Sec 24 Skin in Nutritional, Metabolic and Heritable Disease Pt 2 Flashcards
X-linked disease which is the second most prevalent lysosomal storage disorder, (after Gaucher disease) caused by the partial or complete deficiency of a lysosomal enzyme, α-galactosidase A
Fabry Disease
Cutaneous hallmark of Fabry disease present in 70% of males and 39% of females which are pinpoint to 4-mm diameter, dark-red to blue-black, macular, and papular lesions, which do not blanch on pressure
Angiokeratoma
Histopathology: Dilated, ectatic capillaries in the papillary dermis, a variably thinned epidermis centrally, with epidermal acanthosis at the edges of the lesion (colarette), and variable degrees of overlying focal compact orthohyperkeratosis
Angiokeratoma
The “pseudoacromegalic” facial features in Fabry disease (decreasing order)
periorbital fullness prominent ear lobes bushy eyebrows recessed forehead pronounced nasal angle generous nose/bulbous nasal tip prominent supraorbital ridges shallow midface full lips prominent nasal bridge broad alar base coarse features posteriorly rotated ears prognathism
Classical feature of Fabry disease and thought largely to be a consequence of autonomic neuropathy
Reduced sweating or hypohidrosis
A frequent complaint amongst Fabry disease patients of pain in the extremities in cold environments
Raynaud phenomenon
This occur in 80%–90% of Fabry disease patients typically occur in the first decade described as sensation as pain, feeling like pins and needles in hands and feet, often radiating proximally, triggered by increased body temperature, exercise, or stress due to damage to nerve fibers as a result of inflammation and substrate accumulation.
Acroparesthesia
Most common ocular finding in Fabry disease characterized as opacities in the cornea characterized by one or more lines radiating from the near the center of the cornea
Cornea verticillata
Constant feature and increasingly recognized as the major cause of death in Fabry patients both male and female
Cardiac manifestations
Often reported as the presenting feature of Fabry disease
Stroke affecting the posterior circulation
Definitive Diagnosis for Fabry disease
Demonstration of deficient α-galactosidase A activity in plasma, serum, or leukocytes
Identification of a pathogenic mutation
X-linked disease starts at age of 5–12 years occuring in both males > females, presents with multiple, clustered dark-red to blue– black macules and papules Larger lesions warty (1–4 mm) affecting any part of the body, especially bathing trunk area, umbilicus, lips and can be associated with acroparesthesias, heart and renal failure, stroke, cornea verticillata, deafness
Fabry disease (Angiokeratoma corpus diffusum)
AD disease starts at age of 10–15 years, occuring in both, female > males, presents with grouped, warty, dark-red papules (1–5 mm) on the lateral aspect and dorsa of fingers and toes, hands, and feet associated with acrocyanosis and chilblains
Angiokeratoma of Mibelli
Acquired disease in >60 year old males presenting with multiple warty, blue–black papules (1–4 mm) on the scrotum associated with local venous hypertension
Angiokeratoma of Fordyce
Acquired disease in >60 female presents with grouped, warty, blue–black papules (1–4 mm) on the vulva associated with local venous hypertension
Angiokeratoma of Vulva
Acquired seen in 10–40 males and females presents with single dark-red to black keratotic papules (2–10 mm) which often bleeds or thromboses seen on any part of the body, especially in lower extremities
Solitary angiokeratoma
Acquired usually early onset or at birth presents with unilateral plaque keratotic dark-red papules, may bleed
on the lower legs or foot may be associated with Cobb syndrome or vascular malformations
Angiokeratoma circumscriptum
Typical symptoms of Fabry disease at childhood and adolescence (≤16 years)
Pain (acroparesthesia) particularly in the extremities
Angiokeratomas
Ophthalmological abnormalities (cornea verticillata and tortuous retinal blood vessels)
Hearing impairment
Dyshidrosis (hypohidrosis and hyperhidrosis)
Hypersensitivity to heat and cold
Gastrointestinal disturbances and abdominal pain
Lethargy and tiredness
Onset of renal and cardiac signs, e.g., proteinuria, arrhythmia
Typical symptoms of Fabry disease at early adulthood (17–30 years)
Extension of childhood symptoms
Proteinuria and progressive renal failure
Typical symptoms of Fabry disease at late adulthood (age >30 years)
Worsening of any childhood to early adulthood symptoms
Heart disease (e.g., left ventricular hypertrophy, angina, arrhythmia, and dyspnea)
Stroke and transient ischemic attacks
Osteopenia and osteoporosis
Disease with deficiency in β-Galactosidase with mutation on gene 3p21– 3pter presents with facial dysmorphism, hematologic signs, mental retardation, organomegaly and AK corporis diffusum
EM findings: Electron-lucent lysosomal dilation
GM1 gangliosidosis
Disease with deficiency in Aspartylglycosaminidase with mutation on gene 4q32–33 presents with coarse facies, macroglossia, organomegaly, ocular findings, cardiac valve involvement, AK corporis diffusum, facial angiofibromas, oral fibromatosis and leukokeratosis
EM findings: Electron-lucent lysosomal dilation
Aspartylglucosaminuria
Disease with deficiency in α-Fucosidase with mutation on gene 1p34 presents with mental retardation, coarse facies, growth retardation, recurrent respiratory infections, dysostosis multiplex, visceromegaly, AK corporis diffusum, widespread telangiectasias, acrocyanosis, purple transverse distal nail bands, increased vasculature in hands and feet, and sweating abnormalities
EM findings: Electron-lucent lysosomal dilation
Fucosidosis
Disease with deficiency in β-Mannosidase with mutation on gene 4q22-q25 presents with mental retardation, neuropathy, hearing loss, recurrent infections and AK corporis diffusum in bathing trunk area
EM findings: Electron-lucent lysosomal dilation
β-Mannosidosis
Disease with deficiency in Neuraminidase with mutation on gene 6p21.3 presents with mental retardation, dysostosis multiplex, vacuolated lymphocytes, subtle coarse facial features and AK corporis diffusum
EM findings: Electron-lucent lysosomal dilation
Sialidosis II
Disease with deficiency in β-Galactosidase and neuraminidase with mutation on gene 20q13.1 presents with dwarfism, gargoyle facies, mental retardation, seizures, corneal clouding, dysostosis multiplex, hearing loss and AK corporis diffusum scattered along entire body, especially knees, elbows, and bathing trunk area
EM findings: Electron-lucent lysosomal dilation
Galactosialidosis
Disease with deficiency in α-N-acetylgalactosaminidase (α-Nacetylgalactosaminidase) with mutation on gene 22q11 presents with mental retardation, coarse facial features, ocular signs, hearing loss, neuropathy, AK corporis diffusum of entire body (more dense on the bathing trunk area, axillae, breasts) and telangiectasias on lips and oral mucosa
EM findings: Electron-lucent lysosomal dilation
Kanzaki
Treatment: Angiokeratomas (Fabry disease)
Liquid nitrogen Electrocoagulation Surgical excision Laser (pulsed-dye 585-nm, neodymium YAG 1,064 nm, combined pulsed-dye and Nd:YAG) Intense pulsed light (IPL)
Treatment: Lymphedema (Fabry disease)
Manual lymphatic drainage massage and compression
Treatment: Hyperhidrosis (Fabry disease)
Aluminium chloride hexahydrate
Electrophoresis
Botulinum toxin
Glycopyrrolate sodium
Treatment: Raynaud Phenomenon (Fabry disease)
Avoid smoking Cold and vasoconstrictor therapies Losartan Diltiazem Fluoxetine Sildenafil
Treatment: Pain (Fabry disease)
Avoid triggers
Carbamazepine
Gabapentin
Treatment: Stroke (Fabry disease)
Antiplatelet
Anticoagulant
Treatment: Gastrointestinal (Fabry disease)
Pancrelipase
Metoclopramide
Treatment: Cardiovascular (Fabry disease)
Antihypertensive drugs Antiarrhythmic drugs Artificial pacemakers Implantable defibrillators Coronary bypass
Treatment: Chronic Renal Failure (Fabry disease)
Angiotensin converting enzyme inhibitors
Hemodialysis
Allograft transplant
Treatment: Specific in Fabry disease
Enzyme replacement
α-Galactosidase B (Fabrazyme)
α-galactosidase A (Replagal)
Regulates major functions in the epidermal keratinocytes including proliferation, differentiation, and cell-cell adhesion
Calcium
Three regulatory hormones that control the ionic calcium concentration in serum
- parathyroid hormone (PTH)
- calcitonin
- 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)
Primary stimulant for calcitonin secretion
Calcium
Increases renal tubular reabsorption of calcium and increases renal clearance of phosphate; imulates osteoclastic bone resorption, possibly by stimulating osteoblasts to release factors that activate osteoclasts
Parathyroid hormone
Increases the concentration of plasma calcium with primary action to stimulate the active transport of calcium across the intestine; also plays a major role in the growth and differentiation of tissues
Vitamin D3
Deposition of insoluble calcium salts in the skin
Calcinosis cutis
Most common type of calcinosis cutis and occurs as a result of local tissue injury; frequently occurs in connective tissue diseases
Dystrophic calcification
Precipitation of calcium salts in normal tissue secondary to an underlying defect in calcium and/or phosphate metabolism
Metastatic calcification
Occurs without identifiable underlying tissue abnormalities, abnormal calcium, and/or phosphate metabolism
Idiopathic calcification
Nodules and plaques of calcium deposits occur in the skin, subcutaneous tissue, muscle, or tendons most commonly occur on the upper extremities, especially on the fingers and wrists, but may occur in any area subject to trauma or motion
Dystrophic calcification
Lobular panniculitis that commonly demonstrates dystrophic calcification that occurs in patients with pancreatitis or pancreatic adenocarcinoma and caused by the action of liberated pancreatic enzymes on subcutaneous fat
Pancreatic enzyme panniculitis
Presents with erythematous, well-defined nodules and plaques occur during the first few weeks of life over the cheeks, back, buttocks, and extremities that usually clear spontaneously affecting infants that are generally otherwise healthy
Subcutaneous fat necrosis of the newborn
Subcutaneous calcified nodules and are thought to represent calcified ischemic fat lobules
Spheroids
Most common cutaneous neoplasm that manifest calcification (in 75%) and ossification (15-20%)
Pilomatricoma
Neoplasms that are associated with calcification and ossification
Pilar cyst Basal cell carcinoma Intradermal nevi Desmoplastic malignant melanoma Atypical fibroxanthoma Pyogenic granuloma Hemangioma Neurilemmoma Trichoepithelioma Seborrheic keratoses.
Most commonly occurs in chronic renal failure and takes the form of either benign nodular calcification or calciphylaxis
Metastatic calcification
Life-threatening disorder characterized by progressive vascular calcification, soft tissue necrosis, and ischemic necrosis of the skin which presents as firm, extremely painful, well-demarcated, violaceous plaques associated with soft tissue necrosis and ulceration
Calciphylaxis
Histopathology: medial calcification of small and medium-sized arteries with intimal hyperplasia, primarily in dermal and subcutaneous tissues
Calciphylaxis
Due to chronic ingestion of vitamin D in supraphysiologic doses (50,000–100,000 units/day) with initial signs and symptoms include weakness, lethargy, headache, nausea, and polyuria attributable to hypercalcemia and hypercalciuria
Hypervitaminosis D
Characterized by excessive ingestion of calcium-containing foods or antacids, leading to hypercalcemia
Milk–alkali syndrome
Disorder characterized by the deposition of calcific masses around major joints, such as hips, shoulders, elbows, and knees
Tumoral calcinosis
Familial type of Tumor calcinosis is caused by what mutation
Inactivating mutations in either the GALNT3 or FGF23 genes
Treatment of choice: calcification of the scrotum
Excision (of the lesions)
Three well-described ossifying syndromes
- Fibrodysplasia ossificans progressiva (FOP)
- Albright hereditary osteodystrophy (AHO)
- Progressive osseous heteroplasia (POH)
AD syndrome characterized by the progressive ossication of deep connective tissue presents with abnormal phalanges of the hands, deafness, baldness, and mental retardation
Fibrodysplasia ossificans progressiva (FOP)
Bone morphogenic protein type I receptor and its mutation leads to overactive BMP signaling, leading to ectopic bone formation
ACVR1 or ALK2
Characteristic feature of FOP
Dysmorphic great toes
Negative regulator of bone formation, have been identified in both AHO and POH
G protein of adenyl cyclase (GNAS1)
AD inherited syndrome characterized by the ossification of cutaneous and subcutaneous tissues in childhood which follows a limited course presents with brachydactyly dimpling over the metacarpophalangeal joints (Albright’s sign), obesity, round or moon facies, short stature, and mental retardation; have a deficient end-organ response to PTH or “pseudohypoparathyroidism” with hypocalcemia, hyperphosphatemia, and elevated levels of PTH
Albright hereditary osteodystrophy (AHO)
Characterized by progressive ossification
of skin and deep tissues during infancy or childhood in females presenting with a papular eruption resembling “rice grains” and having a “gritty” consistency; no associated dysmorphic features
Progressive osseous heteroplasia (POH)
Most commonly occurs as multiple small, firm nodules on the faces of young women with a history of acne vulgaris.
Miliary osteoma cutis of the face
Tuberous Sclerosis is caused by mutations in
Tumor suppressor gene -
TSC1 - chromosome 9q34 encoding hamartin
TSC2 (more severe) - chromosome 16p13.3 encoding tuberin
Drug that inhibits mTOR and may be useful for the treatment of internal tumors in Tuberous Sclerosis
Rapamycin
Definite Tuberous Sclerosis
Presence of either 2 major features or 1 major feature and 2 minor features
Probable Tuberous Sclerosis
Presence of 1 major feature and 1 minor feature
Possible Tuberous Sclerosis
Presence of either 1 major feature or 2 or more minor features
Major features of Tuberous Sclerosis Complex
Facial angiofibromas or forehead plaque
Nontraumatic ungual or periungual fibromas Hypomelanotic macules (three or more)
Shagreen patch (connective tissue nevus)
Multiple retinal nodular hamartomas Cortical tubera Subependymal nodule Subependymal giant cell astrocytomas Cardiac rhabdomyoma, single or multiple Lymphangiomyomatosis Renal angiomyolipomas
Minor features of Tuberous Sclerosis Complex
Multiple randomly distributed pits in dental enamel
Gingival fibromas
Confetti skin lesions
Hamartomatous rectal polyps Bone cysts Cerebral white matter migration lines Nonrenal hamartoma Retinal achromic patch Multiple renal cysts
Observed in over 90% of children often present at birth or appear within the first few years of life and may fade or disappear in adulthood which typically measure 0.5–3.0 cm in diameter, off-white and not completely depigmented as in vitiligo
Hypomelanotic macules
Hypomelanotic macules that are oval at one end and taper to a point at the other that can be located anywhere on the body but tend to occur most often on the trunk and buttocks
Ash-leaf spots
Appear at 2–5 years of age and eventually affect 75-90% of patients may number from 1 to over 100, 1–3 mm in diameter pink to red papules with smooth surface which may be hyperpigmented usually unilateral occur on the central face and are often concentrated in the alar grooves extending symmetrically onto the cheeks and to the nose, nasal opening, and chin, with relative sparing of the upper lip and lateral face
Angiofibroma
May be congenital or show gradual development over years present in 20-40% of patients which an irregular, soft to firm, connective tissue nevus may be skin-colored, red or hyperpimented found on the scalp, cheeks or elsewhere on the face
Fibrous facial plaque
1-10cm firm or rubbery irregular plaque observed in 50% of patients which may be present in infancy but usually becomes apparent later, may be skin-colored, or slightly pink or brown most commonly located on the lower back and buttocks found less commonly on the thighs
Shagreen patch
1mm to 1cm red papules and nodules that are firm, pointed, and hyperkeratotic, or soft and rounded that appear after the first decade and eventually affect up to 88% of adults, more common on the toes than on fingers arise from under the proximal nail fold and under the nail plate
Koenen’s tumors or Ungual fibroma
Multiple skin colored or hyperpigmented fibroepithelial polyps in Tuberous Sclerosis patients
Molluscum fibrosum pendulum
Patches of multiple minute papules, usually on the neck or trunk that appear like “goose flesh” in Tuberous Sclerosis patients
Miliary fibromas
Benign thickening of the proximal fingers in Tuberous Sclerosis patients
Pachydermodactyly
Tiny pinpoint lesions or larger crater-like lesions observed in 100% of Tuberous Sclerosis patients that occur on both deciduous and permanent teeth
Dental pitting
Classic triad of Tuberous Sclerosis
Seizures
Mental retardation
Angiofibromas
Occur in 6-14% of individuals with Tuberous Sclerosis. which may increase intracranial pressure and cause headache, vomiting, and bilateral papilledema
Subependymal giant cell astrocytomas
Asymptomatic neoplasms that often regress seen in 50-70% of infants with Tuberous Sclerosis, may cause fetal hydrops and stillbirth or heart failure shortly after birth, or may cause dysrhythmias, commonly Wolff-Parkinson-White syndrome
Cardiac rhabdomyomas
Seen in 75% of Tuberous Sclerosis patients over 10 years of age which may cause cause renal insufficiency, hypertension, and potentially fatal retroperitoneal hemorrhage
Angiomyolipomas
Histopathology: Contain plump, spindle-shaped, or stellate broblastic cells in the dermis among increased numbers of dilated vessels. Collagen fibers are oriented in an onionskin pattern around follicles and vessels. The epidermis shows melanocytic hyperplasia and flattening of rete ridges.
Angiofibroma
Initial evaluation of a patient suspected to have Tuberous Sclerosis includes
- Cranial computed tomography (CT) or cranial magnetic resonance imaging (MRI)
- Renal ultrasonography (or MRI or CT)
- Electrocardiography
Group of inherited disorders that share in common developmental defects involving at least two of the major structures classically held to derive from the embryonic ectoderm—hair, teeth, nails, and sweat glands
Ectodermal dysplasias
Defective gene - protein:
X-linked Hypohidrotic Ectodermal Dysplasia
EDA, EDA1, HED - ectodysplasin
at Xq12-13.8
Most frequent signs in X-linked Hypohidrotic Ectodermal Dysplasia
Patchy hypotrichosis
Hypodontia
Affected males may present at birth with a collodion membrane or with marked scaling of the skin, scalp hair sparse, fine, and blonde and other body hair is usually sparse or absent; ability to sweat is compromised with heat intolerance; sweat pores undetectable and fingerprint ridges effaced; periorbital wrinkling and hyperpigmentation are typical
X-linked Hypohidrotic Ectodermal Dysplasia
Early clue to the diagnosis of X-linked Hypohidrotic Ectodermal Dysplasia
Hypoplastic gum ridges
Defective gene:
Hidrotic Ectodermal Dysplasia
GJB6 or connexin-30
AD with variable expression equally affecting males and females presents with wiry, brittle and pale scalp hair with patchy alopecia progressing to total alopecia in adults;
nails may be milky white in infancy gradually thickening and becoming dystrophic with thick, short and slow growing nail plates; normal sweating and teeth conjunctivitis and blepharitis, possibly due to poor function of sparse eyelashes, are common.
Hidrotic Ectodermal Dysplasia
Histopathology: thickened palms and soles show orthohyperkeratosis with a normal granular layer
Electron microscopy: increased number of desmosomes in the stratum corneum
Hidrotic Ectodermal Dysplasia
Defective gene:
Ankyloblepharon Filiforme Adnatum-Ectodermal Dysplasia-Cleft Palate Syndrome (Hay-Wells Syndrome)
Rapp-Hodgkin syndrome
p63 tumor-suppressor gene