting of chronic and acute renal failure due to a variety of renal diseases • Recent reports suggest gadolinium containing MRI contrast is a trigger in such predisposed individuals • Patients present with woody indurated nodules/plaques with a peau d’orange appearance. The lesions are usually confined to the extremities but can occasionally appear on the trunk. Besides renal disease, other associated conditions include coagulation abnormalities, DVT, and recent surgery (especially vascular surgery) • No serological evidence of paraproteinemia, peripheral eosinophilia, thyroid disease or collagen-vascular disease Cutaneous Manifestations of Systemic Disease  361
  10. 10. • Histopathology demonstrates a diffuse fibroblastic proliferation in the dermis with minimal to slight increase in dermal mucin • The disease course is variable. Less than 5% have fulminant and fatal disease. This is caused by impaired ventilation due to fibrosis of respiratory muscles • Treatment is usually not satisfactory. Correction of kidney function via hemodialysis or transplant produces variable improvement Porphyria Cutanea Tarda (PCT) • The pathogenesis may be related to the suboptimal clearance of uroporhyrins from the circulation • Has an identical clinical presentation to sporadic PCT • Patients may present with bullae, skin fragility, photodistributed hyperpigmentation and hypertrichosis • Path demonstrates a subepidermal bulla lined by well-preserved dermal papillae (festooning), thickening of basement membrane zone and vessels • reatment includes erythropoietin to raise hemoglobin followed by phlebotomy to T decrease iron load Pseudo-PCT  • imilar clinical and histological findings of PCT, in setting of normal porphyrin profile S  U  • sually due to certain medications such as furosemide, naproxen, tetracycline, nalidixic acid, or amiodaroneAcquired Disorders with Renal and Cutaneous Manifestations There are many acquired disorders that have both renal and cutaneous findings. Some of themore important ones will be briefly reviewed below. • In systemic lupus erythematosus patients develop malar erythema, photosensitivity, and oral ulcers. Renal biopsy will reveal focal proliferative, diffuse proliferative or membranous glomerulonephritis • Systemic sclerosis is characterized by Raynaud’s phenomenon acral or diffuse sclerosis, esophageal dysmotility and pulmonary disease. Rarely, patients can develop renal failure • Henoch-Schonlein purpura (HSP) is an IgA mediated small vessel vasculitis. Clinically, patients present with palpable purpura of the lower extremities and buttocks, GI vasculitis and glomerulonephritis. Direct immunofluorescence of lesional and perilesional skin will demonstrate IgA, C3, and fibrin deposits in small vessel walls •  egener’s granulomatosis is characterized by necrotizing granulomas and vasculitis of the W upper/lower respiratory tract and kidneys. Dermatological manifestations include palpable purpura, oral ulcers, nodules, gingival hyperplasia, and livedo reticularis. Renal involvement can lead to hypertension and edema; renal failure is uncommon but a major cause of morbidity10.4 CUTANEOUS MANIFESTATIONS OF GASTROINTESTINAL DISORDERSHereditary Hemorrhagic Telangiectasia (Osler-Weber Rendu) • Autosomal dominant disorder caused by mutations in Endoglin (ENG) or Activin receptor- like Kinase-1 (ACK1, ACVRLI) genes resulting in HHT1 or HHT 2, repsectively. Both genes encode proteins that belong to TGF-b receptor complex and play a role in formation of vascular system • Characteristic findings include macular telangiectasias on the oral mucosa, face and acral surfaces. These patients have direct arteriovenous connection without an intervening capillary362  2011/2012 Dermatology In-Review l Committed to Your Future
  11. 11. • Typical initial symptom is epistaxis. Melena, related to angiomas in the GI tract, is the presenting sign in 25%. AV malformations may develop in the liver, lung and CNS. Treatment with systemic estrogen may reduce epistaxis. Laser is also beneficial for nasal and GI bleeding. Usually presenting sign is epistaxis; painless gastrointestinal (GI) bleeding, mostly from nodular angiomas in stomach or duodenum; AV malformations of liver, lung, and eyeBlue Rubber Bleb Nevus Syndrome • Autosomal dominant or sporadic condition, caused by mutations in VMCM1 gene (unknown protein) • Soft compressible blue tumors develop usually on the trunk and arms. Nocturnal pain is characteristic • Melena occurs when gastointestinal hemangiomas rupture. Less common sites of involvement are the lung, eye and CNS. Disseminated intravascular coagulation has been reportedKaposi’s Sarcoma (KS) • Pathogenesis: HHV-8 infection causes abnormal vascular proliferation (other HHV-8 associated conditions include: primary effusion lymphoma, solid lymphoma, and Castleman’s disease). Types include Classic, African endemic, African Lymphadenopathic, drug- induced immunosuppression, and HIV-associated • Classic form is seen in middle aged men of Southern-Eastern European heritage. Typically, patients present with red to blue-black patches, plaques or nodules on the feet • African endemic KS is a locally aggressive process that affects middle aged men in Northeast Congo, and Rwanda-Burundi • African lymphadenopathic KS is an aggressive disease which affects children younger than ten years. Lymph node involvement may preceed skin. Eyelid and conjunctival lesions are characteristic. Death occurs within one to two years • Drug-induced immunosuppression KS is similar to classic KS but location of the lesions is more variable • HIV associated KS is an aggressive form. There is a tendency toward upper body and facial distribution of skin lesions. Viscera is involved in 70% of cases • Radiation therapy, local excision, cryotherapy, alitretinoin gel, intralesional vincristine or interferon and laser ablation have all been successful in treating local disease • HAART is effective in HIV associated KS, irrespective of whether medication is a protease inhibitor or non-nucleoside reverse transcriptase inhibitorHenoch-Schonlein Purpura (HSP) • Preceded by upper respiratory infection. Other proposed triggers include bacterial infections, medications, foods and lymphoma. It typically affects youngsters under the age of 20. However, adult variants exist • Palpable purpura, urticaria, and necrotic ulcers on buttock, distal legs, extensor extremities symmetrically. Histology shows leukocytoclastic vasculitis. Direct immunofluoresence shows perivascular IgA, C3 and fibrin deposits Cutaneous Manifestations of Systemic Disease  363
  12. 12. • Constitutional symptoms such as low grade fever, headache and joint aches may preceed skin eruption. Arthralgias and arthritis of the knee and ankles can develop. GI involvement presents as abdominal pain, vomitting, distension, GI bleeding, or ileus. Renal involvement in the form of gross or microscopic hematuria occurs in more than 25% of patients. Treatment is supportive. Systemic corticosteroids is quite effective for abdominal pain, although controversial for renal disease. Long term sequelae include hypertension and renal involvementMalignant Atrophic Papulosis of Degos • A condition of unknown etiology which typically affects men women  • Pink dome-shaped papules on the trunk, bulbar conjunctiva, and oral mucosa are the initial manifestations. Lesions become umbilicated and ultimately atrophy to create a white center with telangiectatic rim. Subsequently, GI involvement ensues, producing hematemasis, cramping, and fever. Death is related to perforation and peritonitis. CNS involvement occurs to a lesser extent and presents as headache, hemiparesis, aphasia, and cranial nerve involvement • Histology shows epidermal atrophy overlying wedge-shaped dermal necrosis and mucinous degeneration overlying thrombotic vasculitis with minimal inflammationGardner’s Syndrome • Autosomal dominant disorder caused by mutations in tumor suppressor APC gene leading to disturbed signal transduction and uninhibited growth •   pidermal cysts in 50-100% of patients and occur mostly on the face and scalp. Histology E often shows pilomatricoma-like features foci. Other findings uTIP include: desmoid tumors, fibromas, lipomas, leiomyomas, a ongenital hypertrophy of C osteomas of mandible/maxilla, impacted teeth, supranum- retinal epithelium (CHRPE) is mery teeth, dental cysts, and early tooth loss an early sign of Gardner’s syndrome •  ll patients develop adenenomatous polyposis of colon and A rectum with 100% transformation to carcinoma by age 30 in 50%Peutz-Jeghers Syndrome u TIP •  utosomal dominant disorder in which 50% of patients have muta- A a yperpigmentation of H tions in STK11 gene. This gene encodes a serine threonine kinase that the lip begins in infancy is important for signal transduction • Hyperpigmented macules may develop anywhere in the oral mucosa, on the genitalia and dorsal acral surfaces. Once the clinical pattern is recognized, then endoscopy should be performed to detect hamartomatous polyps of the GI tract. Frequency of involvement is: small intestines stomach colon rectum • These polyps can progress to cancer and thus screening every two years is recommended. In addition, screening for pancreatic cancer should be considered since the lifetime risk of developing such is 10%. Malignancies can also develop in the gallbladder, breast, ovary, and testes • Laugier-Hunziker (LH) and Cronkhite- Canada syndrome should also be considered in the differential diagnosis. atients with LH present with mucosal pigmentation and pigmented P nail streaks onlyCronkhite-Canada Syndrome • Clinically, patients present with melanotic macules of the u TIP fingers and GI polyps. Most affected patients are Japanese. a nlike Peutz-Jegher syndrome, U Extensive alopecia and onychodytrophy are also characteristic onset is in adulthood364  2011/2012 Dermatology In-Review l Committed to Your Future
  13. 13. •  The GI polyps are benign, although they may result in protein-losing enteropathy, bleeding, and a small risk of malignant transformationMuir-Torre Syndrome (MTS) •  utosomal dominant disorder caused by mutations in either MSH2 or MLH1 genes. The latter A encodes a mismatch repair enzyme •  haracteristic features are sebaceous neoplasms, (especially adenomas), multiple keratoac- C anthomata and internal malignancy. These internal malignancies often preceed cutaneous lesions by 10-20 years •  The most common malignancy is colon cancer, but laryngeal, uterine, and breast cancer can also developBannayan-Riley-Ruvalcaba Syndrome •  utosomal dominant disorder caused by mutations in PTEN gene in 60% of cases. PTEN is A also mutated in Cowden’s syndrome • Clinically, patient present with macrocephaly, genital lentigines (Bannayan syndrome affects the “banana” aka penis), developmental delay, GI hamartomatous polyps, lipomas, myopathies and hemangiomasMultiple Endocrine Neoplasia (MEN) • Mucocutaneous findings are more common in types I and IIB • Type I “Wermers’s syndrome”: Autosomal dominant disorder involving mutations in MENI gene, which encodes menin, a nuclear protein. They include: facial angiofibromas, collagenomas, lipomas, hypopigmented macules, and café-au-lait macules. Sytemic findings are related to parathyroid, pancreatic, and pituitary tumors • Type IIA “Sipple’s syndrome”: Autosomal dominant disorder caused by mutations in RET gene, which encodes a tyrosine kinase receptor. It is a syndrome of cutaneous amyloidosis, pancreatic tumors, parathyroid tumors, pheochromocytoma and medullary thyroid carcinoma. Clinically, patients present in childhood with notalgia paresthetica, macular or lichen amyloidosis. Workup should include calcitonin, calcium, PTH, and urine catecholamines • Type IIB: Autosomal dominant disorder involving RET gene. Characteristic features are multiple mucosal neuromas, marfanoid body habitus, and protruding lips. These patients are also at risk for medullary thyroid carcinoma, pheochromocytoma, and GI ganglioneuromasBowel-Associated Dermatosis-Arthritis Syndrome • ccurs in those with ulcerative colitis (UC), Crohn’s disease (CD), s/p bypass surgery, or O blind loop syndrome. Involves bowel bacterial overgrowth causing complement activation with subsequent deposition of antibody complexes in skin/synovium •  linically, patients present with crops of red and purpuric papulovesicles on proximal C extremities or trunk associated with fevers, chills, malaise, and arthritis • Histology shows a perivascular lymphocytic infiltrate and a leukocytoclastic vasculitis of dermal capillaries. Direct IF is positive with immunoglobulins and complement at DE junction and around vessels • Pustular pyoderma gangrenosum should be considered in the differential diagnosisDermatitis Herpetiformis or “Duhring’s Disease” • Virtually all patients with DH have gluten-sensitive enteropathy, although most are asymptomatic Cutaneous Manifestations of Systemic Disease  365
  14. 14. • There is a high incidence of HLA-B8, DR3 and DQw2 haplotypes • Pathogenesis is unclear. The major problem lies in the development of antibodies to tissue transglutaminase (this enzyme metabolizes gliadin protein found in gluten-rich foods such as wheat, barley, and rye). These antibodies cross-react with epidermal transglutaminase and cause the cutaneous findings. Patients also have circulating IgA antibodies against smooth muscle endomysium • Severely pruritic grouped vesicles occur on the extensor surfaces, scalp, neck and buttocks. Lesions are “herpetiform” because they start as grouped and arise from an erythematous base • Histology of lesional skin shows subepidermal clefting. Indirect IF is negative • Oral iodides should be avoided Table 10-1. Manifestations of Inflammatory Bowel Disease (IBD) Association Cutaneous Findings Fissures and Fistulas CD UC Commonly involves perineum Associated with edema and inflammation Oral Crohn’s CD Edema, cobblestone, ulcerations, nodules Metastatic Crohn’s CD Nodules, plaques, ulcerations; commonly on extremities or intertrigenous regions Mimics Erythema Nodosum Erythema Nodosum UC CD Tender red nodules on anterior Females males lower legs; precedes or occurs simultaneous with IBD flare Pyoderma Gangrenosum (PG) UC CD Papules, pustules, hemorrhagic Clinical course blisters → enlarge, ulcerate follow GI disease with dusky undermined edges; exacerbated by trauma; frequently on legs Pyoderma Vegetans UC Vegetating plaques, vesiculopustules of intertrigenous areas; heal with hyperpigmentation; when process involves mucosa = Pyostomatits vegetans Chronic Apthous Ulcers UC CD Identical to common aphthous ulcers; develop with IBD flares Polyarteritis Nodosa (PAN) CD Tender red nodules that may ulcerate on legs; associated with starburst livedo reticularis, peripheral neuropathy, arthralgias, myalgias Other less common manifestations: Epidermolysis bullosa acquisita, erythema multiforme, urticaria, clubbing, psoriasis, vitiligo. Note: CD = Crohn’s disease UC = Ulcerative Colitis366  2011/2012 Dermatology In-Review l Committed to Your Future
  15. 15. 10.5  CUTANEOUS MANIFESTATIONS OF NEUROLOGIC DISEASENeurofibromatosis 1 (NF1) • Autosomal dominant disorder involving mutations in tumor suppressor gene NF1, which encodes neurofibromin. This protein is thought to down regulate proto-oncogene ras • The initial presenting sign is the café-au-lait macule (CALM). They begin to develop prior to, or shortly after birth • Axillary or inguinal freckling (Crowe’s sign) is pathognomonic for NF • If NF is suspected in a child, a slit lamp exam should be performed since Lisch nodules (pigmented iris hamartomas) are present in this age group and can confirm the diagnosis • Neurofibromas typically appear after puberty and occur in 3 different forms: 1.) The first is pedunculated. These have a positive button-hole sign 2.) Plexiform neuromas develop along the course of a peripheral nerve 3.) Diffuse neuromas can cause gross deformity. The Elephant Man, Joseph Merrick of London, had diffuse neuromas u TIP • Other associated findings include: a  lexiform lesions can transform P 1.) Skeletal: macrocephaly, kyphoscoliosis, lordosis, spinal into neurofibrosarcoma or bifida, sphenoid wing dysplasia, pseudoarthrosis of the malignant peripheral nerve long bones sheath tumor (MPNST) 2.) CNS: Learning disabilities, optic gliomas, seizures, unidentified bright objects (UBO) in the basal ganglia, brainstem, and cerebellum visualized by T2-weighted MRI 3.) alignancy: patients with NF 1 who develop juvenile xanthogranulomas are at 20-30 M times greater risk for juvenile chronic myelogenous leukemia (“triple association”), pheo- chromocytomaSegmental Neurofibromatosis or NF5 • Segmental distribution of CALMS and neurofibromas • Arise from a post-zygotic mutation. Most of these patients do NOT have a family history of NF1 • Transmission of NF to offspring is rare, but possibleBasal Cell Nevus Syndrome (BCNS, Gorlin Syndrome) • utosomal dominant disorder caused by mutations in PATCH gene that encodes PTC pro- A tein involved in sonic hedge hog pathway. Inactivating PATCH mutations leads to loss of inhibition of smoothen (SMO) and suqsequent increased expression of other genes • ultiple basal cell carcinomas begin in early adulthood (20-30s) M • Palmoplantar pits occur in nearly all patient. Histologically, they show basaloid proliferation but do not progress to BCC • keletal defects that hare highly suggestive of BCNS include: bifid ribs and shortened S metacarpal and metatarsal bones. This results in dimpling of the overlying skin (Albright’s sign). haracteristic facies are related to frontal bossing, hypoplastic maxilla, a broad nasal C root, and ocular hypertelorism • Jaw cysts are common and develop in the first decade of life • CNS abnormalities include: falx cerebri calcifications, agenesis of the corpus callosum, mental retardation, and medulloblastoma Cutaneous Manifestations of Systemic Disease  367
  16. 16. • Other syndromes with development of multiple BCCs: 1.) Bazex syndrome: This is an X-linked dominant disorder characterized by hypotrichosis, hypohidrosis, and follicular atrophoderma of the extremities 2.) Rombo syndrome is distinguished by the vermiculate atrophoderma and hypotrichosisXeroderma Pigmentosum (XP) • n autosomal recessive disorder caused by mutations in DNA excision repair enzymes A involved in UV induced-thymidine dimers. There are eight complementation groups (XP A thru G) that have different molecular defects, some involve helicase. Complementation groups are defined by the correction of excision repair when fibroblasts from different patients are fused • t is characterized by acute sun sensitivity and premature aging by age 1-2 years. Skin can- I cers (BCC SCC melanoma) develop by age 20 u TIP • Ocular abnormalities develop in 40% and include: a e-Sanctis-Cachione syndrome = XP D conjunctivitis, keratitis, corneal opacities or ulcerations, plus mental retardation, dwarfism, and blepharitis, symblepharon, and ectropion gonadal hypoplasiaCockayne Syndrome u TIP • utosomal recessive disorder associated with defects in A an contrast to XP, there is neither I nucleotide excision repair. Some have mutations in the XPG premature aging nor skin cancer gene. Others have mutation in the CSA or CSA genes which development in Cockayne encode proteins that associate with RNA polymerase syndrome. Bird-headed facies, “Mickey-Mouse” ears, and dwarfism • Similar to XP, photosensitivity and neurologic degeneration are hallmarks of Cockayne occurs syndrome • Deafness, retinal atrophy, basal ganglia calcifications, and peripheral neuropathy are the CNS abnormalitiesIBIDS Syndrome (Ichthyosis, Brittle Hair, Intellectual Impairment, Decreased Fertility,Short Stature) or Tay’s Syndrome u TIP • utosomal recessive disorder caused by mutations in XPD/ A a hotosensitivity is prominent, P ERCC2or XPB/ERCC3 genes. (Same genes as XP) as in XP. However, there is no • air is sparse hair and demonstrates a reduced sulfur content H increased risk for skin cancer (50% of normal). This sulfur deficiency results in the following patterns noted on polaroscopy: trichoschisis, pili torti, trichor- rhexis nodosa and trichothiodystrophy (“tiger tail” or alternating bright and dark bands) • Systemic findings include: impaired intelligence, cataracts, short stature, joint contractures, osteosclerosis, decreased fertility, and hypogonadism • PIBIDS syndrome = photosensitivity + IBIDS syndrome. Condition is very similar to IBIDS but gonad size is normal, and photosensitivity is presentAtaxia-Telangiectasia (AT) or Louis-Bar Syndrome u TIP • A utosomal recessive disorder associated with mutations in ATM gene encoding phosphatidylinositol 3-kinase-like protein aatients are at risk for B-cell P lymphomas, leukemias, and that senses DNA damage at the G1/S check point. It initiates breast cancer DNR repair. Cells are hypersensitive to ionizing radiation • he initial finding is ataxia. This is noted when child starts to T walk. Ultimately, patients are wheelchair bound by age ten368  2011/2012 Dermatology In-Review l Committed to Your Future
  17. 17. • By age three, there are telangiectasias of the conjunctiva. Later telangiectasis develop on the malar face, ears, roof of the mouth, chest, flexures, and dorsal hands and feet • Eye abnormalities are pseudopalsy and nystagmus • ecurrent sinopulmonary infections begin between three to eight years of age. R Susceptibility to infection is related to IgA deficiency, lymphopenia and hypoplastic thymus • iagnosis is made by radiosensitivity study of fibroblasts. Elevated alpha fetoprotein and D CEA are also supportive of ATIncontinentia Pigmenti or Bloch-Sulzberger Disease • X-linked dominant disorder caused by mutations of NEMO gene. The protein product is a subunit of a kinase that activates NFkB thereby protecting against TNF induced apoptosis. Variable phenotypes occur in girls due to X lyonization. IP is lethal in males • Girls present within a few weeks of birth with a blaschkoid pattern of vesicles (stage 1). Over the following weeks to months, hyperkeratotic verrucous lesions develop (stage 2). Hyperpigmentation then ensues (stage 3). This may fade or become atrophic (stage 4) • CNS findings are: psychomotor retardation, microcephaly, seizures, spasticity, and cerebellar ataxia • Ocular abnormalities include colobomas, retinal detachment, strabismus, cataracts, optic atrophy, corneal opacities • Dental findings may present as absent teeth, small teeth, and peg-shaped teeth • Skeletal changes include: syndactyly, skull deformity, dwarfism, spina bifida, club foot, supernummary ribs, hemiatrophy and shortening of the limbs • P should be distinguished from Incontinentia Pigmenti Achromicans (Hypomelanosis of I Ito). In the latter condition, the predominant finding is hypopigmentation along Blaschkos lines. Abnormalities of the CNS, skeletal system, eyes and teeth may also occurPiebaldism • An autosomal dominant disorder caused by defects in the pro- uTIP to-oncogene c-KIT. The gene encodes tyrosine kinase receptor aatchy leukoderma containing P smaller spots of hyperpigmenta- on melanocytes tion and a white forelock are • Associated CNS abnormalities are impaired motor coordina- present at birth tion, cerebellar ataxia, mental retardation, and deafnessWaardenburg Syndrome • his is a heterogeneous group of disorders. All manifest a white forelock, premature gray- T ing, leukoderma, synophrys, deafness, dystopia canthorum, heterochromia irides, and a broad nasal root • Inheritance is autosomal dominant for all types except type 4, which has both AD and AR inheritance • Type 1: Defects in PAX 3 gene. Patients present with white forelock, premature graying, leukoderma, synophrys, deafness, dystopia canthorum, heterochromia irides, and a broad nasal root • Type 2: Defects in MITF gene. Phenotype is similar to type 1, but dystopia canthorum is absent and deafness is more common • Type 3: Defects in PAX 3 gene. Phenotype is similar to type 1, but limb abnormalities are present • Type 4: Defects in SOX10, EDN3, and EDNRB genes. Similar to type 1 along with Hirschsprung disease (congenital megacolon) Cutaneous Manifestations of Systemic Disease  369
  18. 18. KID Syndrome (Keratitis-Ichthyosis-Deafness) • Inheritance is both autosomal dominant and autosomal recessive. It is caused by mutations in GJB2 gene, which encodes the gap junction protein, connexin 26 • This disorder is characterized by vascularizing keratitis, transient erythroderma at birth fol- lowed by erythro keratoderma, reticulated palmoplantar keratoderma, hypotrichosis, partial anhidrosis and dystrophic nails • Deafness is the major CNS finding • The face and ears have a distinct appearance. There is a leathery texture, absent eyebrows and prominent perioral furrowsVohwinkel Syndrome u TIP • Autosomal dominant disorder caused by a utaneous features are mutilating, honeycombed palmo- C mutation of GJB2 gene, which encodes plantar keratoderma, constricting bands around the digits Connexin 26 (same as KID syndrome) (pseudoainhum) resulting in autoamputation, star-shaped keratosis over the knuckles, nail dystrophy, and alopecia • Deafness is the major CNS abnormalitySjorgen-Larsson Syndrome • Autsomal recessive disorder caused by a deficiency of FALDH uTIP (fatty aldehyde dehydrogenase). Phenotype is related to a elpful hint: a seizing, spastic, H scaly Swede has Sjogren-Larsson accumulation of fatty alcohol or fatty aldehyde lipids syndrome • More common in Northern Sweeden • linical triad of congenital ichthyosis, di- or tetraplegia, mental C retardation. The ichthyosis is notable in that there is accentuation of the flexures and lower abdomen • Perifoveal glistening white dots of the eye are characteristic. Grand mal seizures also occurRefsum Disease • Autosomal recessive disorder common in Northern Europeans. It involves the peroxisomal enzyme, phytanoyl-CoA hydroxylase (PhyH). Other mutations involve the PEX 7 gene • Phenotype is related to impaired metabolism of phytanic acid (found in dairy and chlorophyll-rich foods), with resultant accumulation of phytanic acid • he characteristic features include: adult onset of mild ichthyosis with accentuated palmar T creases, atypical retinitis pigmentosa, EKG changes, cardiomy- uTIP opathy, and renal tubular dysfunction a NS abnormalities are deafness, C • Diagnosis made by elevated serum phytanic acid anosmia, peripheral neuropathy, decreased deep tendon reflexes, • Treatment involves dietary restriction of phytanic acid and and cerebellar ataxia extracorporeal LDL-aphoresisBjornstad’s Syndrome • disorder characterized by pili torti and deafness. Inheritance can be both autosomal dom- A inant and recessiveMenkes Disease u TIP • X-linked recessive disorder caused by muta- a irls develop variably depigmented lusterless hair. G tions of ATP7A gene (encodes copper-trans- Polaroscopy reveals monilethrix, pili torti, trichorrhexis porting ATPase). The disease is lethal in males nodosa. In addition, there is diffuse cutaneous hypopig- mentation, doughy skin, and an exaggerated cupid bow370  2011/2012 Dermatology In-Review l Committed to Your Future
  19. 19. • CNS abnormalities include: severe psychomotor retardation, seizures, and growth failure • Diagnosis made by low serum copper and cerruloplasmin10.6  CUTANEOUS MANIFESTATIONS OF DIABETES MELLITUS Diabetes Mellitus, the most common endocrine disorder, affects an estimated 11 million indi-viduals in the United States. At least 30% of diabetics have cutaneous manifestations of their dis-ease; these findings may appear before or after the development of diabetes.Diseases Associated with Diabetes Acanthosis Nigricans • African Americans and Hispanics are affected more frequently than Caucasians. This finding is associated with obesity, insulin resistance, total lipodystrophy, malignancy, medications and HAIRAN syndrome (hyperandrogen, insulin resistance, acanthosis nigricans) • Hyperpigmented velvety plaques of the flexures. The face, external genitalia, medial thighs, dorsal joints, conjunctiva, lips and umbilicus can be involved in extensive cases • Pathogenesis involves: – Genetic sensitivity of the skin to hyperinsulinemia – Aberrant keratinocyte and fibroblast proliferation stimulated by excess growth factor (e.g., IGF-1, TGF-b) • Treatment: Tight blood glucose control, treatment of underlying malignancy, weight control, and discontinuation of offending agent Diabetic Limited Joint Mobility (LJM) = Cheiroarthropathy • Incidence is proportional to duration of diabetes and poor glucose control; correlated with microvascular disease • Patients develop tightness and thickening of the skin and periarticular tissue of the fingers with resultant painless loss of joint mobility. Patients are unable to approximate the palmar surfaces and interphalangeal joint spaces with the hands pressed together and fingers separate (prayer sign) • Tight glucose control and physical therapy help to preserve range of motion Scleroderma-like Syndrome • A disorder involving thickened waxy skin over the dorsal hands and feet, usually in conjunction with LJM. No specific treatment Scleredema Diabeticorum • Occurs more commonly in type 2 diabetics, long-standing disease, and obese men • Painless, symmetric woody “peau d’orange” induration the upper back and neck. No specific treatment is available Necrobiosis Lipoidica Diabeticorum (NLD) • Patients classically present with single or multiple red-brown papules, which progress to sharply demarcated yellow-brown atrophic, telangiectatic plaques with a violaceous, irregular border. Common sites include shins followed by ankles, calves, thighs and feet. Ulceration occurs in about 35% of cases. Cutaneous anesthesia, hypohidrosis and partial alopecia can be found • Pathology: Palisading granulomas containing degenerating collagen (necrobiosis). Inflammatory infiltrate contains plasma cells and multinucleated histocytes. Involves entire dermis. Mucin is NOT increased Cutaneous Manifestations of Systemic Disease  371
  20. 20. • Approximately 20% of NLD patients have diabetes or glucose intolerance. Conversely, up to 3% of diabetics have NLD. Women are more affected than men. Pathogenesis is thought to involve the nonenzymatic glycosylation of dermal collagen and elastin • Treatment: Ulcer prevention. No impact of tight glucose control on likelihood of developing NLD but diabetics with NLD have higher rate of microvascular complications and limited joint mobility Diabetic Bullae or Bullosis Diabeticorum • Rarest cutaneous complications of diabetes; M F, long standing diabetics. Most microvascular complications. Trauma and microangiopathy may play a role • Presents with diffuse orange-yellow skin with sparing of the sclera (distinguishes from jaundice) • Clinical: Rapid onset of painless tense blisters on the hands and feet • Pathology: Intraepidermal and/or subepidermal split without acantholysis. DIF is negative • Pathogenesis: Trauma and microangiopathy may play a role • Treatment: Spontaneous healing in two to five weeks Yellow Skin or Carotenosis • Affects about 10% of diabetics. Half have elevated serum carotene • Proposed Pathogenesis: Involves high yellow fruit/vegetable diet, impaired hepatic metabolism of carotene, and non-enzymatic glycosylation of dermal collagen Diabetic Dermopathy or “Shin Spots” or Pigmented Pretibial Papules • Most common cutaneous manifestation of diabetes; M F, males over age 50 years with long standing diabetes • There are bilateral asymptomatic red-brown atrophic macules on shins • There is no effective treatment Eruptive Xanthomas • Occurs in setting of uncontrolled diabetes. Also associated with hypertriglyceridemia (2000 mg/dl), medications (retinoids, estrogens), and alcohol • Sudden crops of firm non-tender yellow papules with a red rim on extensor surfaces • Tight glucose control and lipid reduction results in regression of lesions Granuloma Annulare (GA) • Association between granuloma annulare and diabetes is controversial. Generalized and perforating forms of GA are most closely associated with DM. These variants often have a chronic and relapsing course • Asymptomatic red-purple dome shaped papules arranged in annular configuration • Treatment is difficult. Screen for diabetes with patients with chronic relapsing, perforated or generalized GA Other Conditions associated with Diabetes • Neurotrophic ulcers, lichen planus, lipodystrophy, Dupuytren’s contractures, vitiligo, rubeosis of the face, skin tags, and clear cell syringomataCutaneous Infections Diabetic patients are predisposed to developing cutaneous infections due to poor micro-circulation, hypohidrosis, impaired phagocytosis, killing, leukocyte adhesion and chemotaxis. Theincidence of infections correlates with serum glucose levels.372  2011/2012 Dermatology In-Review l Committed to Your Future
  21. 21. Candida • Candida infections, usually due to C. albicans, occur with increased frequency and severity in diabetics. They can take many forms: 1.) Angular cheilitis: A classic complication of childhood diabetes, presents as a white curd- like material adherent to red, fissured oral commissures 2.) Median rhomboid glossitis 3.) Chronic paronychia: Involves the proximal nailfold; erythema, swelling, separation from the nail margin with nail dystrophy. Superinfection by bacterial organisms may occur 4.) Erosio interdigitale blastomycetica: Interdigital infection between the 3rd and 4th fingers or 4th and 5th toes 5.) Genital infections: Vulvovaginitis and candida intertrigo of the inframmamary region in women. In contrast, balanitis and phimosis in men are relatively less common • Treatment includes control of blood sugar and topical or systemic antifungals Bacterial Infections Diabetics are at greater risk for Group A and B streptococcal, staphylococcal infections,necrotizing fasciitis, malignant otitis externa (Pseudomonas aerugenosa), and erythrasma(Corynebacterium minutissimum). Fungal Infections • Dermatophyte infections do not occur with greater frequency in this population, but tinea pedis may serve as a portal of entry for superinfection and cellulitis • Rhinocerebral mucormycoses occurs in uncontrolled diabetics with ketosis. This condition involves the terbinates, septum, palate, maxillary and ethmoid sinuses. Symptoms include headache, fever, lethargy, nasal congestion and facial ocular pain, swelling, unilateral ptosis, and ophthalmoplegia. Treatment involves correction of ketosis, debridement, and intravenous antifungal agents. Mortality ranges from 15-34%Cutaneous Reactions to Diabetic Treatment • 1st generation sulfonylureas (chlorpropamide and tolbutamide)- Allergic reactions occur 5% of patients. The most common cutaneous reaction is a maculopapular eruption. Chlorpropamide causes a disulfiram-like reaction characterized by flushing, headache, tachycardia, and shortness of breath occurring after alcohol consumption • Insulin-allergic reactions occur in up to 50%. They are related to impurities, beef or pork proteins, preservatives or zinc additives. Systemic allergic reactions (generalized urticaria, angioedema, or anaphylaxis) are uncommon. Other reactions include lipoatrophy and lipohypertrophy10.7 CUTANEOUS MANIFESTATIONS OF CARDIAC DISEASEMarfan’s Syndrome • utosomal dominant disorder caused by mutations in Fibrillin 1, a major component of A intermediate fibrils found in skin, skeletal, ocular and cardiovascular system • haracterized by extensive striae distensae, abdominal wall hernias, elastosis perforans ser- C piginosa, and upward lens dislocation • Skeletal findings include: tall stature, a long head (dolicocephalic), long ears, hyperexten sible joints, pectus excavatum, arachnodactyly, kyphoscoloiosis, and flat feet • ardiac irregulaties include: aortic root aneurysms, rupture, and dissection. Mitral valve pro- C lapse (MVP) can also occur • Occasionally emphysema and pneumothorax can develop Cutaneous Manifestations of Systemic Disease  373
  22. 22. Homocystinuria • his condition is autosomal recessive inheritance in most uTIP T cases. Phenotype is related to elevated serum homocys- an contrast to Marfans, Homocystinuria I presents with arterial and venous teine and methionine levels due to a deficiency of cysta- thromboses, generalized osteoporosis, thionine beta synthase. Elevated homocysteine is thought and mental retardation. In addition, the to inhibit collagen cross-linking lens displacement in Homocystinuria is downward (whereas Marfan’s is • Treatment involves avoidance of methionine and upward) homocysteine. Supplementation with cysteine, pyridoxine, folate and vitamin B12 has produced variable resultsEhlers-Danlos Type IV, Vascular Type •  utosomal dominant disorder caused by mutations in COL3A1, which encodes procollagen A type 3. This collagen type is abundant in skin, lung and vasculature • Cutaneous features include: thin translucent skin, easy bruisability, thin nose, and thin upper lip • There is a predisposition to arterial, bowel and uterine rupture •  Joint mobility is normal, although there atlantoaxial subluxation can occurCutis Laxa (Generalized Elastolysis) • ype I: Disorder than can be inherited in an autosomal dominant or recessive manner. It T is caused by mutations in either elastin or fibulin 5. Mutations in fibulin 4 can lead to the recessive form. utaneous findings of Type I cutis laxa include loose wrinkled skin causing C “blood hound” facies, and large pendulous folds of the abdomen. Cardiac manifestations are mitral valve prolapse, aortic aneurysms, and car-diomegaly. Pulmonary emphysema, cor pulmonale and right sided heart failure are often noted in infancy. Other systemic features include: GI or GU diverticula, dental cavities, and osteoporosis • Type II or “Congenital Horn syndrome”: This condition was formerly categorized as type IX Ehlers Danlos. It is an X-linked recessive disorder caused by a defect in the copper binding transport ATPase, ATP7A. It is allelic to Menkes disease. eatures of Type II include mild F skin laxity, hooked nose, long philtrum, inverted nostrils, joint hypermobility, and low-pitched voice • Type III or Acquired Form: The generalized form is similar to Type I. It is associated with penicillamine, penicillin, complement deficiency, SLE, and amyloidosis. The localized form is preceeded by erythema multiforme, contact dermatitis, and Sweet’s syndrome • Costello syndrome is characterized by coarse facies, cardiomyopathy, growth retardation, and an outgoing personality. Patients are prone to abdominal rhabdomyosarcomas during childhood. Patients with de Barsy syndrome have mental and growth retardation, joint laxity, ocular defects and skeletal abnormalities • Other conditions with loose skin are Costello syndrome and de Barsy syndromeOsteogenesis Imperfecta (OI) • here are seven different forms of OI. All are associated with defects in type I collagen T • he predominant finding is brittle bones with a tendency toward fractures. There is also T joint laxity, blue sclerae, deafness, scoliosis and abnormal teeth • utaneous findings are thin translucent skin, easy bruising, and wide atrophic scars C • ardiac disease manifests as aortic regurgitation, mitral regurgitation, and large vessel fragility C • Treatment involved surgical stabilization of fractures as well as bisphosphonates and Vitamin D to improve bone density374  2011/2012 Dermatology In-Review l Committed to Your Future
  23. 23. • Mortality is related to impaired ventilation secondary to kyphoscoliosis • Brack syndrome = OI plus arthrogryposis multiplexWerner Syndrome (Adult Progeria) • utosomal recessive disorder caused by muta- uTIP A tions in WRN (Recql2) gene, which encodes a haracteristic features include premature aging, C balding, and graying. Other skin changes include: DNA helicase a sclerodermoid appearance, poikeloderma, leg • Most findings are manifestated by middle age ulcers, and painful callosities of the feet and ankles • There is growth arrest at puberty and cataracts by age 30 • remature cardiac atherosclerosis accounts for early death P • There is also a tendency toward type II DM, and tumors of the uterus, breast, liver and thyroidProgeria or Hutchinson-Guilford Syndrome • This is a rare autosomal dominant disorder caused by mutations in the LMNA gene which encodes lamin A and C • t is distinguished from adult progeria by its earlier onset and characteristic facies. Patients I have a large bald head, prominent scalp veins, and lack of eyebrows and eyelashes • Similar to adult progeria, premature death is related to cardiac diseaseNoonan’s Syndrome • utosomal dominant disorder that resembles Turners syndrome. Men and women are A equally affected. It is caused by mutations in the PTPN11 gene, which encodes a protein tyrosine phosphatase • Patients have a characteristic face with hypertelorism, prominent ears, webbed neck, short stature, and lost posterior hairline • Some have cutaneous manifestations such as: curly or woolly hair, lymphedema, elastic skin, multiple melanocytic nevi, keratosis pilaris atrophicans, dystrophic nails, abnormal fingerprints and a tendency toward keloids • Typical cardiac abnormalities include: hypertrophic cardiomyopathy, pulmonic valve stenosis, and septal defects • Cryptorchidism in boys MNEMONICLEOPARD Syndrome (Multiple Lentigines Syndrome) LEOPARD Syndrome • Autosomal dominant disorder caused by mutations in lassic Features are: C entigines L PTPN11 gene. Leopard syndrome is allelic to Noonan’s EKG changes (including AV block, syndrome arrhythmias, bundle branch block, ven- • Other findings include: Café-au-lait macules, melanoma, tricular hypertrophy) local hypopigmentation, triangular face, frontal bossing, Ocular hypertelorism Pulmonic stenosis low ears, joint hypermobility, scapula winging, and Abnormal genitals (hypoplasia, cryp pectus deformity torchidism) Retardation of growthCarney Complex includes LAMB and NAME Sydromes Deafness  • utosomal dominant disorder. Most cases are caused A by mutations in PRKAR1A gene. A variant form of Carney complex associated with distal arthrogryposis is associated with mutations in the MYH8 gene that encodes perinatal myosin • Multiple myxomas are the hallmark of this condition • arly diagnosis and removal of atrial myxoma can be life saving E Cutaneous Manifestations of Systemic Disease  375
  24. 24. Naxos Disease MNEMONIC • Autosomal recessive disorder caused by defects in LAMB plakoglobin Lentigines (face and mucoas) Atrial myxoma (complicated by CHF,  • It is characterized by non-transgradient palmoplantar angina, pulmonary edema, and embolic keratoderma and wooly hair in infancy events) • ardiac disease is manifested as arrhythmogenic right Mucocutaneous myxoma C ventricular cardiomyopathy (ARVC) and sudden car- Blue nevi (spares hand and feet)  diac death in puberty • Carvajal syndrome is similar to Naxos in that both MNEMONIC demonstrate palmoplantar keratoderma and wooly NAME hair. In contrast, the cardiomyopathy of Carvajal is left Nentigines (face and mucoas) sided. It is caused by autosomal recessive mutations in Atrial myxoma Myxoid neurofibromata desmoplakin Ephilides and Endocrine neoplasms (Cushing’s syndrome, testicular tumors,Conradi-Hunermann-Happle Syndrome growth-hormone secreting pituitary • A form of chondrodysplasia punctata which only tumors) affects girls. It is an X-linked dominant disorder caused by mutations in EBP gene encoding emopamil binding protein. The phenotype is related to impaired cholesterol synthesis • haracteristic features are congenital ichthyosiform erythroderma along blaschko’s lines C which resolves and is replaced by follicular atrophoderma • Cardiac anomalies include: ventricular septal defect and patent ductus arteriosus • Chondrodysplasia punctata (stippled epiphyses due to bony calcifications) can be appreci- ated with X-ray until the age of 4 • Asymmetric limb shortening and cataracts can occur Table 10-2. Paraneoplastic Diseases Diagnosis/Management/ Disease Clinical Manifestations Associated Malignancy Miscellaneous Hypertrichosis Abrupt onset of downy, May have an associated Rule out underlying causes Lanuginosa soft non-pigmented hair glossitis. Lung carcinoma of hypertrichosis, i.e., thy- Acquisita on face → trunk and rotoxicosis, corticosteroids, extremities phenytoin, and spirono- lactone. May resolve with treatment of underlying malignancy Acquired Ichthyosis Similar to autosomal Hodgkins lymphoma, Course parallels that of dominant form, with breast and lung carci- underlying malignancy involvement of exten- noma sors and sparing of flex- ural creases. Diagnosis is usually made after malignancy376  2011/2012 Dermatology In-Review l Committed to Your Future
  25. 25. Table 10-2. Paraneoplastic Diseases (cont.) Diagnosis/Management/Disease Clinical Manifestations Associated Malignancy MiscellaneousBazex Syndrome Erythematous/viola- Squamous cell carci- Skin disease follows course(Acrokeratosis ceous psoriasiform noma of larynx, orophar- of underlying malignancy.Paraneoplastica) dermatitis affecting ynx, esophagous and Age appropriate cancer ears, nose, hands and tongue screening in suspected feet. Nail dystrophy, and patients is recommended aquired keratoderma may be found. Skin find- ings usually preceed the underlying malignancyErythema Gyratum Men women. Lung carcinoma most Path: hyperkeratosis,Repens Concentric erythema- common. Also reported parakeratosis, hydropic tous rings with trail- in association with degeneration, and pigment ing scale on trunk and breast, cervical, bowel, incontinence. Symptoms proximal extremities. and bladder cancer improve with treatment of Skin described as having underlying malignancy a “wood grain appear- ance.” Intense pruritus. Skin findings precede the diagnosisMulticentric Non-tender reddish 20% of patients develop Pathology: nodular infiltrateReticulohistiocytosis brown nodular lesions malignancy, no predom- composed of multinucle- most commonly located inant type ated oncocytic giant cells on dorsal hands and nail with eosinophillic cyto- folds, also found in para- plasm displaying a ground nasal areas, ears, fore- glass appearance arms, cornea, and trunk. Mucosal lesions can also occur. Symmetric arthri- tis of interphalangeal, knee, elbow, vertebral and temporomandib­ular joints. Can progress to a mutilating form in 50% of patients. Weakness and weight loss also presentNecrolytic Migratory Erythema, vescicles, Alpha 2 glucagon pro- Path: necrosis of keratino­Erythema pustules and erosions in ducing islet cell pancre- cytes in granular layer,(Glucagonoma periorificial, acral flex- atic carcinoma acanthosis and parakera-Syndrome) ural distribution. Lesions totic scale. Elevated serum have a circinate pattern glucagon. CT to localize due to peripheral spread. tumor. Mainstay of man- Can also develop a glos- agement is surgical resec- sitis and chelitis. Adult tion of tumor. Somato­ tatin s onset diabetes, glucose and IV amino acids helpful intolerance, weight loss. in some cases 75% of cases are meta- static by time of diag- nosis Cutaneous Manifestations of Systemic Disease  377
  26. 26. Table 10-2. Paraneoplastic Diseases (cont.) Diagnosis/Management/ Disease Clinical Manifestations Associated Malignancy Miscellaneous Cushing’s Skin findings: hirsut- Glucorcorticoid excess Elevated urine cortisol lev- Syndrome ism, hyperpigmentation, due to underlying oat els. Corticortopin not sup- facial plethora, buffalo cell lung carcinoma pressed w/administration hump, striae, telangi- of dexamethasone ectasia and atrophy. Hypertension, kypokale- mia, hypoglycemia Carcinoid Facial flushing that Neoplasm originating in Test urine for elevated Syndrome spreads to neck and the endocrine argentaf- 5-hydroxyindole-acetic upper trunk, diarrhea, fin cells. 80-85% found acid (5-HIAA). Chest/ and intermittent bron- in the GI tract: appendix abdominal/pelvic CT. chospasm. Patients can g small bowel g rectum. Surgical removal of tumor. also develop telangi- Mediators involved in Medical treatment includes ectasia, pellagra-like or producing symptoms are somatostatin, methly- sclerodermoid-like erup- bradykinin, serotonin, his- sergide, cyproheptadine, tion. Symptoms develop tamine substance -P, and beta-blockers, and pheno- after liver metastases prostaglandins thiazine derivatives or if the primary tumor does not involve the GI tract Acanthosis Rapid onset of hyperpig- Most commonly seen Can improve with treat- nigricans mented velvety plaques with gastric carcinoma. ment of underlying involving the inter- Also seen with lung, malignancy triginous areas. Unusual breast, uterine, ovarian locations include dorsal carcinomas, lymphoma hands and lips. May be and mycosis fungoi- seen in association with des. May be result of tripe palms and florid increased growth hor- oral papillomatosis mone produced by the tumor Sweet’s Males=Females in cases Acute myelogenous leu- Anemia, leukocytosis, neu- Syndrome associated with underly- kemia = most common. trophilia, elevated ESR. (Febrile neutrophilic ing malignancy. Also lymphoma, polycy- Pathology: Prominent dermatosis) Tender erythematous themia vera edema in the superficial plaques that may devel- dermis, dermal infiltrate rich op pustules or vesicles in neutrophils with leukocy- distributed on face, neck, toclasis. Leukocytoclastic upper trunk, and vasculitis is absent. extremities. Treatment: prednisone, Accompanied by fever, SSKI, and management of possibly arthritis, con- Underlying malignancy junctivitis, episcleritis, and oral ulcers. +/– pul- monary infiltrates Cryoglobulinemia Type I cryoglobulins Multiple myeloma Elevated cryoglobulins (monoclonal IgM) Waldenstroms macro- Pathology: eosinophilic, Palpable purpura, globulinemia intravascular deposits Raynaud, livedo reticu- laris378  2011/2012 Dermatology In-Review l Committed to Your Future
  27. 27. Table 10-2. Paraneoplastic Diseases (cont.) Diagnosis/Management/Disease Clinical Manifestations Associated Malignancy MiscellaneousSign of Lesser- Trelat Rapid increase in size Gastric or colon May improve with treat- and/or number of seb- carcinoma ment of underlying malig- orrheic keratosis. Can nancy be seen in association with acanthosis nigri- cans and tripe palms. Appears before or after malignancy. Can have an associated generalized pruritusParaneoplastic Painful oral erosions/ sto- Non-Hodgkins Pathology: suprabasalPemphigus matitis. Polymorphous lymphoma acantholysis, dyskeratosis. skin eruption: with Chronic lymphocytic Vacuolar interface dermati- lichenoid lesions, ery- leukemia tis with lichenoid infiltrate. thema-multiforme-like Thymoma Direct immunofluoresence lesions or flaccid or Castleman’s tumor of perlesional skin demon- tense bullae. Sarcoma strates intercellular IgG Most patients die and granular C3 at the from complications of DEJ. Indirect immunofluo- underlying malignancy. rescence with rat bladder Bronchiolitis obliterans substrate shows intercel- also a reported com- lular IgG. plication and cause of Target antigens include death desmoplakin (250KD), envoplakin (210KD), BPAg- 1(230 KD), periplakin (190 KD), desmogleins 3 and 1. Treatment includes man- agement of underlying malignancy, prednisone or other immunosuppressive agentsDermatomyositis Proximal symmetrical Risk of malignancy Elevated muscle enzymes muscle weakness greater in patients older (CPK more specific than Periorbital edema w/ than 40. More likely to aldolase). heliotrope discoloration occur within first three Muscle biopsy with evi- Gottron’s papules/ years of diagnosis. dence of inflammation. Gottron’s sign. Women: ovarian and Abnormal EMG. Periungal telangiecta- breast carcinoma Thorough history and sia, cuticular dystrophy. Men: gastric carcinoma physical exam. Violaceous erythema in and lymphoma Age appropriate cancer shawl or photodistribu- screening. tion. Poikiloderma vascu- Treatment includes cor- lare atrophicans, hyper- ticorsteroids, methotrex- keratosis/ scale over ate, other steroid sparing palms and soles, and agents psoriasiform scalp der- matitis. Calcinosis cutis in pediatric patients Cutaneous Manifestations of Systemic Disease  379