L-26 Cutaneous Manifestations of Systemic Disease

Cutaneous Manifestations of Systemic Disease

• Cutaneous manifestations of systemic disease are skin conditions that result from underlying systemic illnesses.

Acromegaly

• Acromegaly can cause hypertrophy (enlargement) of the face.
• This condition can lead to thickening of the skin.
• Cutis verticis gyrata is observed in 30% of acromegaly patients and causes folds and furrows that resemble the surface of the brain.

Addison Disease

• Addison disease can cause hyperpigmentation of mucous membranes, palmar creases, perineum, nipples, and nevi (moles).
• The disease results in adrenal insufficiency due to damage to the adrenal glands, which leads to a deficiency in cortisol and aldosterone production.

Rheumatoid Papules

• Rheumatoid papules manifest as multiple red-brown papules, sometimes with a scale crust, typically seen on the lower extremities.

Pseudoporphyria in Rheumatoid Arthritis

• Pseudoporphyria in rheumatoid arthritis can be caused by non-steroidal anti-inflammatory drugs.

Amyloidosis

• Systemic amyloidosis can be primary, involving AL amyloid, or associated with myeloma, also involving AL amyloid.
• Systemic amyloidosis can cause macroglossia (enlarged tongue), purpura, and carpal tunnel syndrome.
• Cutaneous amyloidosis can be primary, presenting as macular/lichenoid or nodular AL amyloid.
• Secondary cutaneous amyloidosis can manifest as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC).
• AL (primary systemic) amyloidosis can cause periorbital ecchymoses, known as 'raccoon sign'.
• One sign of AL Amyloidosis can be macroglossia with dental impressions on the tongue.
• Primary systemic amyloidosis results in waxy and translucent facial papules.
• Macular amyloidosis is associated with hyperpigmentation and a rippled pattern on the skin.
• Lichen amyloidosis is characterized by keratotic, hyperpigmented plaques, predominantly on the legs, that show individual keratotic papules upon close inspection.

Angiokeratomas

• Angiokeratomas are associated with Fabry's Disease, which results from a deficiency in alpha-galactosidase A.
• Fabry's Disease causes pain.
• Maltese cross formations and mulberry cells are seen.

Hepatitis C (HCV)

• Hepatitis C is associated with leukocytoclastic vasculitis (LCV).
• It is linked to Porphyria cutanea tarda (PCT), caused by a deficiency in uro decarboxylase.
• HCV can interfere with iron storage, leading to free iron radicals and oxidation, which exacerbates Uro decarboxylase deficiency.
• Lichen planus, especially erosive mucosal disease, is associated with HCV.
• Polyarteritis Nodosa(PAN) has a strong association with Hepatitis B Virus (HBV), and 12-31% of PAN patients are also HCV positive.

Porphyria Cutanea Tarda

• Porphyria cutanea tarda is characterized by yellow-brown morpheaform plaques.
• Plaques typically appear in sun-exposed areas, especially in individuals with a history of alcohol abuse.

Lichen Planus

• Lichen Planus (LP) on the hand's dorsal surface can present with Wickham's striae, identified by the flat-topped nature of the lesions.
• Oral Lichen Planus presents as a white, lacy pattern on the buccal mucosa, or as multiple erosions on the tongue.
• Lichen Planus can cause violaceous papules and plaques with white scales and Wickham's striae.
• Nail lichen planus can cause thinning of the nail plate with lateral loss and violaceous discoloration of the periungual area with pterygium formation.

Thyroid Disease

• A thyroglossal duct cyst presents as a midline, mobile anterior neck mass and represents the number one cystic abnormality of the neck. Also, thyroid follicles in the cyst wall are found on pathology.
• Thyroid cancer (CA), specifically medullary thyroid carcinoma (MEN) 2a and 2b/III and Cowden's Syndrome, leads to follicular type CA, duct cysts, adenomas, and goiter.
• Graves Disease results in infiltrative ophthalmopathy, goiter, and pretibial myxedema.
• Dermopathy (thyroid) manifests as increased hyaluronic acid in the dermis of the lower and upper extremities.

Renal Disease

• Renal disease can cause a yellowish hue to the skin from carotenoids and urochrome.
• Renal disease can cause Lindsay's nails, a condition with half-white and half-pink nail beds.
• Pruritus, especially uremic pruritus, is a common symptom.
• Renal disease is associated with perforating dermatoses.
• Calcification and calciphylaxis, which is associated with a mortality rate of 60-80%, can occur, and increased parathyroid hormone levels are related to calciphylaxis
• Nephrogenic Fibrosing Dermopathy (NFD) is characterized by woody, indurated papules and plaques.
• NFD can cause scleroderma-like fibrosing conditions with nodules and contractures that typically spares the palms, soles, and face.

Calciphylaxis

• Calciphylaxis is found with necrotic skin lesions and is linked to severe end-stage renal disease secondary to amyloidosis of the kidney.

Gastrointestinal Disease

• Pyoderma gangrenosum is a condition that presents with typical lesions in patients with inflammatory bowel disease.

Gastrointestinal Disease (Hereditary)

• Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu) is an autosomal dominant (AD) condition due to ENGL or ACVRLK1 gene mutations.
• A first sign is Epistaxis.
• Cutaneous telangiectasia on the face and acral surfaces can occur.
• GI bleeding is associated with increased risk.
• Liver, lung, and eye AVM can be seen.

Gastrointestinal Disease (Blue Rubber Bleb Syndrome)

• Blue Rubber Bleb Syndrome may be autosomal dominant or sporadic, linked to the VMCM1 gene.
• Cavernous hemangiomas are found in the skin.
• Those with Blue Rubber Bleb Syndrome get systemic hemangiomas.

Gastrointestinal Disease (Henoch-Schonlein Purpura/HSP)

• Henoch-Schonlein Purpura (HSP) primarily affects young adults and children, often following an upper respiratory infection (URI).
• HSP causes LCV on the lower extremities and buttocks.
• DIF: perivascular IgA, C3, and fibrin is present.

Gastrointestinal Disease (Gardner's Syndrome)

• Gardner's Syndrome is characterized as AD, APC gene.
• Gardner's Syndrome presents with epidermal cysts.
• It is associated with congenital hypertrophy of the retinal pigment (CHRPE).
• It leads to Adenomatous polyps that result in cancer in 100% of cases.
• The syndrome influences thyroid, liver, and CNS tumors.

Gastrointestinal Disease (Cronkhite-Canada Syndrome)

• Cronkhite-Canada Syndrome causes lentigines, alopecia, and nail disease.

Gastrointestinal Disease (Muir-Torre Syndrome)

• Muir-Torre Syndrome's is AD, caused by MSH2 or MLH1 (mismatch gene).
• Muir-Torre Syndrome's causes Sebaceous neoplasms and KA's.
• This syndrome influences colon polyps and cancer, as well as breast and NHL.

Gastrointestinal Disease (Cowden's Disease)

• Cowden's Disease autosomal dominant, caused by the PTEN gene.
• Cowden's Disease presents with tricholemmomas, sclerotic fibromas, oral papillomas, acral keratoses, and lipomas.
• Hamartomatous polyps span from the stomach to the anus.
• Thyroid, breast, and ovarian associations.

Gastrointestinal Disease (Bannayan-Riley-Ruvalcaba)

• Bannayan-Riley-Ruvalcaba is AD, due to the PTEN gene in some cases.
• Pigmented macules are located on the genitals.
• Bannayan-Riley-Ruvalcaba presents with lipomas, acanthosis nigricans, and skin tags.
• Hamartomatous polyps of the intestines.

Gastrointestinal Disease (Peutz-Jeghers)

• Peutz-Jeghers is autosomal dominant, attributed to the STK11 (serine threonine kinase) gene.
• Periorificial lentigines are present.
• Peutz-Jeghers presents with Hamartomatous intestinal polyps with an intussusception.
• It is linked to cancers of the pancreas, gallbladder, ovaries, and testicles.

Gastrointestinal Disease (Dermatitis Herpetiformis)

• Dermatitis Herpetiformis is related to duhring's Disease.
• Dermatitis Herpetiformis causes Gluten-sensitive enteropathy is 90% of patients
• Anti-gliadin antibody can be present.
• Dapsone does not help the associated bowel disease.
• Majority of DH patients have the HLA class II DQ2 genotype.

Gastrointestinal Disease (IBS)

• Irritable Bowel Sydrome (IBS) links Crohns with Ulcerative Colitis.
• Metastatic Crohn's Disease has non-contiguous granulomatous inflammation of the skin , often manifested by deep inflammatory fissures in the inguinal folds.

Gastrointestinal Disease (Peristomal pyoderma gangrenosum)

• Those with Peristomal pyoderma gangrenosum have a total colectomy for ulcerative colitis many years prior to the onset of ulcers.

Neurological Disease

• Neurofibromatosis includes NF-1 and NF-2, and is autosomal dominant for both types, from NF-1 or NF-2 genes.
• Neurofibromatosis type 1 (NF-1) symptoms includes CALMs, freckling, neuromas.
• Juvenile xanthogranuloma (JXG) increases chances of developing chronic myelogenous leukemia (CML) in NF-1.
• Schwannomas and other CNS manifestations are in NF-2 cases.

Neurological Disease (Ataxia-Telangiectasia)

• Ataxia-Telangiectasia is autosomal recessive, caused by the ATM gene.
• Ataxia-Telangiectasia causes telangiectasias, lymphoma, and leukemia.
• A symptom for those Ataxia-Telangiectasia is defects in humoral immunity.

Neurological Disease (Menkes Disease)

• Menkes Disease is X-linked recessive, caused by the ATP7A gene.
• Menkes Disease encodes copper-transporting ATPase.
• It causes lusterless hair, pili torti, and CNS defects.
• It's lethal in males.
• Menkes Disease has a low serum ceruloplasmin.
• Neurofibromatosis is marked by café-au-lait macules and axillary freckling, along with an oval-shaped light-brown patch present in the axilla containing multiple small lentigines (Crowe's sign).

Neurofibromatosis

• Neurofibromatosis includes cutaneous neurofibromas, which includes small, soft, skin-colored to pink polypoid neurofibromas and plexiform neurofibroma, it causes soft tissue swelling alongside hyperpigmentation.

Lisch Nodules

• Lisch nodules are also yellow brown papules in the iris.
• Menkes Disease prevents dietary copper from reaching the brain, skin, hair, and bones, resulting in deficiencies in these areas.

Diabetes

• Diabetes can cause Acanthosis Nigricans, particularly the HAIR-AN Syndrome.
• HAIR-AN Syndrome is the combination of HyperAndrogenism, Insulin Resistance, and Acanthosis Nigricans.
• Diabetes can affect thick skin.
• Diabetes can affect cause tight joints, known as "prayer sign".
• Scleredema and type II DM can cause “Peau d’Orange on upper back”.
• Necrobiosis Lipoidicum Diabeticorum (NLD) occurs in 20% of NLD patients with DM, or 0.3-3% of DM patients with NLD.
• Diabetic Dermopathy is the most common skin manifestation, presenting as skin hyperpigmentation typically on the tibia.
• Eruptive Xanthomas, is associated with increased levels of triglycerides.
• Diabetes can cause Granuloma Annulare.
• Acanthosis nigricans is acanthosis nigricans of the neck, usually caused by insulin resistance, obesity, and can cause velvety texture of the skin.
• Acanthosis nigricans can rarely indicate the sign of Leser-Trélat, found in patients with gastric carcinoma.

Bullous Diabeticorum & Necrobiosis

• Diabetes related complications include Bullous diabeticorum and Necrobiosis lipoidica.

Diabetic Dermopathy

• Diabetic Dermopathy presents typically as brown macules and patches on the shins.

Eruptive Xanthomas

• Eruptive Xanthomas are signs of poorly controlled diabetes mellitus.

Hemochromatosis

• Hemochromatosis presents as a diffuse hyperpigmentation (bronzing) of the skin.

Diabetic Neuropathy

• Diabetic Neuropathy, through neurotropic ulcers, causes ulcers on the toes of a patient with diabetic sensory neuropathy.

Hyperlipidemia

• Classic cutaneous lesions related to Hyperlipidemia feature eruptive Xanthomas, tendinous Xanthomas, palmar Xanthomas, and Xanthelasma.
• In patients with hypertriglyceridemia, xanthomas are features on the extensor surfaces of the lower extremities.

Eruptive Xanthomas

• Note the yellowish hue and 'mulberry' pattern.
• Tendinous xanthomas of the fingers are found in patients with homozygous familial hypercholesterolemia, with intertriginous plane xanthomas of the web spaces.
• Linear swelling of the Achilles area in a patient with dysbetalipoproteinemia.
• The plane xanthomas of the palmar creases manifests in patients with dysbetalipoprotenemia (arrows).
• Xanthelasma palpebrarum occurs with typical yellowish hue. Courtesy of Yale Residents Slide Collection.

Cardiac - Quick Hitters

• Marfan Syndrome can cause Aortic aneurysms and mitral valve prolapse (MVP).
• Ehlers-Danlos syndrome can cause Aortic rupture.
• Cutis Laxa can cause Aneurysms, mitral valve prolapse, and Cardiomegaly.
• Fabry's disease can cause Mitral Valve Prolapse, Congestive Heart Failure, HTN, and Myocardial Infarction.
• Homocystinuria can cause Atherosclerosis and Thrombosis.
• Progeria can cause Early Mycoardial Infarctions
• Cardiac issues affect on the integument can be noted with Leopard Syndrome (EKG changes), Carney's (Atrial Myxomas), and Naxos (Right Ventricular cardiomyopathy)

Paraneoplastic Dieases - Quick Hitters

• Basal cell-like acral keratoses (Bazex) cause SCC's of the head and neck.
• Erythema Gyratum Repens causes Lung CA as well as Breast CA.
• Necrolytic migratory erythema presents with Alpha-2 glucagon producing islet cell pancreatic CA.
• Cushing Syndrome is identified by oat Cell ca of lung.
• Carcinoid tumors show Endocrine argentaffin cells and is best found in the appendix (#1 site). Check the test for Urine 5-HIAA.
• Gastric CA accounts for acanthosis nigricans (#1).
• Leser-Trelat accounts for Gastric or Colon CA.
• Bazex syndrome is acrokeratosis paraneoplastica, which indicates oesophageal carcinoma and causes involvement of the distal nose.
• Erythema Gyratum Repens indicates a tumor affecting the breast
• Necrotizing migratory erythema manifests as a lesion in a patient with both Hepatitis C virus and HIV infections.
• Cushing's disease manifests as a 'Buffalo hump' caused by fat redistribution.

Paraneoplastic Pemphigus

• Paraneoplastic Pemphigus accounts for is NHL, CLL, Thymoma, Castleman's, and Sarcoma
• Dermatomyositis cases stem from Ovarian and breast CA in women in addition to Gastric and Lymphoma in men
• Sweet's Syndrome causes AML.
• Cryoglobulinemia indicates Multiple myeloma, Waldenstrom's macroglobulinemia.
• Howell-Evans causes Esophageal CA.
• Amyloidosis results from multiple myeloma and plasma cell.
• Erythroderma cases are also caused by Leukemia and Lymphoma.
• Sweet's Syndrome presents as acute febrile neutrophilic dermatosis, and manifests alongside acute myelogenous leukemia. It also includes a hemorrhagic component, secondary severe thrombocytopenia.

HIV

• Paget's disease of the breast includes a chronic, erythematous, scaly plaque surrounding the nipple.
• Chronic ulcerative herpes simplex viral infection appears in HIV-infected patients, and slow enlarging of ulcers shows mainly on the buttocks and perianal area.
• Eosinophilic folliculitis indicates associated pruritus, and follicular papules shows on the head and upper torso.
• Zidovudine-associated melanonychia presents as receiving receives longitudinal streaks, horizontal bands and diffuse hyperpigmentation
• HIV exacerbates and treats resistance to AIDS
• Kaposi's sarcoma manifests with red-violet papules on the palate.
• Oral herpes simplex and oral candidiasis come together in an otherwise healthy young man that proves to be HIV positive.

Other Cutaneous Manisfestations of Systemic Diseases

• Relapsing Polychondritis is the inflammation of the earlobes, which means it spares cartilage.
• Antiphospholipid syndrome triggers bland thromboses with cardiac valvular vegetations.

Sarcoidosis

• Periorificial and facial papules of sarcoidosis comes with granulomatous inflammation of the upper respiratory tract.

Tuberous Sclerosis

• Tuberous sclerosis can present with ash leaf macule(with tuberous symptoms), Shagreen patch on the lower back, or fibrous plaques on the face and confetti’ macules.
• Facial angiofibromas of tuberous sclerosis forms dome-shaped papules on the cheeks and nose in an adolescent (A) and an adult (B)..
• Fibromas of the toes are in a periungual location.
• Retinal hamartomas and Guttate leukoderma of tuberous sclerosis, are also tuberous.