Sec 24 Skin in Nutritional, Metabolic and Heritable Disease Pt 1 Flashcards by Charlene DPA

Clinical features of Marasmus

Affects infants <1 year
Failure to thrive
Dry, thin, loose, wrinkled skin
Hair loss; fine brittle hair; alopecia 
Fissuring and impaired growth of nails 
Loss of subcutaneous fat and muscle mass 
Loss of buccal fat (monkey facies)
Rectal prolapse, abdominal distension
Diarrhea, constipation
Angular cheilitis

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Clinical features of Kwashiokor

Affects children between 6 months and 5 years
Failure to thrive, edema
Irritability, lethargy, apathy
Generalized dermatitis - “flaking enamel paint,” “cracked pavement”
Increased pigmentation on arms and legs
Hair color changes (red tint → gray–white; “flag sign”)
Distension of abdomen

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Skin manifestations of Essential Fatty Acid Deficiency

Xerosis 
Scaly erythema, intertriginous erosions 
Traumatic purpura, poor wound healing 
Brittle nails, alopecia 
Hyper- and hypopigmentation of hair

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Ocular manifestations of Vitamin A deficiency

Impaired dark adaption Xerophthalmia
Corneal xerosis, ulceration, keratomalacia
Corneal perforation, blindness

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Mucocutaneous manifestations of Vitamin A deficiency

Xerosis
Dermatomalacia (skin fissuring)
Phrynoderma

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Mucosal manifestations of Vitamin A deficiency

Xerostomia
Hypotonia
Hypogeusia

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Manifestations of Vitamin A toxicity

Dry, scaly skin with desquamation
Peeling of palms and soles, follicular hyperkeratosis
Cheilitis, fissuring of lips and angles of mouth
Alopecia
Anorexia, nausea, vomiting
Myalgias, arthralgias
Blurred vision, pseudotumor cerebri
Skeletal changes: premature closure of the epiphyses, spontaneous bone fractures

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Rickets

Rachitic rosary
Craniotabes, frontal bossing 
Lateral bowing of lower extremities 
Widening of wrists, scoliosis, fractures 
Dental defects 
Rarely hypocalcemic seizures

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Chromosome 12q14
Mutations in Vitamin D receptor
End-organ unresponsiveness to Vitamin D
Atrichia with papilla and milia + eyebrows/eyelashes
Alopecia by 1-3 months of age

Vitamin D-resistant Rickets Type I

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Chromosome 8p12
Mutations in human hairless gene
Defect in Cartagena remodeling
Atrichia with papules and milia; + eyebrows/eyelashes
Alopecia by 40 days to 4 months

Generalized atrichia

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Acute signs of Riboflavin deficiency

Erythema
Epidermal necrolysis
Mucositis

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Chronic signs of Riboflavin deficiency

Ariboflavinosis

Angular stomatitis
Cheilosis with erythema, xerosis, and fissuring
Glossitis
Seborrheic dermatitis-like dermatitis (typical sites and flexural areas of limbs and genitalia)
Dyssebacia (plugging of sebaceous glands)
Photophobia and conjunctivitis

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Skin manifestations of Scurvy

Follicular keratotic plugging 
Corkscrew hairs 
Perifollicular purpura 
Lower extremity edema with ecchymosis 
Poor wound healing and dehiscence

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Mucosal manifestations of Scurvy

Swelling, ecchymoses, and bleeding of gingiva

Hemorrhagic gingivitis, necrosis, loss of teeth

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Cutaneous findings in Iron deficiency

Nails: Fragile, longitudinally ridged
Lamellated brittle nails → thinning, flattening of nail plate, koilonychia
Hair: Lusterless, dry, focally narrow and split hair shafts, heterochromia of black hair. Hair loss.
Mucous membranes: Aphthous stomatitis, angular stomatitis, glossodynia, atrophied tongue papillae
Blue sclerae
Pruritus

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Clinical features of Acrodermatitis Enteropathica

Eczematous and erosive dermatitis (periorificial and acral areas)
Alopecia
Diarrhea
Lethargy, irritability
Whining and crying
Superinfection with Candida albicans and Staphylococcus aureus

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Clinical presentation of Noma

Rapid progression of soreness of mouth, halitosis, purulent oral discharge, tenderness of lips and cheeks
Necrotizing stomatitis starting at alveolar margin and extending to mucosal surface of cheek Swelling and blue–black discoloration of cheek → cone-shaped black necrosis, tissue destruction, and ulceration

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Key finding in PEM which appear first as wasting then stunting

Failure to thrive

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Poor weight gain

Wasting

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Decreased rates of linear growth

Stunting

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Earliest manifestation of Vitamin A deficiency

Ocular changes

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Alternate bands of light- and dark-colored within the hair shaft

Flag sign

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Indicator of protein energy wasting

Elevated soluble CD14

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Derivative of linoleic converted into prostaglandins, eicosanoids, and leukotrienes

Arachidonic acid

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Two most clinically important metabolites of Vitamin A

1. Retinal | 2. Retinoic acid

White patches on the sclera from corneal keratin desquamation and overgrowth

Bitot spots

Severe deficiency in VAD manifesting as deep skin fissuring

Dermomalacia

Water-soluble form of Vitamin A that is not absorbed or hydrolyzed to retinoic acid in Vitamin A replete humans

Retinoyl glucoronide

Recommended daily allowance of Vitamin A

1,000-5,000 IU

Recommended treatment for VAD

100,000-300,000 IU

Acute Vitamin A toxicity

20x RDA - child | 100x RDA - adult

Chronic Vitamin A toxicity

>25,000 IU for more than 6 years | >100,000 IU for more than 6 months of preformed

Early cutaneous sign of Vitamin A toxicity

Dryness of the lips

Benign disorder characterized by yellow-orange skin pigmentation

Carotenemia

Carotene deposits here because of high lipid content

Stratum corneum

Carotenemia

3-4x normal levels or >250 ug/dL

Essential for regulation of calcium and phosphorus metabolism by acting on the GI tract to increase calcium and phosphate absorption, by stimulating bone resorption of calcium and phosphate, and by stimulating renal tubules to increase reabsorption of calcium and phosphate

Vitamin D

Vitamin important in retinal photoreceptor function, epithelial proliferation, and keratinization

Vitamin A

Vitamin D can be synthesized in the epidermis from this precursor

7-dehydrocholesterol

Autosomal recessive defect in renal vitamin D-1-a-hydroxylase treated with supplements of 1,25-hydroxyvitamin D

Type I Rickets

Rare autosomal recessive end-organ resistance to physiologic levels of 1,25-hydroxyvitamin D treated with supplementation of high doses of 1,25-hydroxyvitamin D

Type II Rickets

Fraying and widening of the metaphysis in the costochondral junctions of the anterior ribs seen in Vitamin D deficients

Rachitic rosary

Poor calcification of the skull bones giving a ping-pong ball feel seen in Vitamin D deficients

Craniotabes

Early radiographic signs of rickets

Widening of the epiphyseal plate | Blurring of the epiphyseal and metaphyseal junction

Potentially fatal manifestation of vitamin D deficiency

Dilated cardiomyopathy

RDA of Vitamin D

5-10 ug

Treatment for Vitamin D deficiency

200-400 ug daily for 2-3 months

Fat-soluble vitamin that excessive intake may augment effects of anti-coagulant medications

Vitamin E

Rare autosomal recessive severe spinocerebellar neurodegenerative disorder with mutations in a-tocopherol transfer

Ataxia with isolated Vitamin E

Necessary cofactor in the carboxylation of glutamate residues on coagulation factors II, VII, IX, X and proteins C and S

Vitamin K

Vitamin K deficiency in neonates leading to impaired coagulation and hemorrhage

Hemorrhagic Disease of the Newborn (HDN)

Unexpected bleeding from severe Vitamin K deficiency in 2-12 week old infants who are primarily breastfed and receive no or inadequate Vitamin K prophylaxis

Late HDN

Lab findings in Vitamin K deficiency

Increased PT | Increased aPTT

Abnormal "protein induced by vitamin K absence" (PIVKA)

des-g-carboxyprothrombin (DCP)

Neonatal prophylaxis of Vitamin K

0.5-1.0 mg

Acute treatment for Vitamin K deficiency

Fresh frozen plasma | 5-10mg Vitamin K Parenteral or IM

``` Vitamin B1 Vitamin B2 Vitamin B3 Vitamin B6 Vitamin B9 Vitamin B12 ```

``` Thiamine Riboflavin Niacin Pyridoxine Folate Cobalamin ```

Essential co-enzyme in: 1. NADPH synthesis 2. Carbohydrate metabolism 3. Deoxyribose and ribose synthesis

Vitamin B1 1. NADPH synthesis - transketolase 2. Carbohydrate metabolism - pyruvate dehydrogenase 3. Deoxyribose and ribose synthesis - a-ketoglutarate dehydrogenase

Thiamine deficiency state arising in chronic alcoholism

Beriberi

Early signs of Beriberi

Irritability, apathy, restlessness, vomiting

Classic manifestation of infantile beriberi

aphonia - laryngeal nerve paralysis

Symmetric distal peripheral neuropathy involving both sensory and motor systems

Dry beriberi

Neuropathy and signs of cardiac involvement (cardiomegaly, cardiomyopathy, congestive heart failure, peripheral edema, tachycardia), rarely pulmonary hypertension, peripheral edema and painful burning tongue

Wet beriberi

Diagnosis of thiamine deficiency

Erythrocyte thiamine transketolase | Blood thiamine transketolase

Thiamine RDA

0.5 mg per 1,000 kcal

Used in oxidation-reductions in cellular respiration and oxidative phosphorylation

Riboflavin as 2 coenzymes: 1. Flavin mononucleotide 2. Flavin-adenine dinucleotide

Diagnosis for Riboflavin

Screening: Erythrocyte glutathione reducatase activity Confirm: Trial of riboflavin supplementation

RDA Riboflavin

0.6 mg per 1,000 kcal

Treatment for Riboflavin deficiency

1-3 mg (infants and children) | 10-20 mg (adults)

Vitamin cofactor that can be obtained for the diet or synthesized endogenously from tryptophan

Niacin Exists as: 1. Nicotinamide adenine dinucleotide (NAD) 2. Nicotinamide adenine dinucleotide phosphate (NADP) to Nicotinamide to Nicotinic acid

Deficiency in niacin

Pellagra

Rare autosomal recessive disorder with pellagra-like symptoms in childhood caused by defect in neutral brush border system resulting in malabsorption of amino acids

Hartnup disease

Metabolic disorder where 60% of tryptophan is converted to serotonin

Carcinoid syndrome

Medications that can induce pellagra symptoms

``` Isoniazid 5-Fluorouracil 6-mercaptopurine phenytoin chloramphenicol azathioprine sulfonamides antidepressants ```

Pellagra 4D

1. Dermatitis - painful erythematous pruritic patches in photodistributed areas 2. Diarrhea 3. Dementia 4. Death

Diagnosis of pellagra

Measurement of urinary metabolites 1. N-methynicotinamide 2. Pyridone

Treatment of pellagra

500 mg per day

RDA of Vitamin B3

15-20mg niacin | 60 mg tryptophan

Most common form of Vitamin B6

Pyridoxal-5-phosphate

Medications causing Pyridoxine deficiency

Isoniazid Hydralazine Penicillamine OCP

RDA Vitamin B6

2mg adult males 1. 6mg adult females 0. 3mg infants

Treatment of pyridoxine deficiency

100mg pyridoxine per day

Medications implicated in folate deficiency

``` Methotrexate Trimethoprim OCP Pyrimethamine Phenobarbital Phenytoin ```

Treatment of folate deficiency

1-5mg folic acid

Important coenzyme for 1. DNA protein and lipid metabolism and 2. fat and carbohydrate metabolism

Cobalamin 1. methycobalamin 2. 5'-adenosylcobalamin

Deficiency in Vitamin B12 from malabsorption

1. Decreased gastric acid states leaving more b12 food-bound 2. Decreased intrinsic factor 3. Microbial competition in the gut 4. Impaired absorption

Atrophic red and painful tongue with atrophy of the filiform papillae

Hunter's glossitis

Hyperpigmentation in Vitamin B12 most commonly affects

palmar creases flexural regions pressure points

Cobalamin deficiency diagnosis

Measure serum cobalamin levels | <200 pg/mL

Treatnment of Cobalamin deficiency

1mg per week for 1 month cyanocobalamin then 1mg every month

Antioxidant and essential cofactor in several biological reactions (collagen biosynthesis, prostaglandin metabolism, fatty acid transport, norepinephrine synthesis)

Vitamin C

Vitamin C deficiency

Scurvy

Scurvy 4H

1. Hemorrhagic signs 2. Hyperkeratosis of hair follicles 3. Hypochodriasis 4. Hematologic abnormalities

Radiograph: metaphyseal spurs with marginal fractures

Pelkan sign

Radiograph: a ring of increased density surrounding the epiphysis

Wimberger sign

Radiograph: widening of the zone of provisional calcification

White line of Frankl

Radiograph: transverse band of radiolucency in the metaphysis

Scurvy line or Trummerfeld zone

RDA Vitamin C

40-60mg

Therapeutic dose of Vitamin C

100-300mg

Biotin as coenzyme

1. acetyl-CoA carboxylase - FA synthesis and lipogenesis 2. pyruvate carboxylase - gluconeogenesis 3. propionyl-CoA carboxylase 4. 3-methylcrotonyl-CoA carboxylase

Associated with defect in holocarboxylase synthetase with symptoms developing during first 6 weeks of life presenting with bright red scaling dermatosis on scalp, eyebrows, and eyelashes typically fatal

Neonatal (early onset) form Multiple carboxylase deficiency

Presents after 3 months of age caused by biotidinase deficiency with scaly erythematous perioroficial dermatitis may have irreversible sensorineural hearing loss and reversible metabolic encephalopathy

Juvenile (infantile or late onset) form Multiple carboxylase deficiency

RDA Biotin

``` 30 ug (neonates) 100-200 ug (adults) ```

Treatment Biotin deficiency

150 ug acquired 10-40 mg holocarboxylase deficiency 5-10 mg biotinidase deficiency

X-linked syndrome of neurologic disorder (loss of developmental milestones, hypotonia, seizures), failure to thrive, steel wool appearance of hair, depressed nasal bridge, ptosis and reduced facial movements

Menkes disease - MNK gene

Selenium deficiency associated with multifocal myocarditis leading to fatal cardiomyopathy seen in women and young children

Keshan disease

Selenium deficiency associated with osteoarthropathy that affects the epiphyseal and articular cartilage and epiphyseal growth plates, resulting in enlarged joints and shortened fingers and toes

Kaschin-Beck disease

Used in several biological pathways including heme synthesis, oxidation-reduction reactions and collagen synthesis

Iron

Important micronutrient that is an essential component of many metalloenzymes important in protein and nucleic acid synthesis

Zinc

Rare autosomal recessive disorder of zinc absorption with defect in intestinal zinc transporter human ZIP4 protein encoded on SLC39A4 gene

Acrodermatitis Enteropathica

Treatment zinc deficiency

0.5-1.0 mg/kg children | 15-30 mg adults

AR presents with characteristic psoriasiform dermatitis on trunk and extremities with diffuse alopecia and brittle hair associated with poor feeding, lethargy, hypotonia, vomiting and dehydration

Acrodermatitis acidemica

Semiessential AA derived from phenylalanine starting point for synthesis of cathecholamines, thyroid hormones, and melanogenesis

Tyrosine

Rare AR distinctive clinical symptom complex involving the eyes (lead to permanent visual impairment), skin (hyperkeratotic yellowish skin on pressure-bearing areas which are painful non pruritic) and CNS (mental retardation)

Tyrosinemia type II | Richner-Hanhart syndrome

Ophthalmologic features of Tyrosinemia type II

early - tearing, redness, pain and photophobia | late - corneal clouding and central or paracentral opacities

Urinary tyrosine metabolites

p-hydroxyphenylpyruvic acid p-hydroxyphenyllactic acid p-hydroxyphenylacetic acid N-acetyltyrosine

AR disorder of aromatic AA metabolism caused by deficiency of phenylalanine hydroxylase presents with mental retardation, diffuse hypopigmentation, seizures, eczematous dermatitis and photosensitivity

Phenylketonuria

Disease - deficient enzyme: Ochronosis Dark urine (when pH is above 7) Black cerumen, eccrine, and apocrine secretions Scleral pigmentation (triangular) Xray: marked intervertebral disk calcification

Alkaptonuria - Homogentisic acid oxidase (AR)

``` Disease - deficient enzyme: Trichorrhexis nodosa Rough skin Hepatomegaly Mental retardation ```

Argininosuccinic aciduria - Argininosuccinase (AR)

``` Disease - deficient enzyme: Thick skin Coarsening of face Sagging skinfolds Increased acne Photosensitivity ```

Aspartylglycosaminuria - Aspartylglycosamidase (AR)

``` Disease - deficient enzyme: Erythematous rash Alopecia Oral candidiasis Seborrheic dermatitis Glossitis ```

Biotinidase deficiency - Biotinidase (AR)

Disease - deficient enzyme: Light, short hair with interrupted cuticle Somatic and metal retardation Ammonia intolerance

Citrullinemia - Argininosuccinate synthetase (AR)

Disease - deficient enzyme: Pellagra-like lesions Photosensitivity

Hartnup Disease - Defect of neutral amino acid transport in renal and intestinal brush border (AR); increases excretion of tryptophan metabolites

Disease - deficient enzyme: | Light-colored hair and eyes

Histidinemia - Histidase (AR)

Disease - deficient enzyme: Seborrheic dermatitis Alopecia

Holocarboxylase synthetase deficiency - Holocarboxylase synthetase (AR)

``` Disease - deficient enzyme: Fine, sparse, friable hair Thin skin Livedo reticularis Malar flush Vascular occlusions Marfanoid habitus ```

Homocystinuria - Cystathionine B-synthetase (AR)

Disease - deficient enzyme: Chronic stomatitis Ulcerated gums, gingivitis Photosensitivity

Hydroxykynureninuria - Kynureninase (AR)

Disease - deficient enzyme: | Ichthyosis

Hyperprolinemia - Proline oxidase (AR)

Disease - deficient enzyme: Chronic skin ulcers Recurrent infections

Iminodipeptiduria (prolidase deficiency) - Prolidase (AR)

Disease - deficient enzyme: | Odor of sweaty feet, alopecia

Isovaleric acidemia - Isovaleryl-coenzyme A dehydrogenase (AR)

Disease - deficient enzyme: White hair Dried celery or oasthouse odor Edema

Methionine malabsorption syndrome - Defective methionine transport

Disease - deficient enzyme: Hypopigmentation Atopic dermatitis Scleroderma

Phenylketonuria - Phenylalanine hydroxylase (AR) Dihydropterine reductase Defective dihydropterine synthesis

Disease - deficient enzyme: Painful, acral erosions Hyperkeratosis Corneal/conjunctival plaques and erosions

Tyrosinemia II - Tyrosine aminotransferase (AR)

Disease - deficient enzyme: | Urticaria

Xanthurenic aciduria - Kynureninase (AD)

Caused by extra cellular deposition of insoluble abnormal fibrils derived from aggregation of misfolded proteins

Amyloidosis

Most common type of systemic amyloidosis more than 60% of cases, and may occur in association with any monoclonal B cell dyscrasia may present with macroglossal and periorbital ecchymoses

AL amyloidosis

Derived from monoclonal immunoglobulin light chains and consist of the whole or part of the VL domain

AL fibrils

An apolipoprotein of HDL which like CRP is synthesized by hepatocytes under the transcriptional regulation of cytokines

Serum amyloid A protein

Most common cause of hereditary amyloidosis causes FAP thus presenting with progressive severe peripheral and/or autonomic neuropathy sometimes with cardiac involvement

Transthyretin TTR systemic amyloidosis

Potential complication of any disorder associated with a sustained acute phase response can be inflammatory (95%), infective or neoplastic disorder with nephrotic syndrome in 50% of cases

AA amyloidosis

Systemic amylodosis with cutaneous findings of petechiae and purpura on eyelids, beard area and upper chest, xanthomatous papules or plaques and amyloidotic hyperpigmented keratotic lesions

AL amyloidosis

Hereditary amyloidosis with petechial eruptions

Lysozyme amyloidosis

Hereditary amyloidosis with yellowish infiltrated plaques and acanthosis nigricans-type lesions

Apolipoprotein AI amyloidosis

Usually affects upper back and limbs which can persist for many years with pruritic small brownish macules distributed in a rippled pattern with female preponderance

Macular amyloidosis

Histopathology: Macular amyloidosis

Amyloid deposits confined to the papillary dermis later coalescing expand the papillae and displace the rete ridges laterally

Most common type of cutaneous amyloidosis in Chinese individuals characterized by intensely pruritic eruption of multiple discrete hyperkeratotic paules that coalesce to form gray-brown plaques distributed on the extensor surfaces of the lower extremities spreading to the extensor aspects of arms and trunk

Lichen amyloidosis

Rare syndrome in Japanese and Chinese males in which pigmented macules and glossy hyperkeratotic lesions raduate out from anus

Anosacral cutaneous amyloidosis

A rare complication of long-term insulin use in diabetics at sites of repeated insulin injection

Insulin-derived amyloidosis

Very rare AD disorder characterized by chronic pruritus from childhood or early teenage years and hyperkeratotic papules and/or hyperpigmented macules on limbs or trunk associated with mutations in OSMR and IL31RA

Familial primary localized cutaneous amyloidosis

Observed when tissue stained with aniline dye Congo red is viewed under cross-polarized light in amyloidosis

Red-green dichroism

T or F: Immunohistochemistry is definitive for AL amyloidosis

False | Immunohistochemistry is definitive for AA amyloidosis

This safe noninvasive method can be used for diagnosis and quantitative monitoring of amyloid deposits

SAP scintigraphy

Presenting feature and ultimate cause of death in AL amyloidosis

Restrictive cardiomyopathy

Hereditary amyloidosis with characteristic clinical picture of corneal lattice dystrophy and cranial neuropathy

Gelsolin-related amyloidosis

Treatment of choice to prevent AA amyloidosis in FMF

Colchicine

Periarticular and, occasionally, systemic amyloidosis associated with long-term dialysis

Aβ2M Amyloidosis | β2-microglobulin

Senile systemic amyloidosis with prominent cardiac involvement

ATTR Amyloidosis | Normal plasma transthyretin

Autosomal dominant systemic amyloidosis Familial amyloid polyneuropathy

ATTR Amyloidosis | Genetically variant transthyretin

Hereditary cerebral hemorrhage with cerebral and systemic amyloidosis

ACys | Genetically variant cystatin C

Systemic amyloidosis with predominant renal involvement

ALECT2 | Leukocyte cell-derived chemotaxin-2 Systemic amyloidosis with predominant renal involvement (LECT2)

Autosomal dominant systemic amyloidosis | Non-neuropathic with prominent liver and renal involvement

ALys | Genetically variant lysozyme

Autosomal dominant systemic amyloidosis | May be neuropathic, prominent liver and renal involvement

AApoAI | Genetically variant apolipoprotein AI

Autosomal dominant systemic amyloidosis Non-neuropathic with prominent renal involvement

``` AApoAII Genetically variant apolipoprotein AII or AFib Genetically variant fibrinogen A α chain ```

IL-1-mediated Monogenic Autoinflammatory Syndromes

Familial Cold Autoinflammatory syndrome (FCAS) Muckle–Wells syndrome (MWS) Neonatal-onset Multisystem Inflammatory Disease (NOMID) Deficiency of the IL-1-receptor Antagonist (DIRA)

Partially IL-1-mediated Monogenic Autoinflammatory Syndromes

Familial Mediterranean Fever (FMF) Hyperimmunoglobulin D syndrome (HIDS) Mevalonic aciduria (MA) Pyogenic Arthritis, Pyoderma gangrenosum, and Acne syndrome (PAPA)

Other Monogenic Autoinflammatory Syndromes

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) Pediatric granulomatous arthritis (PGA) Majeed’s syndrome Early-onset in ammatory bowel disease (IBD)

Cryopyrinopathies

1. Familial Cold Autoinflammatory syndrome (FCAS) 2. Muckle–Wells syndrome (MWS) 3. Neonatal-onset Multisystem Inflammatory Disease (NOMID)

Cryopyrinopathies are autosomal dominant disorders with gain of function mutations in

NLRP3/CIAS1

Cryopyrin and adaptor proteins form this multimolecular complex that activates caspase-1, an ezyme that cleaves pro-IL-1B into IL-1 fragment

NLRP3 inflammasome

Presents with fever, urticaria-like eruption that is nonpruritic, conjunctivitis, arthralgia and elevations in acute-phase reactants

Cryopyrinopathies

CAP with episodes are triggered by exposure to cold temperatures or air drafts and present with fevers, eruption, joint pain, conjunctivitis and headaches that lasts for 12-48 hours then resolve which starts in early childhood

Familial Cold Autoinflammatory syndrome (FCAS)

CAP with urticaria-like eruptions at birth or within hours of birth can have fevers, eruption, joint pain, conjunctivitis and headaches that are continuous and not precipitated by cold exposure; may have episcleritis, optic disc edema or sensorineural hearing loss

Muckle–Wells syndrome (MWS)

CAP with urticaria-like eruptions at birth or within hours of birth with initial presentation of fevers, urticaria-like eruption, leukocytosis, elevated acute phase reactants, joint swelling, arthralgia, conjunctivitis and sensorineural hearing loss; may have CNS inflammation with aseptic leptomeningitis and neutrophilic pleocytosis

Neonatal-onset Multisystem Inflammatory Disease (NOMID)

Most commonly involved in characteristic bony overgrowth in patients with NOMID

Epiphyses of distal femur and proximal tibia of knee

Histopathology: Epidermis is unaffected with mild edema of papillary dermis and the superficial dermal capillaries are dilated; predominantly neutrophilic inflammatory infiltrate (neutrophilic urticaria)

Cryopyrinopathies (CAPS)

Treatment: Cryopyrinopathies

IL-1 blocking agents

Complications: Muckle–Wells syndrome (MWS)

Hearing loss | Development of amyloidosis

Complications: Neonatal-onset Multisystem Inflammatory Disease (NOMID)

``` Early onset hearing loss Mental retardation Progressive vision loss due to progressive optic nerve atrophy Central atrophy Severe bony overgrowth Joint contractures ```

Recombinant IL-1 receptor antagonist

Anakinra FCAS: 0.5-1.5 mg/kg/day NOMID: 6-10 mg/kg/day

Long acting IL-1 Trap - a fusion of the IL-1 receptor and the Fc portion of IgG (FDA approved for FCAS and MWS)

Rilonacept

IL-1B-blocking antibody | FDA approved for FCAS and MWS

Canakinumab

Does not respond to IL-blocking agents

Bony overgrowth

AR disease caused by mutations in gene MEFV encoding pyrin

Familial Mediterranean Fever (FMF)

Most common monogenic autoinflammatory disease

Familial Mediterranean Fever (FMF)

Presents with 1-3 day episodes of fever with serositis, which typically consists of sterile peritonitis, pleuritis, arthritis that can last upto 1 week and eruption that can be induced by physical exertion and emotional stress

Familial Mediterranean Fever (FMF)

Second most common clinical finding in FMF

Abdominal pain

Most characteristic eruption of FMF but rarely present in isolation usually in the lower limbs as warm, tender, swollen erythematous plaques 10-15 cm in diameter with well-defined borders which may be bilateral initiated by prolong walking and subside within 24-48 hours

Erysipeloid erythema

Histopathology: Perivascular and interstitial inflammatory infiltrate composed of neutrophils and lymphocytes in dermis with prominent edema of the papillary dermis and dilation of superficial dermal capillaries

Familial Mediterranean Fever (FMF)

AR disorders caused by mutations in MVK gene which encodes mevalonate kinase, an enzyme involved in the cholesterol and isoprenoid biosynthesis pathyway

``` Hyperimmunoglobulin D syndrome (HIDS) Mevalonic aciduria (MA) ```

Two missense mutations in HIDS

V377I | I268T

Enzyme that catalyzes the first step in mevalonate metabolism, rate-limiting step in conversion from mevalonate to mevalonate phosphate and can be examined in patient's fibroblasts, lymphocytes and lymphoblasts

Mevalonate kinase

Presents with erythematous macules, papules and nodules which may be confluent or solitary and oral aphthous ulcers with fever, gastrointestinal symptoms like abdominal pain, vomiting and diarrhea (90%), articular symptoms (80%), painful axillary and/or inguinal lymphadenopathy (90%) and splenomegaly

Hyperimmunoglobulin D syndrome (HIDS)

Presents with erythematous macules, papules and nodules which may be confluent or solitary and oral aphthous ulcers with febrile episodes, systemic inflammation, severe failure to thrive, lymphadenopathy, developmental delay, anemia, hepatosplenomegaly, central cataracts, dysmorphic facies, cerebellar ataxia, diarrhea and malabsorption

Mevalonic aciduria (MA)

Histopathology: Perivascular neutrophilic and lymphocytic infiltrate with slight leukocytoclasis and fibrinoid changes of vessel walls

``` Hyperimmunoglobulin D syndrome (HIDS) Mevalonic aciduria (MA) ```

Immunoflourescence of HIDS/MA

Perivascular deposits of IgD and Ce in granular pattern

Definitive diagnosis for HIDS

Genetic testing

T or F: Colchicine is effective for HIDS/MA

False

Rare AD disorder caused by mutation in CD2BP1 on chromosome 15q24 that encodes proline-serine-threonine-phosphatase-interacting protein 1 (PSTPIP1)

Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome

AD disease caused by mutations in TNFRSF1A on chromosome 12p13 that encodes TNF receptor 1 resulting from loss of cysteine residue

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Presents with fever 38-41 C for more than 3 days, disabling myalgia, abdominal pain, skin eruption, serositis, non erosive asymmetric monoarticular arthritis and eye involvement (conjunctivitis, periorbital edema)

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Characteristic skin lesions in TRAPS

Centrifugal migratory erythematous patch which migrates from periphery to the center

Histopathology: Mild perivascular lymphocytic infiltrate in dermis and edema of upper dermis with C3 and C4 deposition around small vessels in dermis

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

Most severe complications of TRAPS

Systemic AA amyloidosis | Development of renal failure

Treatment: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)

NSAIDs - mild attacks Etanercept Anakinra

Very rare AD with mutation in gene NOD2 on chromosome 16q12 encoding NACHT-leucine-rich repeat receptors presenting with early-onset "sarcoidosis" with generalized skin eruption and arthritis and uveitis

Pediatric Granulomatous Arthritis Familial - Blau syndrome Sporadic - de novo mutations in early sarcoidosis

Very rare AR with mutation in LPIN2 on chromosome 18p encoding lipin-2 with neutrophilic dermatosis; with chronic recurrent multifocal osteomyelitis and congenital dyserythropoeitic anemia

Majeed syndrome

Treatment for chronic recurrent multifocal osteomyelitis in Majeed syndrome

NSAIDs or corticosteroids

Treatment for congenital dyserythropoeitic anemia in Majeed syndrome

RBC transfusion

Very rare AR with mutation in IL10RA on chromosome 11q23 encoding IL-10 receptor presenting with early onset folliculitis, enterocutaneous fistulae, perianal abscess and anocutaneous fistula

Early-onset inflammatory bowel disease (IBD)

Plaques or nodules consisting of abnormal lipid deposition and foam cells in skin or tendons

Xanthomas

Multiple, reddish-yellow papules that appear suddenly and are arranged in crops on the extensor surface of the extremities and the buttocks

Eruptive xanthomata

Nodules that are frequently localized to the extensor surfaces of the elbows, knees, knuckles, and buttocks

Tuberous xanthomata

Firm subcutaneous nodules found in fascia, ligaments, Achilles tendons, or extensor tendons of the hands, knees, and elbows

Tendinous xanthomata

Yellow macules, soft papules, or plaques found commonly on the upper eyelids (xanthelasma palpebrarum), the wrists and palms (xanthoma striatum palmare), and in intertriginous areas

Planar xanthomata

Treatment options for xanthelasma

Surgical excision Ablative laser therapy Trichloroacetic acid Cryotherapy

Macrophages that contain lipid

Foam cells

Most abundant sterol in the body

Cholesterol

Cholesterol is a precursor for

Bile acids - cholic acid and chenodeoxycholic acid | Steroid hormones - estrogen, testosterone and cortisol

Eruptive xanthomata

``` Familial lipoprotein lipase deficiency ApoC-II deficiency ApoA-I and apoA-I/C-III deficiency Familial hypertriglyceridemia Familial hypertriglyceridemia with chylomicronemia Obesity Cholestasis Diabetes Medications: retinoids, estrogen therapy, protease inhibitors ```

Tuberous xanthomata

``` Familial hypercholesterolemia Familial dysbetalipoproteinemia Phytosterolemia Monoclonal gammopathies Multiple myeloma Leukemia ```

Tendinous xanthomata

``` Familial hypercholesterolemia Familial defective apoB Familial dysbetalipoproteinemia Phytosterolemia Cerebrotendinous xanthomatosis ```

Palmar xanthomata

Familial dysbetalipoproteinemia | Homozygous apoA-I deficiency

Intertriginous xanthomata

Familial homozygous hypercholesterolemia | Cholestasis

Diffuse planar xanthomata

Familial hypercholesterolemia

Xanthelasma

Familial dysbetalipoproteinemia | Monoclonal gammopathies

Corneal arcus

Familial hypercholesterolemia

Plant sterols

B-sitosterol | Campesterol

Most effective treatment for Phytosterolemia because it is a specific inhibitor of NPC1L1

Ezetimibe

LDL levels in Familial Hypercholesterolemia

Heterozygotes - 300 mg/dl | Homozygotes - 600 mg/dl

Optimal therapy in Homozygotic Familial Hypercholesterolemia

LDL apheresis Ezetimibe High dose statin

Optimal therapy in Heterozygotic Familial Hypercholesterolemia

Ezetimibe | Statin

Defects in ABCG5 and ABCG8 with elevated plasma levels of B-sitosterol and campesterol

Phytosterolemia

Definitive diagnosis: Phytosterolemia

Measurement of plant sterols by gas chromatography

Rare disease with cholestanol in tendons and brain tissue thus at risk for developing cerebellar ataxia and dementia

Cerebrotendinous xanthomatosis

Definitive diagnosis: Cerebrotendinous xanthomatosis

Measurement of cholestanol by gas chromatography

Treatment of choice: Cerebrotendinous xanthomatosis

Chenodeoxycholate 250mg TID

Characteristic cutaneous feature of Dysbetalipoproteinemia

Xanthoma striatum palmare

Treatment for marked HDL deficiency (<10mg/dL)

``` LDL <70 mg/dL Triglyceride <150 mg/dL Smoking cessation SBP <130 mmHg HBA1c <7.0% ```

Inherited syndrome of biliary hypoplasia leading to elevated serum cholesterol that decrease over time presents with facies of prominent forehead, hypertelorism, pointed chin, and nasal dystrophy

Alagille syndrome

Nonacute Porphyrias

``` Porphyria Cutanea Tarda Erythropoietic Protoporphyria Congenital Erythropoeitic Porphyria Hepatoerythropoeitic Porphyria X-linked Dominant Protoporphyria ```

Acute Porphyrias

Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria ALA Dehydratase Deficiency Porphyria

Porphyrias that are not photosenstive

Acute Intermittent Porphyria | ALA Dehydratase Deficiency Porphyria

Ezymatic Defect: Porphyria Cutanea Tarda

``` Decreased UROD (all tissues - familial; liver - sporadic) Increased ALAS1 (liver, kidney, fibroblasts and lymphocytes) ```

Ezymatic Defect: Erythropoietic Protoporphyria

Decreased FECH (BM and fibroblasts)

Ezymatic Defect: Congenital Erythropoeitic Porphyria

Decreased UROS (erythrocytes and fibroblasts)

Ezymatic Defect: Hepatoerythropoeitic Porphyria

Decreased UROD (erythrocytes and liver)

Ezymatic Defect: X-linked Dominant Protoporphyria

Increased ALAS2 (erythrocytes)

Ezymatic Defect: Acute Intermittent Porphyria

Decreased PBGD (erythrocytes, liver, fibroblasts, lymphocytes, amnion cells)

Ezymatic Defect: Variegate Porphyria

Decreased PPOX (liver and fibroblasts)

Ezymatic Defect: Hereditary Coproporphyria

Decreased CPOX (fibroblasts, lymphocytes, liver)

Ezymatic Defect: ALA Dehydratase Deficiency Porphyria

Decreased ALAD

Decreased in Lead poisoning

Aminolevulinic acid dehydratase (ALAD) | Ferrochelatase (FECH)

Heme biosynthetic pathway

``` Aminolevulinic acid synthase ALAS Aminolevulinic acid dehydratase ALAD Porphobilinogen deaminase PBGD Uroporphyrinogen III synthase UROS Uroporphyrinogen decarboxylase UROD Coproporphyrinogen oxidase CPOX Protoporphyrinogen oxidase PPOX Ferrochelatase FECH ```

Soret band

400-410 nm

Acute symptoms are notably absent in patients with chronic hepatic prophyrias

Porphyria Cutanea Tarda | Variegate Porphyria

Most common type of porphyria worldwide

Porphyria Cutanea Tarda

Second most common cutaneous prophyria

Erythropoietic Protoporphyria

Most recent type of protoporphyria recognized

X-linked Dominant Protoporphyria

Most mutilating of the cutaneous prophyria

Congenital Erythropoeitic Porphyria

Pathognomonic finding in Congenital Erythropoeitic Porphyria

Erythrodontia (red-stained teeth)

Most common acute porphyria

Acute Intermittent Porphyria