Cutaneous Manifestations of Internal Disease and Metastases


Figure 10-1 (A) Trichodiscomas and (B) fibrofolliculomas and acrochordons in a patient with Birt-Hogg-Dubé. (With permission López V, Jordá E, Monteagudo C. Birt-Hogg-Dubé Syndrome: An Update. Actas Dermo-Sifiliográficas (English Edition) 2012;103(3):198–206)




Genetics



Folliculin (FLCN) gene mutation (involved in mTOR pathway)



Associations/comments



Fibrofolliculoma, trichodiscoma, perifollicular fibroma and acrochordons are identical lesions just viewed in different histologic planes


Important associated findings:


Pulmonary cysts (most common; up to 90%) lead to spontaneous pneumothorax (30%)


Multiple renal carcinomas (15%, most commonly chromophobe renal carcinoma and oncocytoma)


Medullary thyroid carcinoma


+/− colon cancer (inconclusive association)




Cardio-facio-cutaneous syndrome (CFC)


Cutaneous findings



Coarse facies (long and broad), generalized ichthyosis-like scaling, keratosis pilaris, CALMs, nevi, and sparse curly hair



Genetics



AD; one of the RASopathies; mutations in BRAF (most common) and other MAPK pathway genes



Associations/comments



A/w mental retardation, pulmonic stenosis, atrial septal defect, hypertrophic cardiomyopathy, and short stature


All RASopathies (CFC, NF1, Noonan, Costello syndromes, and LEOPARD) affect RAS/MAPK pathway and have similar clinical presentations → often need genetic tests to distinguish



Carney complex (LAMB and NAME syndromes)


Cutaneous findings



LAMB = Lentigines, Atrial (and cutaneous) Myxomas, Blue nevi (classically epithelioid blue nevi)


NAME = Nevi, Atrial (and cutaneous) Myxomas, Ephelides



Genetics



AD, mutations in PRKAR1A gene (encodes subunit of Protein Kinase A)



Associations/comments



A/w variety of endocrine neoplasms;


most commonly affected = adrenal gland; p/w primary pigmented nodular adrenocortical disease → Cushing’s


Other endocrine abnormalities: pituitary adenomas and testicular cancer (Sertoli type)


A/w psammomatous melanotic schwannoma



Carvajal Syndrome


Cutaneous findings



Striate epidermolytic palmoplantar keratoderma; wooly scalp hair



Genetics



AR, desmoplakin mutations



Associations/comments



A/w dilated left ventricular cardiomyopathy


Mnemonic: “CarvajaL = Linear/striate PPK + Left ventricular cardiomyopathy”



Churg-Strauss syndrome (allergic granulomatous angiitis)


Cutaneous findings



Skin involvement in 60%; LCV, urticaria, livedo reticularis, subcutaneous nodules, PNGD (palisaded neutrophilic granulomatous dermatitis), and extravascular granulomas



Associations/comments



Most commonly a/w allergic rhinitis, severe asthma, peripheral eosinophilia of ≥10%, sinusitis, transient pulmonary infiltrates, and mononeuritis multiplex


↑IgE levels


Most common causes of mortality: myocarditis and coronary arteritis


ANCAs detectable in 50%; p-ANCA (anti-MPO) ≫ c-ANCA (PR-3)


ANCAs less frequently positive compared with Wegener’s (50% vs ~100%)


May be a/w leukotriene inhibitors (montelukast and zafirlukast)



Costello syndrome


Cutaneous findings



Lax skin on hands and feet, coarse facies, low-set ears, deep palmoplantar creases, periorificial papillomas, acanthosis nigricans, and curly hair



Genetics



AD, one of the RASopathies; mutations in HRAS (85%) > KRAS (10%–15%)



Associations/comments



A/w mental and growth retardation, pulmonic stenosis, hypertrophic cardiomyopathy, and arrhythmias


↑risk of rhabdomyosarcoma and transitional cell (bladder) CA


All RASopathies (CFC, NF1, Noonan, Costello syndromes, and LEOPARD) have similar clinical presentations → need genetic tests to distinguish



Cutis laxa


Cutaneous findings



Loose, pendulous skin of face (esp. periocular and cheeks→ “bloodhound facies”), neck, axillae, and thighs; skin lacks elastic recoil (vs EDS)



Genetics



Multiple forms:


AR: most common and most severe; Fibulin-5 (FBLN5)


AD: benign course; Elastin (ELN) > FBLN5


XLR: ATP7A (copper transporter)



Associations/comments



Occipital horn syndrome is the current name for XLR cutis laxa, (which was also formerly called Ehlers-Danlos type IX); OHS a mild variant of Menkes kinky hair syndrome


AR cutis laxa is most frequently a/w internal organ dysfunction and death:


Pulmonary: bronchiectasis, emphysema → right-sided heart failure


Cardiac: aortic dilation/rupture; right-sided heart failure


GI: diverticulae



Dermatomyositis


Cutaneous findings



Gottron’s papules, heliotrope rash, shawl sign, holster sign, photodistributed poikiloderma, and psoriasiform dermatitis of scalp



Associations/comments



A/w ECG changes and pericarditis


Cardiac involvement = poor prognostic sign; a/w anti-SRP autoantibodies


Pulmonary fibrosis a/w antisynthetase syndrome (Jo-1, PL7, and PL-12; autoantibodies target tRNA synthetase)



Ehlers-Danlos syndrome (classic form)


Cutaneous findings



Skin hyperelasticity, “cigarette paper” and “fish mouth” scars, ecchymoses, Gorlin sign, and molluscoid pseudotumors



Genetics


See Table 4-13. Ehlers-Danlos Syndrome Classification in Pediatric Dermatology chapter



Associations/comments



A/w aortic root dilation, mitral and tricuspid prolapse or regurgitation


Identical cardiac findings may also be seen in hypermobility type of EDS (traditionally, EDS type III)



Ehlers-Danlos syndrome (vascular form; formerly type IV EDS)


Cutaneous findings



Thin, translucent skin w/ visible veins (most prominent on chest), diffuse bruising



Genetics



AD; caused by mutations in collagen III (COL3A1)



Associations/comments



Most dangerous form of EDS because of the risk of death from rupture of internal organs (arterial rupture > GI tract [esp. sigmoid colon], uterus [particularly in pregnancy])


Arterial rupture sites: thorax/abdomen > head/neck > extermities


Most important feature is vascular fragilityarterial aneurysms, dissection, and rupture (Mnemonic: “IV = vascular”)



Endocarditis


Cutaneous findings



Purpura, Janeway lesions (not painful; palms and soles), Osler’s nodes (painful; “Osler’s = Oww!”; fingers and toes) nail-fold infarction



Associations/comments



A/w cardiac vegetations and valvular dysfunction



Erythroderma


Cutaneous findings



Diffusely red skin, exfoliative dermatitis



Associations/comments



A/w high-output cardiac failure


May be as a result of multiple dermatoses, CTCL, or drug eruptions



Fabry disease


Cutaneous findings



Angiokeratoma corporis diffusum (angiokeratomas in “bathing suit distribution”), hypohidrosis, episodic pain in hands/feet (acroparesthesia), and whorled corneal opacities (cornea verticillata)



Genetics



XLR; GLA gene mutation → α-galactosidase deficiency



Associations/comments



Most serious complications: atherosclerotic disease of CV and CNS → MI and stroke; chronic proteinuria → renal failure


α-galactosidase deficiency leads to ↑globotriaosylceramide deposits in tissues → end organ damage


Maltese crosses” (birefringent lipid globules) seen on polarization of urine sediment



Hemochromatosis


Cutaneous findings



Generalized bronze hyperpigmentation



Genetics



HFE gene mutation



Associations/comments



A/w CHF (congestive heart failure), supraventricular arrhythmias, diabetes mellitus, and cirrhosis



Hereditary hemorrhagic telangiectasia (pulmonary disease in type I > type II)


Cutaneous findings



Multiple macular/“mat-like” telangiectasias most commonly on lips, oral mucosa, and extremities (Fig. 10-2)


image

Figure 10-2 Patient with HHT and multiple telangiectasias on tongue and lip. (With permission Irani F, Kasmani R. Hereditary hemorrhagic telangiectasia: fatigue and dyspnea. Can Med Assoc J 2009;180(8):839–839)


Genetics



AD, mutations in genes involved in TGF-β transduction pathway:


HHT1 = endoglin (ENG)


HHT2 = Alk-1 (ACVRL1)



Associations/comments



Epistaxis (often the initial symptom), AV malformations of lungs (HHT-1 most commonly), liver (HHT-2 most commonly) and CNS; recurrent upper GI hemorrhage


*Mnemonic: “Alk-1 is a/w liver” (think of Alkaline phosphatase, which is found in liver)



Homocystinuria


Cutaneous findings



Livedo reticularis, malar rash, tissue-paper scars, diffuse pigment dilution, Marfanoid habitus, and ectopia lentis (downward lens dislocation)



Genetics



AR; caused by a variety of mutations leading to ↑homocysteine levels in blood and urine; most common = cystathionine β-synthase (CBS gene)


Other gene mutations: MTHFR, MTR, MTRR, and MMADHC



Associations/comments



A/w atherosclerosis and vascular thrombosis (arterial + venous)


A/w mental retardation and seizures



Hyperlipoproteinemias


Cutaneous findings



Type I (familial LPL deficiency and hyperchylomicronemia): eruptive xanthomas


Type II (familial hypercholesterolemia): tendinous, tuberous, tuboeruptive, interdigital xanthomas (pathognomonic), and plane xanthomas


Type III (familial dysbetalipoproteinemia, “broad beta disease”): tendinous, tuberous, tuboeruptive xanthomas, and plane xanthomas of palmar creases (pathognomonic)


Type IV (endogenous hypertriglyceridemia): eruptive xanthomas


Type V: eruptive xanthomas



Genetics



Type I: LPL deficiency and ApoC-II deficiency


Type II: LDL receptor defect and ApoB-100 defect


Type III: ApoE abnormality (results in ↓hepatic clearance)


Type IV: ↑VLDL as a result of diabetes, alcoholism, and/or obesity


Type V: ↑chylomicrons and VLDL; as a result of diabetes



Associations/comments



Associated systemic findings:


Type I, type IV, and type V: acute pancreatitis (as a result of ↑TGs)


Type II and III: atherosclerosis → MI and stroke



Kawasaki disease


Cutaneous findings



Strawberry tongue,” cheilitis, polymorphous skin eruption (favors trunk), acral erythema/edema (w/ subsequent desquamation), conjunctival injection, and anterior uveitis



Associations/comments



A/w coronary artery aneurysms (potentially fatal)


High fever lasting ≥5 days, cervical lymphadenopathy, truncal rash, hand edema/desquamation, oral findings, and conjunctival injection are diagnostic features


Rx: high dose ASA and IVIG are essential to prevent coronary disease



LEOPARD syndrome


Cutaneous findings



Lentigines (upper half of body; appear in childhood), CALMs, ocular hypertelorism (widely spaced eyes), low-set ears



Genetics



AD; is one of the RASopathies; most common mutation is PTPN11 gene (90%)


Less common mutations in MAPK pathway (10%): BRAF and RAF1



Associations/comments



ECG abnormalities, Pulmonary stenosis, Abnormalities of genitalia (cryptorchidism #1, hypospadias), Retardation of growth, and Deafness


Hard to clinically distinguish from other RASopathies (CFC, NF1, Noonan, and Costello syndromes)



Lymphomatoid granulomatosis


Cutaneous findings



Dermal or SQ nodules +/− ulceration on trunk and extremities



Associations/comments



Frequently fatal (60% 5-year mortality), EBV-induced angiodestructive B-cell lymphoma


Classically p/w pulmonary + skin involvement



Marfan syndrome


Cutaneous findings



Striae, long and narrow face, ectopia lentis (upward lens dislocation), myopia, arachnodactyly, and pectus excavatum



Genetics



AD; gene mutation in Fibrillin-1



Associations/comments



A/w mitral valve prolapse and regurgitation, aortic root dilation, and dissection of ascending aorta


Rx: β-blockers and ACE inhibitors to prevent aortic root dilation



Neonatal lupus erythematosus (NLE)


Cutaneous findings



Nonscarring, nonatrophic SCLE-like annular plaques (most commonly periocular), and prominent telangiectasias



Associations/comments



NLE a/w congenital heart block in up to 30% of pts (often irreversible; up to 30% mortality)


Caused by transplacental passage of maternal anti-Ro/SSA antibodies (>anti-La/SSB > anti-U1RNP)


Mothers who have one child w/ NLE have 25% recurrence rate in subsequent pregnancies



PHACES syndrome


Cutaneous findings



Segmental infantile hemangioma (most commonly frontotemporal), typically on face and neck



Associations/comments



A/w coarctation of the aorta, atrial septal defect, and ventricular septal defect


P: posterior fossa malformations


H: hemangiomas


A: arterial anomalies


C: cardiac defects and coarctation of the aorta


E: eye anomalies


S: sternal defects and supraumbilical raphe



Naxos syndrome


Cutaneous findings



Diffuse nonepidermolytic palmoplantar keratoderma, wooly scalp hair



Genetics



AR, plakoglobin mutation



Associations/comments



A/w arrhythmic right ventricular cardiomyopathy



Neurofibromatosis Type 1 (NF-1)


Cutaneous findings



CALMs, axillary freckles (“Crowe’s sign”; seen in 30%; may involve neck and other intertriginous sites), multiple neurofibromas, and Lisch nodules (iris)



Genetics



AD; mutation in NF1 gene (neurofibromin)



Associations/comments



A/w HTN (essential HTN and 2° to pheochromocytoma)



Primary systemic amyloidosis (AL amyloidosis)


Cutaneous findings



Petechiae/pinch purpura most common skin finding; may also see shiny, translucent waxy papulonodules or plaques, alopecia, and macroglossia



Associations/comments



A/w restrictive cardiomyopathy, conduction abnormalities, and proteinuria


As a result of deposition of immunoglobulin light chains (AL) in skin and internal tissues; deposits stain pink-red w/ Congo red (apple-green birefringence on polarized light)


Primary systemic amyloidosis a/w skin findings in 30%; secondary systemic amyloidosis does NOT produce clinical skin changes



Progeria (Hutchinson-Gilford progeria)


Cutaneous findings



Sclerodermoid changes, characteristic facies (prominent eyes, thin beaked nose, protruding ears, and micrognathia), mottled hyperpigmentation, ↓SQ fat, and alopecia



Genetics



AD; mutations in lamin A (LMNA gene; component of nuclear lamina)



Associations/comments



Most important association: premature death as a result of atherosclerosis, MI, or stroke



Psoriasis


Associations/comments



↑risk of cardiovascular, cerebrovascular, and peripheral arterial diseases; ↑risk of metabolic syndrome



Relapsing polychondritis


Cutaneous findings



Intense erythema of cartilaginous portion of ears (spares earlobes) + inflammation of other cartilaginous tissues (nose and trachea)



Associations/comments



A/w tracheal and nasal collapse


A/w aortic insufficiency and dissecting aortic aneurysm



Rheumatic fever


Cutaneous findings



Erythema marginatum, subcutaneous nodules, polyarthritis, chorea, and fever



Associations/comments



Acute phase: pericarditis


Chronic: mitral and aortic valve disease



Sarcoidosis


Cutaneous findings



Red-brown papules, nodules, and plaques w/ “apple jelly” color on diascopy; may arise in preexisting scars; lupus pernio (strongly a/w lung disease), EN (a/w acute bilateral hilar adenopathy and arthritis of ankles = Lofgren syndrome)



Associations/comments



Pulmonary: pulmonary artery HTN and interstitial lung disease


Cardiac: pericarditis and conduction defects; cardiac involvement a/w poor prognosis



Systemic lupus erythematosus


Cutaneous findings



Transient malar erythema; photosensitivity +/− DLE and SCLE lesions


If antiphospholipid antibodies present: necrotizing livedo reticularis, widespread cutaneous necrosis, and leg ulcers



Associations/comments



A/w Libman-Sacks endocarditis (nonbacterial), pericarditis, and coronary artery disease



Wegener’s granulomatosis (granulomatosis with polyangiitis, GPA)


Cutaneous findings



Skin involvement in 50%; LCV, necrotizing cutaneous granulomas, pyoderma gangrenosum-like lesions (“malignant pyoderma”), friable ulcerative gingivae (strawberry gingivae), mucosal ulcerations, and “saddle nose”



Associations/comments



Severe (>90% mortality if untreated) multisystem necrotizing vasculitis


Most common systemic manifestations: respiratory tract (chronic sinusitis is most common presenting symptom of GPA); renal (segmental crescentic necrotizing glomerulonephritis)


c-ANCA (anti-Proteinase-3) autoantibodies in ~100% of pts by ELISA and IIF; detectable ANCAs more common in GPA than in Churg-Strauss (50%)



Yellow nail syndrome


Cutaneous findings



Thick, slow-growing, highly curved, and yellow or yellow-green nails w/ onycholysis; absent cuticles and lunulae



Associations/comments



Classic triad: yellow nails, lymphedema, and pulmonary disease (bronchiectasis and pleural effusions)




10.2 Endocrine


Diabetes



Bullous diabeticorum


Cutaneous findings



Tense, noninflammatory, painless bullae on upper and/or lower extremities (Fig. 10-3)


image

Figure 10-3 Bullous diabeticorum on the lower extremity. (From Bolognia JL, et al. Dermatology Essentials. Elsevier, 2014)


Associations/comments



Usually heals in 2 to 4 weeks


M > F


Treatment with supportive care



Benign acanthosis nigricans


Cutaneous findings



Velvety, brown, digitate plaques on neck and in axillary and inguinal folds



Associations/comments



Slow onset, usually manifests earlier in life


Can indicate insulin resistance and/or diabetes


More common in darkly pigmented individuals


Treatment includes improvement of insulin resistance, topical retinoids, ammonium lactate, and calcipotriene



Granuloma annulare


Cutaneous findings



Often affects trunks and extensor limbs, or may be generalized and eruptive; p/w nonscaly, flesh-colored, pink, violaceous, or reddish brown papules that can be grouped in an arcuate or annular pattern



Associations/comments



Usually asymptomatic and spontaneously resolves over months to years


DDx: NLD (favors lower legs), cutaneous sarcoidosis, lichen planus, and rheumatoid nodules


Rx: observation, topical steroids, intralesional steroids, cryotherapy, and phototherapy


May also be a/w hyperlipidemia



Carotenemia


Cutaneous findings



Diffuse orange-yellow discoloration



Associations/comments



Secondary to increase in serum carotene level



Neuropathic ulcers


Cutaneous findings



Ulcerations at pressure sites, commonly on sole of foot; painless


May 4, 2017 | Posted by in Dermatology | Comments Off on Cutaneous Manifestations of Internal Disease and Metastases
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