CONGENITAL ADRENAL HYPERPLASIA

CONGENITAL ADRENAL HYPERPLASIA (CAH)

CAH is a familial autosomal recessive disorder of adrenal steroid biosynthesis in which one of enzyme necessary for cortisol production has defiant activity.

Decreased serum cortisol levels stimulate adrenocorticotropic hormone (ACTH) release via negative feedback. The adrenal glands undergo hypertrophy, apparently due to ACTH-stimulated production of insulinlike growth factor 2. Increased ACTH secretion also results in overproduction of both the adrenal steroids preceding the missing enzyme and those that do not require the missing enzyme.

Aldosterone (mineralocorticoid) synthesis and secretion is regulated via renin-angiotensin system (adrenal zone glomerulosa), which is responsive to the electrolyte balance state and plasma volume. Aldosterone secretion is also directly stimulated by high serum potassium concentrations.

Cortisol (glucocorticoid) synthesis and secretion is regulated by ACTH (adrenal zone fasciculate), which stimulates the enzyme P-450scc (20, 22 Desmolase) with subsequent increased production of all adrenal steroids.

Approximately 80-90 % of individuals with ACH have 21α-hydroxylase deficiency: ↓ cortisol (increased ACTH), ↓ mineralocorticoids, ↑ sex hormone. Masculinization, female pseudohermaphroditism, hypotension, hyperkalemia, ↑ plasma rennin activity, and volume depletion. Salt wasting can be lead to hypovolemic shock in the newborn.

The second most common types of ACH is the 11β-hydroxylase deficiency, it has an incidence of about 1 in 100.000.

Finding: ↓ cortisol, ↓ Aldosterone and Corticosterone, ↑ sex hormones

Masculinization, hypertension (like Aldosterone, 11-deoxycorticosterone is a mineralocorticosteroids and is secreted in excess).

17α-hydroxylase deficiency is probably even more rare genetic disorder of steroid biosynthesis that causes decreased production of glucocorticoids and sexual steroids, and increased synthesis of mineralocorticoids precursors.

Finding: ↓ sex hormone, ↓ cortisol, ↑ mineralocorticoids.

Hypertension, hipokalemia.

XY: ↓ Dihydrotestosterone → pseudohermaphroditism (external phenotypic female, no internal reproductive structure).

XX: external phenotypic female with normal internal sex organs, but lacking secondary sexual characteristics (sexual infantilism).

Hypogonadism occurs as a result of deficient sex steroid production. Deoxycorticosterone mineralocorticoid activity causes sodium retention, plasma volume expansion, hypertension, hipokalemia, and decreased renin and Aldosterone levels in most untreated patients with 17α-hydroxylase deficiency.

Exogenous glucocorticoid therapy is the treatment of choice.

All congenital adrenal enzyme deficiencies are characterized by an enlargement of adrenal glands due to an ↑ in ACTH stimulation because of the ↓ levels of cortisol.

ADRENAL PHYSIOLOGY

CHF pathophysiology

CARDIOVASCULAR PATHOLOGY (vasculitis small-medium-large vessels).

Telangiectasia	Dilated vessels on skin and mucous membrane. Osler-Weber-Rendu Syndrome (autosomal dominant inheritance-nosebleeds and skin discoloration)	Affects small vessels
Raynaud’s disease	Decreased blood flow to the skin due to arteriolar vasospasm in response to cold temperature or emotional stress. Most often in the fingers and toes.	Small vessels
Wegener's granulomatosis	Necrotizing vasculitis. Necrotizing granulomas in the lungs and upper airway. Necrotizing glomerulonephritis. (Perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis, cough, dysnea, hemoptysis, hematuria). *c-ANCA Treatment: Cyclophosphamide and corticosteroids.	Small vessels
Microscopic polyangeitis	Like Wegener’s but lacks granulomas *p-ANCA	Small vessels
1º pauci-immune crescentic glomerulonephritis	Limited to the kidneys	Small vessels
Churg-Strauss syndrome	Granulomatous vasculitis with eosinophilia. Involves lungs, heart, skin, kidneys, and nerves. Often seen in atopic patients. *p-ANCA	Small vessels
Sturge-Weber disease	Congenital vascular disorder. Port-wine stain on face and leptomeningeal angiomatosis (intracerebral AVM)	Small vessels

Henoch-Schönlein purpura	Most common form on childhood. Skin rash on buttocks and legs, arthralgia, intestinal hemorrhage, abdominal pain, and melena. Follows with URIs. Associates with IgA nephropathy. Lesions at the same age	Small vessels. Common triad -skin -joints -GI
Buerger’s disease (thromboangiitis obliterans)	Idiopathic, segmental, thrombosing vasculitis. Seen in heavy smokers. Intermittent claudication, superficial nodular phlebitis, cold sensitivity (Raynaud’s phenomenon), severs pain in affected part. May lead to gangrene and autoamputation digits. Treatment: smoking cessation	Small and medium vessels. Cause thrombosis/ Infarction of arteries.
Kawasaki disease	Acute, self-limiting disease of infants/kids. May develop coronary aneurysms. Fever, congested conjunctiva, strawberry tongue, lymphadenitis.	Necrotizing vasculitis of small and medium vessels.
Polyarteritis nodosa	Fever, weight loss, malaise, abdominal pain, melena, headache, myalgia, hypertension, neurologic dysfunction, cutaneous eruption. Hepatitis B + in 30 % Aneurysms and constrictions on arteriogram. Treatment: corticosteroids, Cyclophosphamide.	Necrotizing immune complex inflammation of medium sized muscular arteries. Lesions at different ages.
Takayasu’s arteritis (pulseless disease)	Asian females <40 years old. Fever, arthritis, night sweats, myalgia, skin nodules, ocular disturbances, weak pulse in upper extremities.	Granulomatous thickening of aortic arch and /or proximal great vessels.

Temporal arteritis (giant cell arteritis)

Most common vasculitis that affects medium and large arteries, usually branches of carotid artery. Focal, Granulomatous inflammation. Affects elderly females. Unilateral headache, jaw claudication, impaired vision. ↑ ESR, systemic involvement and polymyalgia rheumatic. Treatment: high doses of steroids.

Medium and large arteries.

INFECTIVE ENDOCARDITIS (IE).

Infective endocarditis is a microbial infection on the endothelial surface of the heart, which includes one or more heart valve, the mural endocardium or septal defect. IE produce a wide variety of systemic signs and symptoms through a several mechanisms, including both sterile and infected embolic and various immunological phenomena.

IE generally occur as a consequence of nonbacterial thrombotic endocarditis, which result s from turbulence or trauma to the endothelial surface of the heart. A transient bacteriemia then seeds the sterile platelet/fibrin thrombus, which IE as the end result. Pathologic effects due to infection can include local tissue destruction and embolic phenomena. In addiction, secondary autoimmune effects, such as immune complex glomerulonephritis and vasculitis, can occur.

Endocarditis can be broken down into the fallowing categories:

.Native valve endocarditis: Acute (Staphylococcus aureus, high virulence, large

                                            vegetation on previously normal valves). 

                                            Subacute (Streptococcus viridans, low virulence,

                                            smaller vegetation on congenitally abnormal or diseased

                                             vales.

                                             Sequela of dental procedures. More insidious onset)

.Prosthetic valve endocarditis, early and late.

.Intravenous drugs abuse endocarditis.

Other types include.

_Pacemaker IE.

_Nosocomial IE.

Endocarditis may also be nonbacterial secondary to malignancy or hypercoagulable state (marantic/thrombotic endocarditis).

Streptococcus bovis is present in colon cancer and staphylococcus epidermidis on prosthetic valves.

Mitral valve is most frequently involved, closely fallowed by the aortic valve, the combined mitral and aortic valve, the tricuspid valve (associated with intravenous drugs abuse), and, rarely, the pulmonic valve.

General finding:

Fever (most common symptom).

Roth’s spots (round white spot on retina surrounded by hemorrhage).

Osler’s node (tender raised lesions on finger or toes pads)

New murmur (caused by valvular damage)

Janeway lesions (small erythematous lesion on palm or sole)

Anemia.

Splinter hemorrhages on nail bed.

Signs of neurological disease: Embolic stroke with focal neurologic deficit is the most common etiology.

Signs of systemic septic emboli are due to left heart disease and are more common associated with mitral valve vegetation. Multiples embolic pulmonary infections or infarction are due to right heart disease.

Signs of congestive hear failure.

Diagnosis considerations.

The clinical criteria for definitive infectious endocarditis (Duke Criteria) include 2 major, 1 major and 3 minor, or 5 minor.

Major criteria.

Positive blood culture: 2 separate cultures for a typical endocarditis microorganism, persistently positive cultures, or evidence of infection with a Coxiella organism and/or Q fever.

Positive echocardiography finding: oscillating mass and/or vegetation, paravalvular abscess, or dehiscence of prosthetic valve.

New valvular regurgitation.

Minor criteria.

Predisposition: history of IV drug use or congenital heart disease).

Fever with a temperature of more than 38 º C.

Vascular phenomena (arterial emboli, septic pulmonary infarcts, intracranial hemorrhage, conjunctival hemorrhage, Janeway lesions).

Immunologic phenomena (glomerulonephritis, Osler node, Roth spots, a positive result for rheumatoid factor).

Positive blood culture findings without meeting the criteria above or serologic evidence of active infection consistent with endocarditis.

Treatment: Antibiotic are the mainstay of treatment. Goals to maximize treatment success are early diagnosis, accurate microorganism identification, and reliable susceptibility testing, prolonged intravenous administration of bactericide antimicrobial agents, proper monitoring of potentially toxic antimicrobial regimens, and aggressive surgical managements of correctable mechanical complications.

Prognosis largely depends on whether or not complications develop. If left untreated, IE is generally fatal. Early detection and appropriate treatment of this uncommon disease can be lifesaving.

CONGENITAL LONG QT SYNDROME (LQTS)

Long QT syndrome remains an underdiagnosed disorder especially because at least 10-15% of LQTS gene carriers have a normal QTc duration. 

Long QT syndrome is a congenital disorder characterized by a prolongation of QT interval on ECG and a propensity to ventricular tachyarrhythmia, which may lead to syncope, cardiac arrest, or sudden death.

The QT interval represent the duration of activation and recovery of the ventricular myocardium. The Bazett formula is the most common form to calculate the QTc, as follows:

            QTc    =   QT/ square root of R-R interval (in seconds)

(QT interval corrected)

Group	Prolonged QTc (s)	Borderline QTc (s)	Reference Range (s)
Children and adolescents (< 15 y)	>0.46	0.44-0.46	< 0.44
Men	>0.45	0.43-0.45	< 0.43
Women	>0.46	0.45-0.46	< 0.45

Prolonged recovery from electrical excitation increases the likelihood of dispersing refractoriness, when some part of myocardium might be refractory to subsequent depolarization.

In LQTS the transmural dispersion of repolarization increases and creates a functional substrate for transmural reentry.

QT prolonged can lead to polymorphic ventricular tachycardia, or torsade de pointes, which itself may lead to ventricular fibrillation and sudden cardiac death. Torsade de pointes is widely thought to be triggered by reactivation of calcium channels, reactivation of delayed sodium current, or a decreased outward potassium current. That result in early afterdepolarization, in a condition with enhanced transmural dispersion of repolarization usually associated with prolonged QT interval.

The transmural dispersion of repolarization also increases the likelihood of early afterdepolarization, the triggering event to torsade de pointes, by prolonging the time window for calcium channels to remain open.

LQTS is caused by mutation of genes encoding for cardiac in channel protein that cause abnormal ion (potassium, sodium, calcium) channel kinetics. At least 10 gene have been identified, 6 types of Roman-Ward syndrome, 1 type of Andersen syndrome, 1 type of Timothy syndrome and 2 types of Jervell and Lang-Nielsen syndrome.

The information about what medication the patient has taken is critical for the differential diagnosis of congenital LQTS and drug-induced QT prolongation; drug-induced LQT also may have a genetic background.

Other causes of LQTS acquired include electrolyte imbalance, marked bradycardia, cocaine, organophosphorus compounds, subarachnoid hemorrhage, myocardial ischemia, protein-sparing fasting, autonomy neuropathy, and human immunodeficiency diseases (HIV).

The Long QT syndrome is usually diagnosed after a person has a cardiac event (the most typical clinical presentation), a family member suddenly dies, or because an ECG shows QT prolongation.

LQTS has been recognized as mainly Romano-Ward syndrome (familial occurrence with autosomal dominant inheritance, QT prolongation and ventricular tachyarrhythmia).

Finding in the physical examination usually do not indicate a diagnosis of LQTS, though some patients may present with excessive bradycardia for their age, hearing loss (congenital deafness), indicating the possibility of autosomal recessive inheritance like the Jervell and Lang-Nielsen syndrome. Skeletal abnormalities, such as short stature and scoliosis are seen in LQT7 (Andersen syndrome), and congenital heart diseases, cognitive and behavioral problems, musculoskeletal diseases, and inmunodysfunction may be see in those with LQT8 (Timothy syndrome).

MEDICAL CARE

All patients with LQTS should avoid drugs that prolong the QT interval or reduce their serum potassium and magnesium levels.

Beta-Blockers are drugs of choice for patient with LQTS.

The implantable cardioverter-defibrillator (ICD) should be implanted for survivor of cardiac arrest and is recommended class IIa for patients with syncope while receiving beta-blockers. ICD can be considered class IIb for primary prevention in patients with high risk (include LQT2, LQT3 and QTc interval greater then 500ms).

Left cervicothoracic stellectomy is another antiadrenergic therapeutic measure used in patients with high risk, especially in those with recurrent cardiac event despite beta-blocker therapy.