AKA: Adrenocortical insufficiency
Clinical: Weakness, fatigueability, weight loss, anorexia, hypotension
Syndromes of multiple autoimmune disorders that include Addison’s Disease fall into two subtypes:
· 2/3 of triad of Addison’s, hypoparathyroidism and mucocutaneous candidiasis
· Schmidt’s Syndrome
Clinical: Masculinization in women, feminization in men and precocious puberty in children
Pathophysiology: Adrenal virilism related to enzymatic defects in biosynthesis of cortical steroids leading to cortisol deficiency: at least 8 distinctive syndromes including 21-hydroxylase deficiency, 11-hydroxylase deficiency
Micro: Adrenocortical hyperplasia
Clinical: Onset later than other leukodystrophies (Metachromatic and Krabbe’s Disease). Males ages 10-20, Females 20-40.
Presents with adrenal failure and segmental demyelinization and axonal degeneration of CNS.
Transmission: X linked recesive
Pathophysiology: Defect in fatty acyl-coenzyme A ligase (a peroxismal transporter enzyme) leads to accumulation of long-chain fatty esters of cholesterol.
EM: Cytoplasmic inclusions of dense, long, thin leaflets enclosing an electron-lucent space in cerebral macrophages, adrenocortical cells, testicular Leydig cells and Schwann cells
Adult Respiratory Distress Syndrome (ARDS)
AKA: Diffuse Alveolar Damage (DAD)
Clinical: Severe respiratory deficiency, tachycardia, cyanosis, severe arterial hypoxemia
Pathophysiology: Many etiologies: shock, sepsis,
Micro: Diffuse alveolar capillary damage with hyaline membranes and type II pneumocyte regeneration
AKA: Arterio-hepatic dysplasia
Clinical: Broad facies, hypertelorism, short stature, butterfly vertebrae, mental retardation, hypogonadism, pulmonary artery stenosis
Transmission: AD, association with Trisomy 21, 18, 17; 45XO
Cytogenetics: Mutation in gene Jagged1 on chromosome 20p, encodes ligand for Notch1, which plays a role in epithelial-mesenchymal interactions
Micro: Congenital absence of intrahepatic bile ducts, portal tract fibrosis, neonatal giant cell hepatitis
AKA: Osteopetrosis, Marble-bone disease
Clinical: Malignant AR form evident in utero or soon after birth: fractures, anemia, hydrocephaly, cranial nerve problems (optic atrophy, deafness, facial paralysis), repeated infections, HSM (from extramedullary hematopoiesis). AD benign adult form usually detected in adolesence or adulthood on X-rays of repeated fractures. Milder cranial nerve deficits and anemia.
Transmission: Malignant AR evident in utero or infancy; AD adult form has a benign course
Pathophysiology: Carbonic anhydrase II deficiency required by osteoclasts and renal tubular cells to acidify their environment; osteoclasts can’t generate superoxide.
Diagnosis: Radiographic features characteristic: diffuse sclerosis and distal metaphyses misshapen
Gross: Overgrowth and sclerosis of bone with marked thickening of cortex and narrowing/filling of medullary cavity. Ends of long bones are bulbous (Erlenmyer flask deformity) and misshapen. The neural formamina are small and compress existing nerves.
Micro: Spongiosa persists and there is no room for hematopoetic marrow. Bone that forms is not remodeled, remains woven.
Treatment: Some benefit from IFN-g, bone marrow transplant.
AKA: McCune-Albright Syndrome
Clinical: Nephrotic syndrome, Eye abnormalities (lens dislocation, posterior cataracts, corneal dystrophy), nerve Deafness, Hematuria. Males are affected more frequently and more likely to progress. Symptoms appear between ages 5 and 20 usually with microscopic hematuria. Renal failure occurs by age 20-50 in med. Auditory defects may be subtle.
Pathophysiology: Defective GBM synthesis due to mutations in a5 chain of collagen IV (COL4A5 gene), X linked form associated with diffuse leiomyomatosis has additional mutations in a6 chain. AR transmission associated with mutations in a3 and a4 chains.
Diagnosis: Skin biopsy also shows lack of a5 collagen staining
Transmission: Most X-linked, Xq22, but AR and AD pedigrees exist
Micro: Early lesion: segmental proliferation or sclerosis with an increase in mesangial matrix and persistence of fetal-like glomeruli. Later: tubular epithelial foam cells and increasing glomerulosclerosis.
EM: GBM shows irregular thickening and thinning with splitting of lamina densa
Stains: Antibodies to a3, a4, and a5 collagen fail to stain both glomerular and tubulat basement membranes
Clinical: “Happy puppets”: mental retardation, ataxic gait, seizures, inappropriate laughter
Cytogenetics: Maternal imprinting of chromosome 15; del(15)(q11q13)
Angiokeratoma Corporis Diffusum Universalis
AKA: Fabry’s Disease
Mneumonic: CHASM (Cerebellum protrudes, Hydrocephalus, Spinal dysraphism, Medulla kinked)
Pathophysiology: Disproportionate growth of posterior fossa
Type I: benign cerebellar tonsillar herniation
Type II: small posterior fossa with extreme cerebellar tonsillar herniation through foramen magnum, kinked cervical spinal cord, tegmental beaking, lumbosacral meningomyelocele, 80% hydrocephalus
Clinical: infertility (Abortions), Adhesions, Amenorrhea, associated with excessive dilatation and curettage (D&C).
Gross: endometrial synechiae
Clinical: cerebellar ataxia, immunodeficiency, sensitivity to ionizing radiation, lymphoid malignancies
Increased risk of NHL, leukemia, brain tumors, gastric cancer, breast cancer (11% chance by age 50 in heterozygotes)
Transmission: AR; 1% of population is a carrier
Pathophysiology: AT protein (ATM gene) is a sensor of DNA damage; absence leads to defective DNA repair and accelerated cell aging
Micro: Gradual loss of Purkinje cells in the cerebellum
Basal Cell Nevus Syndrome
AKA: Gorlin’s Syndrome
Clinical:recanalization of an ectatic portal vein and associated splenomegaly, anemia, ± splenic vein thrombosis; usually occurs years after an occlussive event (e.g. neonatal omphalitis or umbilical vein catheterization).
Bare Lymphocyte Syndrome
Pathophysiology: Lack of MHC Class I or both Class I & II HLA antigens resulting in varying immunodeficiency
AKA: Carrion’s Disease
Clinical: Acute febrile fever (oroya fever) associated with hemolytic anemia and hepatosplenomegaly followed by nodular, inflammatory lesions consisting of inflammatory cells
Pathophysiology: Bartonella bacilliformis, carried by sandfly vector
Clinical: Polyuria with K+ wasting and metabolic alkalosis
Pathophysiology: Secondary hyperaldosteronism from renin overproduction
Diagnosis: Hyperreninemia, Hyperaldosteronemia, Hypokalemia, Metabolic alkalosis, serum HCO3, urine Cl-
Micro: Juxtaglomerular cell hyperplasia
Basal Cell Nevus Syndrome
AKA: Gorlin’s Syndrome
Mneumonic: CAVE (CNS, Apthous ulcers/Autoimmune, Vasculitis/Venous thrombosis, Eye
Clinical: young males with hypopyon, uveitis, iridocyclitis, oral/genital aphthous ulcers, arthritis, inflammatory bowel disease
Pathophysiology: immune complex mediated, leukocytoclastic vasculitis
Clinical: macrosomia, macroglossia, exopthalmos, neonatal hypoglycemia, hemihypertrophy, renal medullary cysts, adrenal cytomegaly; increased risk of Wilms’ tumor, hepatoblastomas, adrenocorticoid tumors, rhabdomyosarcoma, pancreatic tumors. (see also Denys-Drash Syndrome and WAGR Syndrome for other Wilms’ tumor associated syndromes)
Transmission: AR, gene WT-2 on 11p15.5; uniparental disomy in sporadic cases
AKA: IgA nephropathy
Micro: Segmental, diffuse or crescentic glomerulonephritis
IF: IgA deposits in mesangium
Clinical: purpura, epistaxis, gingival bleeding, menorrhagia, hematuria, GI bleeding
Pathophysiology: GPIb/V/IX deficiency on platelet surface; affected platelets can’t bind vWF
Diagnosis: Normal platelet aggregation with ADP, collagen, epinephrine but lack of aggregation with ristocetin
Micro: Large platelets (2-5x normal), reduced numbers
AKA: subcortical leukoencephalopathy
Clinical: Hypertensive patients with progressive dementia
Micro: Diffuse loss of deep hemispheric white matter
Clinical: Leukemia, GI carcinoma
Pathophysiology: spontaneous chromatid breakage
AKA: Tuberous Sclerosis
Clinical: Rickettsial disese in Mediterranean/India, promintn eschar and “tache noire”
Pathophysiology: Rickettsia conorii
Transmission: tick bite
AKA: Dengue Fever
Clinical: gnawing bone pain
Clinical: Typhus group (no eschar) Rickettsial disease; similar to epidemic typhus but milder
Pathophysiology: Rickettsia prowazekii, late reactivation
Brittle Bone Disease
AKA: Osteogenesis Imperfecta
Clinical: Bone fragility, fractures, blue sclera, bony abnormalities in middle and inner ear, abnormal teeth
Pathophysiology: Hereditary disorders of collagen synthesis, mainly type I collagen (90% of bone matrix)
Pathophysiology: Defective B cell maturation
Diagnosis: Near-total absence of immunoglobulins in serum
Budd Chiari Syndrome
Mneumonic: HAT (Hepatomegaly, Ascites/Abdominal pain, Thrombus)
AKA: Hepatic vein thrombosis
Clinical: ascites, portal hypertension, varices
Pathophysiology: Associated with polycythemia vera, pregnancy, postpartum, OCPs, paroxysmal nocturnal hemoglobinuria, intraabdominal CA (particularly hepatoma), infections, trauma, membranous webs.
AKA: Thromboangiitis obliterans
Clinical: Male smokers
Micro: Thromboangiitis obliterans with segmenta; thrombosing acute and chronic inflammation of intermediate and small arteries and veins of the extremities.
Pathophysiology: impairment of bile acids and phosphotidylcholine secretion leading to progressive intrahepatic cholestasis
Clinical: Pulmonary disorder caused by dust from cotton, flax or hemp. Takes form more like asthmatic bronchitis.
AKA: “The bends”, decompression sickness
Clinical: Scuba divers
Pathophysiology: Sudden changes in atmospheric pressure cause nitrogen to come out of fluid and the resulting embolisms lead to multiple foci of ischemic necrosis
Clinical: pulmonary rheumatoid arthritis with pneumoconiosis; distinctive nodular pulmonary lesions on CXR that develop rapidly.
Pathophysiology: Seen in silicosis, asbestosis, other dust-caused pneumoconioses
Micro: pulmonary rheumatoid nodules with central necrosis surrounded by fibroblasts, macrophages, and collagen in a background of progressive massive fibrosis
Clinical: blushing, flushing, diarrhea, cutaneous angiomas, tricuspid valve and pulmonary valve stenosis, bronchial spasm
Pathophysiology: serotonin, 5-HIAA release from carcinoid tumors that have metastasized to the liver
Clinical: cutaneous and soft tissue myxomas, cardiac myxomas, skin pigmentation, adrenal lesions
Clinical: Congenital intrahepatic biliary dilatation; 25% associated with polycyctic kidney. Increased risk of cholangiocarcinoma. Often complicated by intrahepatic cholelithiasis, cholangitis, hepatic abscesses and portal HTN.
Micro: communicating cavernous biliary ectasia; may be seen in conjunction with congenital hepatic fibrosis
Clinical: Lymphadenopathy, fever, multiorgan dysfunction
Often seen in patients with POEMS
AKA: American trypanosomiasis
Clinical: Myocarditis (America), Megaesophagus and megacolon (Brazil)
Pathophysiology: T. cruzi
Clinical: microaneurysms that form at bifurcations of small intraparenchymal cerebral arteries (lenticulostriate arteries) due to hypertension which may rupture and cause spontaneous intracerebral hemorrhages (basal ganglia, pons, cerebellum)
AKA: peroneal muscular atrophy; hereditary sensory motor neuropathy Type I
Clinical: Wasting and weakness of lower leg and foot giving characteristic inverted “champagne bottle limb.”
Micro: onion bulb nerves
Mneumonic: CAMP (Chemotaxis, AR, Microtubules, Phagocytosis)
Clinical: Neutropenia, albinism, HSM, lymphadenopathy, nerve defects, bleeding diathesis
Pathophysiology: Abnormal PMN peroxidase granules, impaired chemotaxis and phagocytosis from defect in microtubute polymerization. Reduced transfer or lysosomal enzymes to phagocytic vacuoles, melanocytes, nerves and platelets.
Diagnosis: Neutrophils have giant granules on peripheral blood smear. ¯ Hct, ¯ Plt,
Clinical: Post-partum patients in which continued secretion of prolactin from the pituitary inhibits reinstitution of menstrual cycle.
Micro: Atrophic vaginal smear.
Chronic Granulomatous Disease
Clinical: Recurrent lymphadenopathy, HSM, rash, recurrent bacterial infections of lung
Transmission: 60% X linked (membrane component), 40% AR (cytoplasmic component)
Pathophysiology: Defect in genes encoding NADPH oxidase ® abnormality in H2O2 generation.
Diagnosis: ¯ Hct, WBC, IgG
Micro: Bowel with LGV like findings
Mneumonic: VEGA (Vasculitis, Eosinophilia, Granulomas, Asthma)
AKA: allergic granulomatous angiitis
Clinical: asthma, fever, eosinophilia
Micro: Eosinophil-rich and granulomatous inflammation involving the respiratory tract. Necrotizing vasculitis affecting small to medium-sized vessels.
Diagnosis: pANCA positive
Clinical: Rare disease characterized by premature aging
Pathophysiology: DGenetic instability in somatic cells
Mneumonic: HANK (Hypertension, Aldosterone/Adenoma, Neuromuscular weakness, K+ wasting) – this has been on more than one exam
AKA: Primary aldosteronism
Clinical: edema, HTN
65% caused by adenoma, 35% caused by adrenal hyperplasia, <5% caused by cancer
Diagnosis: ¯ K, Na, pH, low renin
Clinical: papilloma and benign tumors of ectodermal origin, incidence rhabdomyosarcoma, possibly bladder carcinoma, mental retardation, short stature, macrocephaly, “coarse” facial features, hoarse voice, and redundant skin with deep palmar and plantar creases.
Transmission: sporadic dominant mutation, AD or AR
Pathophysiology: decreased elastin gene expression (?)
Mneumonic: PATH (Polyp/papilloma of cord, Acral keratosis, Tricholemomas/tumor of breast, Hamartoma)
AKA: Multiple hamartoma syndrome
Clinical: hypertrichosis, gingival fibromatosis, oral mucosal papillomas, breast fibroadenomas, breast cancer (30-50% chance by age 50), facial trichilemmomas, small bowel and colonic hamartomatous polyps (non-Peutz Jegher’s), ± thyroid disease
Cytogenetics: Chromosome 10q
Clinical: Calcinosis cutis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly, Telangectasias (a limited form of scleroderma). Clinical course relatively benign.
AKA: Subacute spongioform encephalopathy
Clinical: Rapidly progressive dementia, myoclonus, ataxia
Micro: Cortico-striatal-spinal degeneration
Cri du Chat Syndrome
Clinical: mewing cry, microcephaly, micrognathia, hepertelorism, antimongoloid palpebrae, round facies with epicanthal folds, mental retardation, physical retardation, cardiac abnormalities
Pathophysiology: del 5p-; 46 XX or 46 XY
Crigler Najjar Syndrome
Mneumonic: JUG (Jaundice, Unconjugated hyperbiliruninemia, Glucuronyltransferase)
AKA: familial non-hemolytic jaundice
Clinical: two types
I. AR: severe, kernicterus, pale yellow stool, bile bilirubin glucouronide -, not phenobarb responsive
II. AD: moderate and variable, normal stool, bile bilirubin glucouronide +, phenobarb responsive
Pathophysiology: impaired conjugation of bilirubin by the liver due to absent (Type I) or deficient (Type II) glucoronyl transferase(AKA: uridine diphosphate glucoronyltransferase or UGT) leading to an unconjugated hyperbilirubinemia
Treatment: Type II responds to phenobarbital
Mneumonic: JAHN (Juvenile polyps, Alopecia, Hyperpigmentation, Nail atrophy)
Clinical: hamartomatous GI polyps, diffuse alopecia, nail dystrophy, hyperpigmentation
AKA: Craniofacial dysostosis
AKA: hypercortisolism; Cushing’s Disease when caused by a pituitary adenoma.
Clinical: central obesity, moon facies, acne, buffalo hump, hirsutism, amenorrhea, striae, hypertension, mental status changes
Pathophysiology: adrenocortical secretion of cortisol caused by ACTH levels caused by pituitary adenoma, neoplasms of the adrenal cortex or ectopic ACTH from a neuroendocrine tumor (bronchogenic CA, malignant thymoma, islet cell tumor), may be iatrogenic (steroid Rx).
Pathophysiology: failure of formation of cerebellar vermis
Gross: no room to 4th ventricle, hydrocephalus, polymicrogyria
del Castillo Syndrome
Clinical: Galactorrhea following termination of birth control usage.
Pathophysiology: Pituitary shut-down of FSH and LH production.
Micro: Atrophic vaginal smear.
Dense Deposit Disease
AKA: Type II Membranoproliferative glomerulonephritis
IF: C3 in mesangial rings but not in dense deposits
EM: dense deposits in GBM
Clinical: gonadal dysgenesis (male pseudohermaphroditism) and nephropathy leading to renal failure; increased risk of Wilms’ tumor. (see also WAGR Syndrome and Beckwith-Wiedemann Syndrome for other Wilms’ tumor associated syndromes)
Cytogenetics: 11p13 (WT1)
Pathophysiology: negative missense mutation
AKA: adiposis dolorosa
Clinical: autoimmune inflammatory myopathy, commonly associated with Scleroderma, SLE, Sjogren’s. Increased risk of visceral malignancy. (lung, stomach, ovary)
Clinical: A variant of Multiple Sclerosis (neuromyelitis optica) in which the typical MS plaques coexist with necrotic lesions in the spinal cord and demyelination in the optic nerve.
AKA: congenital chronic pure red cell aplasia
Clinical: presents at 2 weeks-1 year
Pathophysiology: Defective erythroid-committed stem cells
Di George Syndrome
Mneumonic: CATCH 22 (Cardiac abnormalities, Abnormal facies, T cell deficit/tetany, Cleft palate, Hypocalcemia from parathyroid hypoplasia, chromosome 22q11)
AKA: Thymic hypoplasia; 22q11 deletion syndrome (includes velocardiofacial syndrome)
Clinical: Recurrent fungal and viral infections, tetany, risk of squamous cell ca or upper respiratory tract
Patients with partial DiGeorge Syndrome have a small but histologically normal thymus and T cell function improves with age.
Pathophysiology: Failure of third and fourth pharyngeal pouches, loss of T cell mediated immunity
Diagnosis: Low levels of circulating T cells. Deletion 22q11 (90%)
Gross: Absence of thymus, parathyroids, clear cells of thyroid, heart and great vessels (ultimobrachial body)
Di Gugliemo Syndrome
AKA: erythremic myelosis, erythromeloblastic leukemia, AML M6
AKA: Trisomy 21
Clinical: flat facial profile, oblique palpebral fissures and epicanthic folds, mental retardation (severe in 80%), 40% have congenital heart disease (endocardial cushion defects: ostium primum, ASD, AV valve malformations, VSD), atresias of esophaus and small intestine; risk of acute leukemia (10-20x) ALL & AML; age>40 yo develop neuropathic changes similar to Alzheimer’s disease; abnormal immune responses (lung infections, thyroid autoimmunity)
Cytogenetics: 95% have trisomy 21; most common cause is meiotic nondisjunction; 95% extra chromosome is maternal origin;
4% of cases from a robertsonian translocation (familial); 1% are mosaics as a result of mitotic nondisjunction of chrom 21.
facial, neurologic and cardiovascular changes limited to 21q22.2 and 21q22.3
Prognosis: 80% survive to age 30 or beyond
Clinical: Occurs 2-21 weeks s/p MI, cardiac trauma or cardiotomy: fever, pleuritis, pericarditis, pneumonitis, arthritis, leukocytosis
Pathophysiology: autoimmune pericarditis
Dubin Johnson Syndrome
Mneumonic: BCP (Bilirubin, Conjugated, Pigmentation – liver)
AKA: black liver disease
Pathophysiology: absence of glucouronyl transferase leads to defects in bile canalicular transport
Diagnosis: conjugated hyperbilirubinemia
Gross: Dark-gray pigmented liver
AKA: myasthenic syndrome
Clinical: progressive proximal muscle weakness without cranial muscle weakness; associated with oat cell carcinoma
Diagnosis: action potential with repetitive stimulation
AKA: Trisomy 18
Clinical: overlapping fingers, renal and cardiac anomalies
Ehler’s Danlos Syndrome
Clinical: Clinically and genetically heterogeneous group of disorders that result from some defect in collagen synthesis and structure. 10 clinical variants, most show cutis hyperelastica and hyperextendible joints.
EDS Type I: +diaphragmatic hernia
EDS Type IV: +rupture of colon and large arteries (rick in type III collagen)
EDS Type VI: +corneal rupture and retinal detachment
Type IV: mutation in type III collagen gene, pro a1 (III) chains, secretion defect or structurally abnormal
Type VI: mutation in lysyl hydroxylase (enzyme for cross-linking collagens I and III)
Type VII: mutation in conversion of type I procollagen to collagen
Type IX: copper metabolism defect, high in cells, low in serum & ceruloplasmin; copper-dependent enzyme lysyl oxidase essential for cross-linking collagen
Type IV: AD
Type VI: AR
Type VII: AD (dominant negative: mutant chains interfere with the formation of normal collagen helices)
Type IX: X linked recessive
Clinical: reversal of congenital left to right shunt (e.g. ASD, VSD, PDA), pulmonary hypertension, RVH, cyanosis
Empty Sella Syndrome
Clinical: pituitary insufficiency, panhypopituitarism
Pathophysiology: Multiple origins: herniation of sunarachnoid into sella with compression atrophy of pituitary by CSF, Sheehan’s Syndrome, infarction of adenoma followed by scarring, ablation of pituitary by radiation and scarring
Micro: Ususally some residual viable tissue remains, but mostly gliotic scar.
Clinical: autoimmune thrombocytopenia along with autoimmune hemolytic anemia
AKA: angiokeratoma corporis diffusum universalis
Clinical: purple angiokeratomas on thighs, buttocks and genitalia, anhidrosis, parasthesias in lower extremities; CNS, cardiac and renal complications
Transmission: X linked Recessive; Xq21-22
Pathophysiology: No a galactosidase ® sphingolipid (ceramide trihexoside) in histiocytes and vessel walls
Diagnosis: zebra body glomerular deposits
Clinical: renal hypoplasia, absent or hypoplastic thumbs or radii, skin hyperpigmentation, microcephaly, risk of AML, squamous carcinoma, hepatocellular carcinoma
Pathophysiology: Defective DNA repair mechanism
Mneumonic: KAT (Kidney, Aplastic anemia, Thumbs – absent)
Clinical: acute leukemia, squamous carcinomas & hepatomas, cystinosis, osteomalacia
Pathophysiology: 2° to myeloma or poisoning ® defective renal tubular function
Mneumonic: SAUL (Splenomegaly, Arthritis, Ulcers (leg), Leukopenia)
Clinical: Rheumatoid arthritis with leg ulcers, splenomegaly with leukopenia & granulocytopenia
Fetal Alcohol Syndrome
Mneumonic: GAMMAS (Growth retardation, Alcohol, Microcephaly, Maxillary hypoplasia, ASD, Short palpebral fissures)
Clinical: microcephaly, facial dysmorphology (short palpebral fissure, maxillary hypoplasia), malformations of the brain, cardiovascular system (strial septal defect) and genitonurinary system
Pathophysiology: acetaldehyde crosses placenta
Fetal Hydantoin Syndrome
Clinical: IUGR, mental retardation, dysmorphic facies, sleft lip, cardiac abnormalities, ambiguous genitalia
Clinical: stabbing RUQ abdominal pain
Pathophysiology: perihepatitis caused by spread of untreated gonorrheal cervicitis
Clinical: Pituitary chromophobe adenomas or craniopharyngeomas associated with ¯ gonadotropins causing secondary amenorrhea with galactorrhea.
Micro: Atrophic vaginal smear.
Clinical: Mental retardation
Transmission: X linked
Clinical: gait ataxia, hand clumsiness, dysarthria, -DTR, impaired joint position and vibratory sense. +Babinski,
Transmission: AR with male preponderance
Gross: Small spinal cord
Micro: Loss of nerve fibers and gliosis of posterior columns, distal corticospinal tract, spinocerebellar tracts and loss of dorsal root ganglion cells.
Clinical: Stress polycythemia of unknown etiology
Mneumonic: DO STOP (Desmoid/AD, Osteomas, Sebaceous cysts, Thyroid cancer/tooth abnormal, Osteochondromas, Polyps)
Clinical: colonic polyposis with high malignant potential, skull osteomas, soft tissue tumors: calcifying epithelioma of Malherbe, fibromatosis/desmoid, lipomas, sebaceous cysts, fibromas, fibrosarcomas; dental abnormalities
Transmission: AD; APC gene 5q21 variable expressivity
Clinical: The most common lyssomal storage disorder.
HSM, lymphadenopathy, bone destruction
Type I (99%) non-neuronopathic. Splenic and skeletal involvement, lymphadenopath., European Jews. Reduced but detectible activity. Longevity mildly shortened.
Type II (<1%) neuronopathic. Infantile acute cerebral. No predeliction for Jews. No detectible activity. HSM and progressive CNS involvement. Early death.
Type III (<1%) mild neuronal symptoms, “intermediate” usu juveniles wth systemic involvement as in type I but CNS involvement is in teens or 20s.
Transmission: AR; gene 1q21
Pathophysiology: Absence of glucocerebrosidase (cleaves glucose residue from ceramide); accumulates in phagocytic cells.
Diagnosis: Glucocerebrocidase activity in peripheral blood leukocytes or in extracts of cultured skin fibroblasts.
Micro: Gaucher cells: distended phagocytic cells, with fibrillary cytoplasm like crumpled tissue paper and dark, eccentric nuclei. Type I: bone erosion or large, gray tumorous masses. Type II: Gaucher cells in Virchow-Robin spaces. Neurons appear shrivelled and progressively destroyed.
AKA: familial non-hemolytic jaundice
Clinical: Benign hereditary disorder, usually asymtomatic or produces a mild jaundice
Pathophysiology: decreased uptake of bilirubin by the hepatocytes, mild deficiencies in UGT (glocoronyl transferase) and in 50% mild hemolysis
Diagnosis: unconjugated hyperbilirubinemia, especially after fasting
Clinical: Bleeding diasthesis
Pathophysiology: Inactive or deficient GpIIb-IIIa causing defective platelet aggregation
AKA: Anti-GBM Disease
Clinical: nephritic syndrome/RPGN, pulmonary hemorrhage
Pathophysiology: Anti-glomerular basement membrane antibody
Lung – necrotizing, hemorrhagic pneumonia
Kidney – glomerulonephritis
EM: deposits in capillary loops
IF: linear IgG, C3
AKA: massive osteolysis
Clinical: reabsorption of whole or multiple bones and filling of residual spaces with heavily vascularized fibrous tissue
AKA: Basal Cell Nevus Syndrome
Mneumonic: REBOCK (Reproductive organs, Eyes, Bone, Ca+2 of dura, Keratinous cyst of jaw)
Clinical: multiple basal cell carcinomas, odontogenic cysts of the jaw, defective dentition, rib/vertebral/metacarpal abnormalities, ovarian fibroids and carcinoma, calcificantion of falx & dura, increased risk of medulloblastoma
Pathophysiology: hyperthyroidism due to long stimulating thyroid antibodies
Mneumonic: PRE MD
AKA: Congenital Rubella Syndrome
Clinical: Patent ductus, Rubella, Eye (cataract), Mental retardation, Deafness
Mneumonic: MAD (Motor paralysis, Anti-myelin, Demyelination)
AKA: Acute idiopathic polyneuritis
Clinical: Affects all ages, clidren & adults; mild URI precedes neurologic sx by 1-3 weeks in 50% of cases. Presents with weakness of proximal and distal limb muscles, trunk muscles, ascending paralysis. Association with infectious mono, hepatitis, diptheria, porphyria or toxins (triorthocresyl phosphate poisoning, Jamaican ginger)
Pathophysiology: acute demyelinating process
AKA: Idiopathic pulmonary fibrosis, Usual interstitial pneumonitis (UIP)
Clinical: pearly grey vesicles on fingers, toes, palms, soles, buccal mucosa and tongue
Pathophysiology: Coxsackie A-16
Hand-Schüller Christian Disease
AKA: Multifocal Langerhans’ Cell Histiocytosis
Clinical: Triad of calvarial defects, diabetes insipidis and exopthalmos in patients with Langerhans Cell Histiocytosis (compare to Letterer-Siwe Disease).
Histiocytic infiltrates in multiple tissues and involvement of pituitary stalk in 50% leads to diabetes insipidus. Seborrhea-like skin eruption typically present.
EM: Rod shaped inclusions in Langerhans cells (Birbeck granules)
Prognosis: Relatively benign course. Lesions spontaneously regress in 50% and in 50% cured by chemoRx.
Clinical: Tuberculoid (TT) and Lepromatous (LL) forms.
TT: Macular skin lesions with prominent nerve involvement (ulnar and peroneal) leading to skin anesthesia, muscle atrophy and eventually skin ulcers; skin contractures, paralysis, autoamputation of fingers and toes.
LL: Nodular lesions (skin, peripheral nerves, anterior eye, upper airways to larynx, testes, hands, feet) may result in sensory imapirment and “Leonine facies.”
Transmission: TT form is not contagious.
Pathophysiology: Mycobacteria leprae
Diagnosis: Acid fast obligate intracellular bacteria
Few organsims in TT; Lots in LL.
TT: Garnulomatous lesions with scant organisms
LL: Abundant histiocytes and easily identified organisms
Prognosis: LL more difficult to cure.
Clinical: Symptoms of pellagra
Pathophysiology: Defective tryptophan transport system leads to decreased nicotinamide
AKA: Rat bite fever
Pathophysiology: Streptobacillus moniliformis
Clinical: Sarcoidosis, bilateral parotid enlargement, facial nerve palsy, uveitis
Clinical: Hemolysis, Elevated Liver function tests, Low Platelets
Pathophysiology: Caused by severe toxemia of pregnancy
Hemolytic Uremic Syndrome
Clinical: sudden onset hematemesis/melena after GI/flu-like prodrome; severe oliguria, hematuria, microangiopathic hemolytic anemia, neurological changes in children. Familial form – more benign course. In adults associated with postpartum complications (retained placenta), OCPs.
Pathophysiology: infectious etiology include; Salmonella typhi, E. coli, Shigella, Clostridia
Mneumonic: GAAACC (Glomerulonephritis, IgA, Arthralgias, Angiitis, Colic, C3)
Hereditary Angioneurotic Edema
Clinical: Episodic edema of skin, extremities, laryngeal and GI mucosa provoked by emotional stress or trauma
Pathophysiology: C1 inhibitor deficiency
Hereditary Non-Polyposis Colon Cancer Syndrome
Clinical: Early onset colon cancers at a young age <50 years, association with endometrial and ovarian cancers in some families.
Represent 2-4% of all colonic cancers
Transmission: AR; patient inherits one defective copy and the “second hit” is in colonic epithelium.
Pathophysiology: Defects in DNA repair genes hMSH2, hMLH1, hPMS1, hPMD2. When damaged, this leads to mismatch repair defects and microsatellite instability (expansions and contractions in fixed “microsatellite sequences”, tandem repeats).
Diagnosis: Microsatellite instability can be detected in 15% of sporadic (non-HNPCC) colon cancers
Treatment: Cancer screening
Clinical: oculocutaneous albinism, increased ceroid in mononuclear phagocytic system, dense granule deficiency in platelets
Clinical: Congenital megacolon
Pathophysiology: Failure of development of Meissner’s and Auerbach’s plexuses.
Micro: Ganglion cells are absent at anorectal junction. Nerves hypertrophied.
Clinical: ptosis, miosis, anhydrosis
Pathophysiology: lesion in sympathetic chain
AKA: Temporal (giant cell) arteritis
AKA: Type II mucopolysaccharidosis
Clinical: Appear normal at birth but develop HSM by 6-24 months. Growth retardation, coarse facial features, skeletal deformities. Compared to Hurler no corneal clouding and milder clinical course.
Pathophysiology: Deficiency of L-iduronosulfate sulfatase leading to accumulation of heparan sulfate and dermatan sulfate.
Transmission: X-linked recessive
AKA: Type I mucopolysaccharidosis
Clinical: Appear normal at birth but develop HSM by 6-24 months. Growth retardation, corneal clouding, coarse facial features, skeletal deformities. Death by 6-10 years from cardiovascular complications.
Pathophysiology: Deficiency of a-1-iduronidase leading to accumulation of heparan sulfate and dermatan sulfate.
Clinical: splenic agenesis, cardiac malformations
Clinical: excess iodine ingestion in patients with thyroid disorders causing thyroid toxicosis..
Juvenile Polyposis Coli
Clinical: Multiple hamartomatous polyps in stomach and colon.
Mneumonic: SIBS (Situs inversus, Immotile cilia/infertile male, Bronchiectasis, Sinusitis)
Clinical: complete situs inversus, chronic sinusitis, bronchiectasis, ± spleen, infertility
Pathophysiology: defect in protein dynein; congenital absence of cilia
Pathophysiology: giant cavernous hemangioma leading to consumptive thrombocytopenia
AKA: Mucocutaneous LN Syndrome
Clinical: conjunctivitis, pharyngitis, cervical lymphadenopathy, peri-vasculitis/vasculitis, finger and toe desquamation
Clinical: Mitochondrial myopathy resulting in Opthalmoplegia, Heart block & Retinal pigmentary degeneration
AKA: Diabetic nephropathy
Clinical: Diabetes mellitus, hypertension, nephrotic syndrome
Clinical: 1/850 male live births: hypogonadism (atrophic testis, small penis), eunochoid body, lack of secondary sexual characteristics (deep voice, beard) increased risk of breast cancer.
Diagnosis: Increased FSH
Clinical: possible increased risk of Wilms tumor
Pathophysiology: angiomatosis ® underlying bone abnormal, may ® localized gigantism
AKA: Cecal tuberculosis
Clinical: alternating constipation and diarrhea, colic, meteorism, gurgling in RLQ
AKA: Globoid cell leukodystrophy
Clinical: Lysosomal storage disease (sphingolipidosis). Manifests in early childhood as a symmetrical, global disorder or myelinization which leads rapidly to death before age 2.
Pathophysiology: Galactocerebrosidase b-galactosidasedeficiency leading to accumulation of galactocerebrocide
Micro: Demyelination and multinucleated histiocytic cells called globoid cells
Mneumonic: MS eats lambs
Clinical: Myasthenic syndrome associated with malignancy (usually Small cell carcinoma of the lung)
AKA: Lawrence-Moon Syndrome
Clinical: retinitis pigmentosa, extra digits, pelvic girdle obsesity, no genital development at puberty, mental retardation, spastic paraperesis
AKA: Subacute necrotizing encephalomyelopathy
Clinical: Bilateral, symmetrical regions of necrosis in thalamus, midbrain, pons, medulla and spinal cord resulting in ataxia, hypotonia, seizures, intellectual deterioration and death.
Clinical: hyperuricemia with uric acid stones, mental retardation, choreoarthetosis, spastic cerebral palsy, self-mutilation
Transmission: X-linked recessive
Pathophysiology: deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) of purine metabolism
Clinical: Multiple seborrheic keratoses and internal malignancy
Mnemonic: Let’s See HOPE (Letterer Siwe, HSM, Osteolytic bone lesions, Pumonary lesions, Enlarged LN) for these poor kids
AKA: Acute disseminated Langerhans Cell Histiocytosis
Clinical: < 2 years old and sometimes present at birth; cutaneous lesions (diffuse maculopapular, eczematous or purpuric) on trunk and scalp, hepatosplenomegaly, lymphadenopathy, pulmonary lesions, destructive osteolytic bone lesions.
EM: Rod shaped inclusions in Langerhans cells (Birbeck granules)
Prognosis: poor (aggressive course), untreated disease is uniformly fatal. With chemoRx 5 year survival is 50%.
Clinical: Salt-sensitive hypertension
Pathophysiology: Mutation in epithelial sodium channel protein lead to increased distal tubular sodium reabsoption
Clinical: Noninfective verrucous endocarditis attributable to elevated levels of circulating immune complexes occuring in patients with SLE.
Clinical: Multiple sarcomas and carcinomas (breast carcinoma, adrenal cortex), leukemia and brain tumors; 25-fold greater chance of developing a carcinoma by age 50 than general population. Develop in young age and develop multiple primaries.
Cytogenetics: Germ line mutations of p53 (17p13.1) – cell cycle regulator, G1 arrest of DNA damaged cells
Clinical: eosinophilic pneumonia with granulomas; usually self-limited
Clinical: fever, erythema nodosum (lower extremities), possible sarcoid
Clinical: Rheumatic mitral valve stenosis and ASD leading to pulmonary HTN from increased left sided pressure.
AKA: dyschondroplasia with vascular hamartomas
Clinical: multiple cavernous hemangiomas (skin) and enchondromas
Mallory Weiss Syndrome
AKA: Mallory Weiss Tear
Clinical: Small tears in the esophagus as a result of prolonged vomiting.
Gross: Linear, irregular tears at GE junction or proximal gastric mucosa.
Clinical: Herpes virus infection contracted from fowl causing neuro lymphomatosis
AKA: Ankylosing spondylitis, Rheumatoid spondalitis
Clinical: Arthritis of sacroiliac joints and vertebral columns in young men.
Cytogenetics: Association with HLA B-27
Clinical: 1 in 10,000-20,000; 70-85% familial
arachnodactyly, dolichocephalic (long head), lax joints, bilateral ectopia lentis, aortic aneurysms/dissections/ valve incompetence, mitral valve prolapse/regurge, spinal deformities (kyphosis, scoliosis), skeletal abnormalities (pectus excavatum or pigeon-breast)
Transmission: AD or sporadic
Pathophysiology: Mutation in fibrillin 1(major component of extracellular matrix) leads to defect in connective tissue integrity. In heterozygotes mutant fibrillin disrupts the assembly of normal microfibrils (dominant negative mutation).
Diagnosis: Direct gene diagnosis is not feasible. Presymtomatic detection by RFLP analysis.
Cytogenetics: FBN1 in 15q21.1; great interfamilial variability/expressivity
Micro: Aortic cystic medial necrosis
Prognosis: Aortic rupture is the cause of death in 30-45%, other deaths from cardiac failure.
AKA: Type V glycogenosis
Clinical: Congenital myopathy with onset in adulthood (>20 yo) presents with muscle cramps after exercise and failure of exercise-induced rise in blood lactate due to block in glycolysis. 50% myoglobinuria.
Pathophysiology: Myophosphorylase deficiency
Micro: Glycogen accumulations in skeletal muscle only in subsarcolemmal location
AKA: Albright Syndrome
Clinical: Cafe-au-lait spots with irregular serpiginous borders on neck, chest, back, shouder and pelvis, polyostotic Fibrous dysplasia (femur>skull>tibia>jaw>humerus), Endocrine — precocious puberty (females), endocrine dysfunction (hyperthyroidism, primary adrenal hyperplasia, GH secreting pituitary adenoma)
Pathophysiology: Somatic (not hereditary mutation) involving a guanine nucleotide binding protein leading to excess cAMP
Clinical: ovarian fibroma with ipsilateral hydrothorax or ascites
Clinical: 4th-6th decades. Hypertrophic gastropathy; protein-losing enteropathy; ± ZES
Gross: Giant cerebriform enlargement of the rugal folds of the gastric mucosa
Micro: Hyperplasia of surface mucus cells; gastric secretions have excessive mucus and little or no HCl
Clinical: inner ear abnormalities, tinnitus, hearing loss, vertigo, N/V, nystagmus
Clinical: short, sparse, kinky, hypopigmented hair; Mental retardation with CNS deterioration
Transmission: X linked Recessive
Pathophysiology: disorder of intestinal copper absorption, needed by lysyl-oxidase, resulting in changes in aortic collagen and elastin
Clinical: Presents in late infancy with progressive motor impairment with mental deterioration. Congenital, juvenile and adulr presentations occur.
Pathophysiology: Deficiency in arylsulfatase A (cerebroside sulfatase)
Diagnosis: Decreased urinary arylsulfatase A.
AKA: Used to refer to Sjögren’s Syndrome; now refers to any swelling of lacrimal and salivary gland.
Pathophysiology: Lacrimal and salivary gland swelling secondary to lymphoid infiltrate, sarcoidosis, leukemia, lymphoma or tumors
AKA: heredofamilial congenital lymphedema
Milwaukee Shoulder Syndrome
Clinical: Hydroxyapetite arthropathy affecting knees and shoulders
Clinical: Skin reaction to lepromin occuring 3-4 weeks after injection
AKA: type IV mucopolysaccharidosis
Clinical: multiple sebaceous gland tumors; visceral malignancy
Multiple Endocrine Neoplasia I (MEN I)
AKA: Wermer’s Syndrome
parathyroid adenoma > hyperplasia
pancreatic islet cell adenoma
also: thyroid and adrenal cortical neoplasms, gastric hypersecretions and peptic ulcerations
Multiple Endocrine Neoplasia IIa (MEN IIa)
AKA: Sipple’s Syndrome
parathyroid C cell hyperplasia or adenoma
medullary carcinoma, thyroid
pheochromocytoma (bilateral 70%)
Pathophysiology: Germ line mutation of RET proto-oncogene on chromosome 10
Multiple Endocrine Neoplasia IIb (MEN IIb)
AKA: Mucosal Neuroma Syndrome
medullary carcinoma, thyroid
pheochromocytoma (often bilateral)
Clinical: hyperpigmentation, Cranial nerve III damage (opthalmoplegia), skin pigmentation
Pathophysiology: post-adrenalectomy hyperplasia of the pituitary gland (corticotroph cells)
Micro: adenomatous enlargement of the pituitary with a carcinomatous histologic picture
Neurofibromatosis I (NF I)
AKA: “Peripheral” NF, Von Recklinghausen’s Disease
Clinical: 1 in 3000. Multiple neurofibromas, plexiform neurofibromas, café au lait spots (90%: 6 or more spots >1.5 cm in diameter), Lisch nodules (pigmented iris hamartomas: 94% over age 6, usu asymtomatic), meningiomas, optic gliomas, 50% skel abnl (erosive defects, scoliosis & bone cysts, tibial pseudoarthrosis)..
Plexiform NF become maligfnant in 5%.
risk (2-4x) of pheochromocytomas, Wilms tumor, AML, rhabdomyosarcoma, optic gliomas, meningiomas. Children at risk of CML
Transmission: 50% AD, remainder new mutations.
Cytogenetics: 17q11.2 (neurofibromin gene) – tumor suppressor gene, downregulates p21 ras. Penetrance 100% but expressivity variable.
Micro: Neurofibromas are loose proliferation of neurites, Schwann cells and fibroblasts in a myxoid stroma.
Neurofibromatosis II (NF II)
AKA: “central” NF, acoustic NF
Clinical: 1 in 40,000-50,000. Bilateral acoustic schwannomas, café au lait spots, (NO Lisch nodules), meningiomas, cerebellar astrocytomas, ependymomas of spinal cord, schwannosis (benign nodular ingrowth of Schwann cells into spinal cord), meningioangiomatosis, glial hamartomas.
Cytogenetics: del 22q12. Tumor suppressor gene, product called merlin similar to cytoskeletal proteins.
Clinical: absent thymus and cell mediated immunity (like DiGeorge) but with normal parathyroids
Diagnosis: IgG is normal or increased but there is a selective deficiency of isotypes
Clinical: Clinically, biochemically and genetically heterogeneous. risk in Ashkenazi Jewish community.
Type A is severe infantile form (no sphingomyelinase) with severe neurologic impairment and death within first 3 years of life
Type B: hepatosplenomegaly, lymphadenopathy, marrow disease, late or no CNS involvement; survive into adulthood.
Pathophysiology: Lysosomal strorage disease (no sphingomyelinase leading to sphingomyelin accumulation)
Diagnosis: Liver or bone marrow biopsy assays for sphingomyelinase activity.
Gross: Massive splenomegaly; neuronal involvement is diffuse.
Micro: Lipid-laden phagocytic foam cells in spleen, liver, lymph nodes, bone marrow, tonsils, GI tract, lungs.
Stains: Vacuoles stain for fat with Sudan Black and Oil red O.
EM: Lysosomes contain membranous cytoplasmic bodies resenbling concentric lamellated myelin figures, or parallel palisaded lamella called Zebra bodies
AKA: Male Turner’s Syndrome, Ullrich-Turner’s Syndrome
Clinical: Phenotype of Turner’s Syndrome (webbed neck, ptosis, hypogonadism, congenital heart disease and short stature) without gonadal dysgenesis.
Clinical: Blue-black pigmentation in ears, nose and cheeks. Pigment in articular cartilages of the joints. Cartilage brittle and fibrillated, especially in vertebral column, knees, shoulders and hips, leading to a degenerative arthropathy.
Pathophysiology: Lack of homogentisic oxidase: defect in metabolism of phenylalanine-tyrosine with buildup of homogentisic acid. Homogentisic acid binds to collagen in connective tissue, tndons and cartilage.
Diagnosis: Urine turns black due to oxidation
AKA: Parinaud’s Syndrome
Clinical: Non-hereditary. Multiple unilateral enchondromas; often associated with ovarian sex cord-stromal tumors
AKA: Hereditary hemorrhagic telangiectasia
Clinical: Telangiectasias of face and oral mucosa, respiratory, GI, urinary tracts, CNS, liver, and spleen
Pathophysiology: mutations in two TGF-b binding proteins, including the endothelial protein endoglin
arterial blood is shunted into postcapillary venules
Clinical: pain in pinky (ulnar nerve distribution), miosis, ptosis, anhidrosis,
Pathophysiology: upper lobe mass impinges on sympathetic chain or brachial plexus
AKA: Oculoglandular syndrome
Clinical: swelling of the eye, jaw and high cervical lymph nodes caused by cat-scratch disease
Pathophysiology: Bartonella henselae
Paroxysmal Nocturnal Hemoglobinuria
Clinical: Recurrent bouts of intravascular hemolysis leading to complement-mediated lysis of RBC, leading to a chronic hemolytic anemia
Pathophysiology: Cells lack ability to express phosphatidylinositol-linked membrane proteins, including DAF (decay accelerating factor, a complement regulator)
AKA: Trisomy 13
Clinical: atrophic glossitis, microcytic hypochromic anemia (Fe deficiency), esophageal webs with dysphagia
Clinical: melanin spots on lips, buccal mucosa, genitalia and palmar surface of hands; multiple jejunal hamartomatous polyps with low malignant potential; risk SCTAT, adenoma malignum, mucinous ovarian tumors, large cell calcifying Sertoli cell tumor
AKA: Penile fibromatosis
AKA: Frontotemporal dementia
Clinical: Cerebral dementia
Gross: “Walnut brain”
AKA: Obesity hypoventilation syndrome
Clinical: Hypersomnolence leading to apnea, polycythemia and right sided heart failure.
Clinical: atrophic glossitis, microcytic hypochromic anemia, esophageal webs with dysphagia
Clinical: Polyneuropathy, Organomegaly, Endocrinopathy, M-protein spike, Skin changes
AKA: Glycogenosis Type II
Clinical: Cardiomegaly prominent; deposition in all organs with mild hepatomegaly, muscle hypotonia and cardioresperatory failure in 2 years. Milder adult form with only skeletal muscle chronic myopathy.
Pathophysiology: Lysosomal storage disease: deficiency of a-1-4-glucosidase(acid maltase) resulting in accumulation of glycogen in lysosomes
Micro: glycogen accumulations lead to ballooning of lysosomes in hepatocytes: lacy cytoplasmic pattern. Glycogen membrane-bound and sarcolemmal in heart & skel muscle.
Porphyria Cutanea Tarda
Clinical: vesicles on the back of the hand; association with ETOH, DM
Diagnosis: urine turns orange/red under wood’s light
AKA: Tuberculous spondylitis, Vertebral tuberculosis
Clinical: mental retardation, short stature, hypotonia, obesity, small hands and feet, hypogonadism
Cytogenetics: Paternal imprinting of chromosome 15; del(15)(q11q13)
Mnemonic: father Willi is fat while mom’s a happy Angel (maternal imprinting of chr 15 causes Angelman’s Syndrome)
Clinical: Facial paralysis
Pathophysiology: VZV infection of geniculate nucleus
Clinical: Raynaud’s phenomenon occuring in the absence of an anatomic lesion in the vessel walls
Clinical: pain and pallor/cyanosis of distal extremities in response to cold
Clinical: Hypertrophic neuropathy associated with increased levels of phytanic acid
Clinical: Triad of conjunctivitis, non-gonococcal urethritis, arthritis
Cytogenetics: Associated with HLA B-27
Clinical: history of aspirin ingestion in children for a viral URI; presents with encephalopathy and liver failure.
Micro: Liver shows microvesicular fatty change without coagulative necrosis or inflammation; brain shows global edema and ischemic changes but no inflammation.
EM: mitochondrial swelling, irregularity and loss of cristae
AKA: Riedel’s Thyroiditis
Clinical: Inflammatory fibrosing process of the neck that happens to involve the thyroid.
Pathophysiology: Probably autoimmune, l light chains > k, increased IgA plasma cells
Micro: Keloid-like fibrosis with associated lymphs and plasma cells.
Riley Day Syndrome
AKA: familial dysautonomia
Clinical: Asymptomatic conjugated hyperbilirubinemia but the liver is not pigmented (in contrast to Dubin Johnson Syndrome)
Pathophysiology: Secretion of bile into bile canaliculus is impaired.
Pathophysiology: Lysosomal storage disease, sphingolipidosis; deficiency of hexosaminadase A & B resulting in accumulation of GM2 ganglioside and globoside
AKA: type III mucopolysaccharidosis
Clinical: Types A, B, C, D
Pathophysiology: Deficiency of heparin N-sulfatase leading to accumulation of heparan sulfate.
Scalded Skin Syndrome
AKA: Toxic Epidermal Necrolysis (TEN)
Clinical: Rapid subepidermal blebbing and sloughing of skin with scant inflammatory changes occuring in children and occasionally adults
AKA: type II autoimmune Addison’s disease
Clinical: Addison’s disease, autoimmune thyroid disease and/or IDDM (without hypoparathyroidism or candidiasis)
AKA: T cell lymphoma/Mycosis fungoides
Clinical: Generalized exfoliative erythroderma but rarely proceeds to tumefacation.
Micro: Leukemia with Sezary (cerebriform T) cells
Stains: CD4+, CD2+, CD7-
Clinical: post-partum pituitary necrosis and infarction; may also occur ouside the setting of pregnancy or in males. Clinically presents with gonadal deficiency, hypothyroidism or adrenocortical insufficiency.
Pathophysiology: Due to shock but may be secondary to DIC, sickle cell anemia, cavernous sinus thrombosis, temporal arteritis or trauma
Clinical: progressive encephalo-myelopathy, autonomic dysfunction, low BP, impotence, incontinence, anhidrosis, external opthalmoparesis, muscle tremor and wasting (Parkinsonian)
Clinical: Sjögren’s syndrome occuring without another autoimmune disorder (like rheumatoid arthritis)
AKA: MEN IIa
Clinical: dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia) ® caries, bilateral lacrimal and parotid enlargement, ± rheumatoid arthritis, Raynaud’s phenomena, facial telangectasias, increased risk of lymphoid malignancy (40 x)
Pathophysiology: autoimmune destruction of lacrimal and salivary glands
Primary Sjögren’s associated with HLA-DR3 and has organ involvement:
e.g. lung – recurrent infections, interstitial fibrosis, GI – angular cheilitis, beefy red tongue, hepatomegaly and PBC; kidney – RTA, interstitial nephritis;
Secondary Sjögren’s associated with HLA-DR4 and is limited to lacrimal/salivary glands
Diagnosis: Antibodies to SS-A (Ro) and SS-B (La); Schirmer’s test – absorptive paper to eyes
Micro: Renal involvement is tubulointerstitial nephritis (not glomerular as in SLE or Scleroderma)
AKA: Polycystic ovaries
Clinical: hirsutism, obesity, amenorrhea, infertility, risk for endometrial carcinoma
Diagnosis: excess LHRH ® LH ® estrogens, androgens
Gross: large ovaries with thickened tunica albuginea and evenly distributed cysts
Micro: Vaginal smears show intermediate to superficial cell maturation.
Clinical: severe form of erythema multiformemore common in children with mucosal involvement (hemorrhagic crusts involving lips and mucosa, conjunctiva, urethra, genital or perianal areas), high fever
Clinical: post-mastectomy lymphedema of the arm ® angiosarcoma
AKA: Juvenile rheumatoid arthritis
AKA: Encephalotrigeminal angiomatosis
Clinical: Port wine stain (nevus flamus) in the area of the trigeminal nerve, venous angiomas of leptomeninges, retina and cortex, associated mental retardation, seizures, hemiplegia and radiopacities of the skull (intracranial calcifications); choroid angioma ± glaucoma (any 2 fulfill criteria), pheochromocytomas
Pathophysiology: faulty development of mesodermal and ectodermal elements
Syndromic Large Cell Calcifying Sertoli Cell Tumor
Clinical: < 20 years old, LCCSCT, frequently bilateral; pituitary tumor; pigmented nodular adrenal hyperplasia, cardiac myxomas, Peutz Jegher’s polyps
Systemic Lupus Erythematosus
Mnemonic: SOAPBRAIN M.D. (see Clinical)
15-50/100,000 8xF>M, 3x Black females>white females; 50% concordance in identical twins
6% associated with complement C2 deficiency
Arthritis/synovitis (usually peripheral polyarthritis)
Blood Dyscrasias: hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia
Renal: proteinuria, casts, hematuria, azotemia
Immune abnormalities: LE cells, anti-dsDNA, anti-Smith, VDRL/RPR+, decreased C3
Neurological Disease: seizures, psychosis in the absence of drugs or known metabolic derangements
With pregnancy there is an increased incidence of pre-eclampsia, uterine infection, SAb, prematurity, IUGR, congenital heart bloack and endomyocardial fibrosis. There is also exacerbation of disease with decreased renal function, anemia, leukopenia, thrombocytopenia. Avoid oral BCP because they worsen SLE symptoms. IUDs are associated with recurrent pelvic infections.
Pathophysiology: Drug-induced (anti-histone Ab positive): hydralazine, procainamide, penicillamine, INH, phenytoin
Diagnosis: ANA, anti-ds DNA, anti-histone, anti-Sm, SS-A (Ro)
Micro: Hematoxylin bodies – LE cell; fibrinoid necrosis, onionskin lesions
IF: Skin: immunoglobin deposition in dermo-epidermal junction of normal-appearing as well as clinically involved skin
Cytogenetics: Associations with HLA-DR2 and HLA-DR3 (deletion of C4a gene)
Clinical: large orange tonsils, hypolipedemia, corneal opacities, neuropathy, splenomegaly
Pathophysiology: HLA deficiency
Clinical: thrombocytopenia, absent radius, ± congenital heart or renal abnormalities
AKA: GM2 Gangliosidosis, Hemoaminidase a-Subunit Deficiency
Clinical: Easter European (Ashkenazi) Jews. Carrier rate 1 in 30. Present at age 6 months: motor incoordination, mental obtundation leading to muscular flaccidity, blindness and dementia. Death by age 2-3 years.
Pathophysiology: Deficiency of hexoaminidase A causes inability to catabolize GM2 Gangliosides
Diagnosis: Retina cherry-red spot.
Micro: Neurins in CNS and autonomic nervous system.
Stains: Oil red O, Sudan Black positive.
EM: Cytoplasmic inclusions: whorled configurations within lysosomes (onio-skin)
Cytogenetics: Chromosome 15, mutations in a subunit locus
Clinical: multiple sebaceous neoplasms and internal malignancy
Toxic Shock Syndrome
Clinical: Volume-resistant shock, diffuse macular rash, conjunctivitis, sore throat, GI upset.
Pathophysiology: Staphylococcus infection (via tampons or wounds)
Clinical: migratory thrombophlebitis seen in patients with a malignancy (pancreatic carcinoma)
Mneumonic: THAT’S TS (Tubers, Hamartomas, Angiomyolipomas/Angiofibromas/Adenoma Sebaceum, reTinal tumors, Shagreen skin, hearT rhabdomyoma, Subungal/Seizures)
AKA: Bourneville’s Disease
Clinical: cortical hamartomas/tubers (mental retardation, seizures, epilepsy), cutaneous hamartomas (angiofibromas, sebaceous adenomas), retinal phakomas (fibromas), shagreen skin, ash-leaf hypopigmented macules, subungal hamartomas, visceral/pancreatic cysts, renal angiomyolipomas (80%; multiple or bilateral), rhabdomyoma of the heart, increased risk of retinal glial hamartomas and gemistocytic astrocytomas
Transmission: AD with variable expression
Clinical: colon adenomatous polyps with high malignant potential & brain tumors (medulloblastoma and fibrillary astrocytoma)
Clinical: shield chest, webbed neck, short stature, cystic hygroma, valgus deformity of elbows, low hair line, pigmented nevi, risk of atypical polypoid adenomyoma of uterus, aortic coarctation
Cytogenetics: XO, due to nondisjunction of X chromosome, occasionally mosaic
Gross: Ovarian agenesis
Micro: no follicles in ovary (menopause before menarche). Atrophic vaginal smear with maturation index 100/0/0
Clinical: congenital nerve deafness, retinitis pigmentosa
AKA: Infection with body louse
Vanishing bile duct syndrome
Micro: irreversible loss of of bile ducts in >50% of portal tracts following liver transplantation
von Gierke Disease
AKA: Type I glycogenosis
Clinical: Hepatomegaly, renomegaly, hypoglycemia (convulsions), hyperlipidemia, hyperuricemia, gout, skin xanthomas, platelet dysfunction, hepatic adeomas
Pathophysiology: Deficiency of glucose-6-phosphatase
Prognosis: With treatment most survve and develop late complications (hepatic adenomas)
Clinical: hemangioblastomas of the cerbellum, retina or brainstem, hemangiomas and cysts of the pancreas, liver, kidneys, epididymis and increased risk of renal cell carcinoma (60%), pheochromocytomas and testicular cystadenomas/carcinomas
Transmission: AD, gene on 3p25-26 encodes pVHL a tumor suppressor gene
Pathophysiology: pVHL protein inhibits the elongation step of RNA synthesis by interacting with elongin B and elongin C
Diagnosis: Polycythemia associated with the hemangioblastoma in 10% of cases (EPO production by tumor)
Treatment: nephrectomy for RCC, laser therapy for retinal hemangioblastomas
Von Recklinghausen’s Disease
AKA: Neurofibromatosis I
Clinical: white forelock, lacrimal punctae, width of root of nose, synophrus (eyebrows grow together), cochlear deafness,
Transmission: AD: PAX 3
Clinical: Wilms’ tumor, Aniridia, Genital anomalies, mental Retardation
35% chance of developing Wilms’ tumor (see also Denys-Drash Syndrome and Beckwith-Wiedemann Syndrome for other Wilms’ tumor associated syndromes)
Transmission: AD, gene WT-1 on 11p13
Pathophysiology: nonsense or frameshift mutation
Clinical: Acute adrenocortical insufficiency from sudden hemorrhagic destruction of the adrenals, usually secondary to meningococcemia
Prognosis: vasomotor collapse and shock ® death.
AKA: Relapsing febrile nodular (lobular) panniculitis
Clinical: Nonvasculitic panniculitis with crops of erythematous plaques or nodules on lower extremities of kids and adults.
Clinical: Severe leptospirosis with jaundice, bleeding and renal failure
AKA: Infantile progressive spinal muscular atrophy
Clinical: congenital hypotonia (“floppy infant”). Death from respiratory failure or aspiration
Micro: absence/loss of lower motor neurons from anterior horns of spinal cord and neurogenic muscular atrophy
AKA: MEN I
Clinical: Rare disease characterized by premature aging, risk of sarcoma
Pathophysiology: Defective DNA helicase (involved in DNA replication & repair)
AKA: Wernicke’s encephalopathy and Korsakoff’s psychosis
Pathophysiology: Thiamine (vitamin B12) deficiency
Gross: Hemorrhagic lesions in mammillary bodies
Clinical: A systemic disease affecting white males in 30’s-40’s (M:F is 10:1) involving small intestine, skin, CNS, joints, heart, blood vessels, kidney, lungs, serosal memebranes, lymph nodes, spleen and liver. Presents with malabsorption, diarrhea and polyarterthritis, obscure CNS complaints, lymphadenopathy and hyperpigmentation of the skin.
Pathophysiology: Tropheryma whippelii, gram-positive actinomycete
Micro: Small intestinal mucosa laden with distended macrophages in the lamina propria. Villi expansion, mucosal edema, enlarged mesenteric lymph nodes. Bacilli-laden macrophages can also be found in synovium, brain, heart valves, etc. but other inflammation is essentially absent.
Stains: Macrophages are PAS positive
EM: Rod-shaped bacilli
Treatment: Antibiotic therapy
Clinical: Idiopathic hypercalcemia of infancy leading to metastatic calcifications
Pathophysiology: Abnormal sensitivity to vitamin D
AKA: Hepatolenticular degeneration
Clinical: Presentation in childhood, rarely before age 6 with acute or chronic liver disease, neuropsychiatric sx (behavioral changes, psychosis, Parkinson-like). Kayser-Fleisher rings (green-brown deposits in Descemet membrane between limbus and cornea). Copper deposition occurs in liver, brain, cornea, kidneys, bones, joints and parathyroids
Pathophysiology: Accumulation of toxic levels of copper due to defect in ATP7B gene on chromosome 13, encoding a transmembrane copper-transporting ATPase. Majority of patients are compound heterozygotes.
Diagnosis: Decreased serum ceruloplasmin, increased hepatic copper (>250 ug/gm dry weight) and urinary copper excretion.
Micro: Liver can show fatty change, acute or chronic hepatitis leading to cirrhosis; rare massive liver necrosis.Brain has toxic injury to basal ganglia and putamen with atrophy and cavitation.
Stains: Rhodamine or orecin stain copper (can’t be seen on H&E).
Treatment: D-penicillamine chelation therapy
AKA: Immunodeficiency with thrombocytopenia and eczema
Clinical: Thrombocytopenia, eczema, recurrent infections; risk of non-Hodgkin’s lymphomas
Transmission: X linked recessive
Diagnosis: ¯ IgM, Nomal IgG, IgA and IgE; Maps to Xp11.23
Gross: Thymus is morphologically normal
Micro: Depletion of T lymphocytes in the peripheral blood and paracortical lymph nodes
Pathophysiology: Deficiency of acid lipase (lysosomal storage disease) resulting in accumulation of cholesterol esters and triglycerides
Clinical: Anthrax in which a diffuse pneumonia occurs which is characterized by extensive serofibrinous exudation that may produce total lobar consolidation with paucity of pmns, hemorrhagic necrosis of alveolar septa, and overwhelming abundance of gram-positive bacteria within the exudate.
Pathophysiology: Bacillus anthracis
Clinical: extreme photosensitivity, 2000-fold increased risk of skin cancer in sun-exposed skin, neurologic abnormalities
Pathophysiology: inability to repair UV induced DNA damage
AKA: cerebro-hepato-renal syndrome
Clinical: hypotonia, incomplete myelinization, craniofacial malformations, hepatomegaly with cirrhosis, glomerular cysts
Clinical: alcoholic fatty liver, hypercholesterolemia, hypertriglyceridemia with hemolysis, upper abdominal pain and fever.
Micro: stomatocytosis on peripheral smear
Clinical: gastric hyperplasia due to gastrin secreting tumor (pancreatic islet cell tumor)