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

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

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

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

• A/w variety of endocrine neoplasms;

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

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

• A/w psammomatous melanotic schwannoma

• AR, desmoplakin mutations

• A/w dilated left ventricular cardiomyopathy

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

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

• ↑IgE levels

• Most common causes of mortality: myocarditis and coronary arteritis

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

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

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

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

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

• ↑risk of rhabdomyosarcoma and transitional cell (bladder) CA

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

• Multiple forms:

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

• AD: benign course; Elastin (ELN) > FBLN5

• XLR: ATP7A (copper transporter)

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

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

• Pulmonary: bronchiectasis, emphysema → right-sided heart failure

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

• GI: diverticulae

• A/w ECG changes and pericarditis

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

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

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

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

• AD; caused by mutations in collagen III (COL3A1)

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

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

• Most important feature is vascular fragility → arterial aneurysms, dissection, and rupture (Mnemonic: “IV = vascular”)

• A/w cardiac vegetations and valvular dysfunction

• A/w high-output cardiac failure

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

• XLR; GLA gene mutation → α-galactosidase deficiency

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

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

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

• HFE gene mutation

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

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

• HHT1 = endoglin (ENG)

• HHT2 = Alk-1 (ACVRL1)

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

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

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

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

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

• A/w mental retardation and seizures

• Type I: LPL deficiency and ApoC-II deficiency

• Type II: LDL receptor defect and ApoB-100 defect

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

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

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

• Associated systemic findings:

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

• Type II and III: atherosclerosis → MI and stroke

• A/w coronary artery aneurysms (potentially fatal)

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

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

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

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

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

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

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

• Classically p/w pulmonary + skin involvement

• AD; gene mutation in Fibrillin-1

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

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

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

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

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

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

• P: posterior fossa malformations

• H: hemangiomas

• A: arterial anomalies

• C: cardiac defects and coarctation of the aorta

• E: eye anomalies

• S: sternal defects and supraumbilical raphe

• AR, plakoglobin mutation

• A/w arrhythmic right ventricular cardiomyopathy

• AD; mutation in NF1 gene (neurofibromin)

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

• A/w restrictive cardiomyopathy, conduction abnormalities, and proteinuria

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

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

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

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

• A/w tracheal and nasal collapse

• A/w aortic insufficiency and dissecting aortic aneurysm

• Acute phase: pericarditis

• Chronic: mitral and aortic valve disease

• Pulmonary: pulmonary artery HTN and interstitial lung disease

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

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

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

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

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

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

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

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

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

• Diffuse orange-yellow discoloration

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