Low BP with high jugular pressure should always raise the suspicion of cardiac tamponade. Fever and chest pain with dyspnea and tachypnea should raise suspicion of pericardial effusion with hemodynamic compromise. Paradoxical pulse is a typical finding of cardiac tamponade. Therefore, the correct answer is 5.

Low BP with high jugular pressure should always raise the suspicion of cardiac tamponade. Fever and chest pain with dyspnea and tachypnea should raise suspicion of pericardial effusion with hemodynamic compromise. Paradoxical pulse is a typical finding of cardiac tamponade. Therefore, the [HIDDEN].

A patient with a history of fever and chest pain comes to the hospital with dyspnea and tachypnea. On physical examination, the blood pressure cyphrads are low, jugular venous pressure is elevated with a deep descending sinus X, and he has a pulsus paradoxus. What pathology should be suspected?

Pericardial effusion with cardiac tamponade.

ANESTHESIOLOGY, CRITICAL CARE AND EMERGENCIES

[Recurrent autoreactive pericardial effusion. Impact of an aetiological classification of pericarditis].

A 36 year-old man suffered from fever, fatigue, pleurodynia and precordial discomfort. His family physician suspected febrile tracheobronchitis and treated it with ampicillin for 5 days. Because symptoms persisted an ECG was done which suggested acute myocardial infarction. The patient underwent an emergency coronary angiography which excluded coronary artery disease and aortic dissection. Pericarditis was suspected and the patient put on aspirin, 500 mg/d. Because of persisting cardiac symptoms an echocardiography was performed which revealed systolic separation between epi- and pericardium, characteristic of a small pericardial effusion after acute pericarditis. The symptoms improved after one week of treatment with diclofenac and the ECG had become normal. Two months later the patient was seen at our cardiac outpatient clinic. He had night sweats, sporadic precordial pain and severe dyspnoe. Further investigations revealed tachycardia (120/min), hypotension (95/70 mm Hg), pulsus paradoxus and jugular vein sustension. Echocardiography revealed a large pericardial effusion ("swinging heart"), which explained the low voltage and the electrical alternans in the ECG. Pericardiocentesis was carried out the same day to relieve the tamponade. It was followed by pericardioscopy and epi- as well as pericardial biopsy. 485 ml of a serous effusion were drained. Cytology and histology demonstrated a lymphocytic fibrinous pericarditis. Polymerase chain reaction (PCR) on viral and bacterial RNA and DNA of potentially cardiotropic agents remained negative. The pigtail catheter was left in place and 80 mg of gentamycin were given intrapericardially on day 1 and 2, followed by 500 mg of crystalloid triamcinolone acetate after the PCR was found to be negative. Oral treatment with 0.5 mg colchicine three times a day (off-label use) was started and maintained for 6 months. After 9 months no effusion was detected and the patient was free of symptoms. After exclusion of bacterial and viral pericardial infection, a high single dose of intrapericardial triamcinolone combined with long-term oral colchicine has proven to be a highly efficacious treatment of autoreactive pericarditis which will avoid relapses in most cases.

Cases from the Osler Medical Service at Johns Hopkins University.

PRESENTING FEATURES: A 70-year-old African American man was admitted with a history of fever, chills, and malaise of several days' duration. His past medical history was notable for end-stage renal disease requiring hemodialysis, coronary artery disease, and aortic stenosis requiring a bioprosthetic aortic valve replacement. On the day of admission, the patient was noted to have a shaking chill while undergoing dialysis through his catheter and was admitted to the hospital. He complained of pain at the catheter insertion site, shortness of breath, and dyspnea on exertion, but denied chest pain. On physical examination, the patient had a temperature of 100.4 degrees F, with a heart rate of 64 beats per minute, blood pressure of 127/72 mm Hg, and an oxygen saturation of 97% on room air. He was a mildly obese man in no apparent distress. He had shotty cervical lymphadenopathy and a right subclavian dialysis catheter in place, with erythema and pus at the entry site. His jugular venous pressure was 10 cm H(2)O. Lung examination showed bibasilar rales. Heart sounds were normal, with no rub or gallop. He had a 2/6 systolic ejection murmur best heart at the left sternal border as well as a 3/6 holosystolic murmur at the apex that radiated to his left axilla. Examination of the abdomen and extremities was unremarkable. The patient's neurological examination was unremarkable, and he was alert and oriented to person, place, and time. Laboratory studies showed an elevated white blood cell count of 16,700 cells/microL. His blood urea nitrogen level was 43 mg/dL and his serum creatinine level was 4.9 mg/dL. Multiple blood cultures grew methicillin-resistant Staphylococcus aureus. An admission, chest radiograph showed no infiltrate. An admission electrocardiogram showed normal sinus rhythm with first degree atrioventricular block, left anterior fascicular block, and left ventricular hypertrophy. shows rhythm strips from lead II electrocardiograms 5 months before admission (top), on admission (middle) and 5 days after admission (bottom). What is the diagnosis?

Pulsus Paradoxus -- History and Physical

Intracardiac shunts or moderate to severe valvular insufficiency Co-existing disease that significantly increases left or right ventricular diastolic pressure such severe systemic hypertension, aortic stenosis, or cor pulmonale Aortic dissection resulting in pericardial effusion/tamponade Cardiac tamponade in hypovolemia

Cardiac Tamponade -- History and Physical

Patients with cardiac tamponade present similar to patients with other forms of cardiogenic or obstructive shock. They may endorse vague symptoms of chest pain, palpitations, shortness of breath, or in more severe cases, dizziness, syncope, and altered mental status.  They may also present in a pulseless electrical activity cardiac arrest. The classic physical findings in cardiac tamponade included in Beck’s triad are hypotension, jugular venous distension, and muffled heart sounds. Pulsus paradoxus, which is a decrease in systolic blood pressure by more than 10 mm Hg with inspiration is an important physical exam finding that suggests a pericardial effusion is causing cardiac tamponade. Pulsus paradoxus may be absent in patients with ASD, elevated diastolic pressures, pulmonary hypertension and aortic regurgitation. The Kussmaul sign - a paradoxical elevated in JVP and pressure during inspiration is sometimes seen in cardiac tamponade.

Aortic Valve Disease -- History and Physical

Aortic regurgitation when acute and/or severe can be suspected when the patient has a wide pulse pressure, and a low pitched early diastolic murmur is auscultated again over the right sternal border at the second intercostal space. Accentuated P2 may also be noticed due to elevated pressures in the pulmonary vasculature. Chronic aortic regurgitation may illicit a blowing diastolic decrescendo murmur with a positive correlation between the duration of murmur and the severity of the disease. Often auscultation of a laterally and inferiorly displaced apical impulse is present and sustained. Often there is the phenomenon of Corrigan pulse (water hammer), a bounding and forceful pulse that rapidly increases and collapses. Other less common physical exam findings include the de Musset sign, which is subtle head bobbing with a pulse, as well as the Quincke sign and Muller sign (pulsations on the fingernails and uvula, respectively). Similar physical exam findings to aortic stenosis can also be seen late in disease progression. Acute aortic regurgitation will present differently depending on the etiology. If a patient presents with tearing severe chest pain along with physical exam findings such as variation in blood pressure between the right and left extremities, consider aortic dissection as a cause. If the patient presented with a history of streptococcal infection along with fevers, swollen and tender joints, skin nodules, new onset of rash, then rheumatic heart disease would be high on the differential.

Kussmaul's sign

Causes The differential diagnoses of Kussmaul's sign includes constrictive pericarditis, restrictive cardiomyopathy, pericardial effusion, and severe right-sided heart failure. With cardiac tamponade, jugular veins are distended and typically show a prominent x descent and an absent y descent as opposed to patients with constrictive pericarditis (prominent x and y descent), see Beck's triad. Other possible causes of Kussmaul's sign include: Right ventricular infarction - low ventricular compliance Right heart failure Cardiac tumours Tricuspid stenosis Restrictive cardiomyopathy Pulmonary embolism Constrictive pericarditis History Kussmaul's sign is named after the German doctor who first described it, Adolph Kussmaul (1822-1902). He is also credited with describing Kussmaul breathing. See also Pulsus paradoxus References Symptoms and signs: Vascular

Pericarditis

Physical examinations The classic sign of pericarditis is a friction rub heard with a stethoscope on the cardiovascular examination, usually on the lower left sternal border. Other physical signs include a person in distress, positional chest pain, diaphoresis (excessive sweating); possibility of heart failure in form of pericardial tamponade causing pulsus paradoxus, and the Beck's triad of low blood pressure (due to decreased cardiac output), distant (muffled) heart sounds, and distension of the jugular vein (JVD).

Heart

Pericardial disease The sac which surrounds the heart, called the pericardium, can become inflamed in a condition known as pericarditis. This condition typically causes chest pain that may spread to the back, and is often caused by a viral infection (glandular fever, cytomegalovirus, or coxsackievirus). Fluid can build up within the pericardial sac, referred to as a pericardial effusion. Pericardial effusions often occur secondary to pericarditis, kidney failure, or tumours, and frequently do not cause any symptoms. However, large effusions or effusions which accumulate rapidly can compress the heart in a condition known as cardiac tamponade, causing breathlessness and potentially fatal low blood pressure. Fluid can be removed from the pericardial space for diagnosis or to relieve tamponade using a syringe in a procedure called pericardiocentesis. Congenital heart disease

Cardiac Syncope -- History and Physical

A careful physical exam will assess heart rate and rhythm. Any abnormalities will increase suspicion of cardiac arrhythmia. In addition, an elevated respiratory rate or hypoxia will increase suspicion of a pulmonary embolism. Jugular venous distention and hypotension are suggestive signs of an obstructive mechanical cardiac etiology. Pathological cardiac murmurs, specifically new ones, will clue one into a valvular etiology, hypertrophic cardiomyopathy, or an obstructive intracardiac lesion. Muffled sounds can be heard with pericardial tamponade. Pedal edema or other evidence of deep venous thrombosis increases a patient's risk of pulmonary embolism. [10]

InternalMed_Harrison

Diagnosis Due to the unstable condition of these patients, supportive therapy must be initiated simultaneously with diagnostic evaluation (Fig. 326-2). A focused history and physical examination should be performed, blood specimens sent to the laboratory, and an electrocardiogram (ECG) and chest x-ray obtained. Etiologies of Cardiogenic Shock or Pulmonary Edema Acute myocardial infarction/ischemia LV failure Ventricular septal rupture Papillary muscle/chordal rupture–severe MR Ventricular free wall rupture with subacute tamponade Other conditions complicating large MIs Post-cardiac arrest Post-cardiotomy Refractory sustained tachyarrhythmias Acute fulminant myocarditis End-stage cardiomyopathy LV apical ballooning Takotsubo’s cardiomyopathy Hypertrophic cardiomyopathy with severe outflow obstruction Aortic dissection with aortic insufficiency or tamponade Severe valvular heart disease Other Etiologies of Cardiogenic Shockb RV failure due to:

A Rare Case of MRSA Pericarditis with Expanding, Purulent Pericardial Effusion Leading to Uremic Kidney Failure from a Right, Necrotic Toe.

Purulent pericarditis is an extremely rare entity with only a few reported cases so far. This condition deserves prompt diagnosis because of its significant mortality rate if left untreated. A 76-year-old man with a past medical history of coronary artery disease (CAD) with percutaneous coronary intervention (PCI) to the left anterior descending artery (LAD) and right circumflex artery (RCA), ischemic cardiomyopathy with moderately reduced ejection fraction (EF 45-50%), peripheral artery disease (PAD), COVID-19 pneumonia complicated by fibrotic lung disease (on 3 liters of home oxygen), type-2 diabetes mellitus (T2DM), hypertension (HTN), hyperlipidemia (HLD), and chronic kidney disease (CKD) stage III presented with complaints of pleuritic chest pain and shortness of breath. On hospital day 1, he was afebrile and hemodynamically stable with physical exam remarkable for bibasilar crackles and dry gangrene of his right first toe. He developed progressive altered mental status, hypotension, oliguric renal failure, and respiratory distress on hospital day 6. On exam at this time, he had an elevated jugular venous distension (JVD) of 12-14 cm water, pericardial friction rub with decreased heart sounds, and orthopnea; all were consistent with cardiac tamponade clinically. An electrocardiogram (EKG) showed new ST elevations in leads I, II, and aVL with ST depression in aVR and V1 with only mild elevation in troponin I to 0.07 ng/mL. A transthoracic echocardiogram (TTE) was done on hospital day 7 and showed a moderate sized pericardial effusion with inferior vena cava (IVC) enlargement but no atrial collapse, ventricular collapse, IVC collapse, or respiratory variation in the mitral and tricuspid inflow velocities. Blood cultures grew methicillin-resistant <iStaphylococcus aureus</i (MRSA) on hospital day 6, and he was started on intravenous (IV) vancomycin. The differential diagnosis for his enlarging pericardial effusion included purulent pericarditis, uremic pericarditis, or hemorrhagic effusion. He had urgent diagnostic and therapeutic pericardiocentesis with removal of 350 milliliters of fluid. The pericardial fluid was cloudy, tan-brown with a gram stain showing gram-positive cocci in clusters and cultures growing MRSA, which confirmed the diagnosis of purulent pericarditis secondary to MRSA infection. After the pericardiocentesis, his blood pressure, respiratory distress, and renal failure improved. The source of the bacteremia was from osteomyelitis of his gangrenous, right toe with bone biopsy growing both MRSA and <iStreptococcus anginosus</i. He underwent toe amputation for definitive source control. He was discharged on hospital day 24 with a plan to complete 6 weeks of IV vancomycin.

InternalMed_Harrison

Additional clues to the etiology and importance of a heart murmur can be gleaned from the history and other physical examination findings. Symptoms suggestive of cardiovascular, neurologic, or pulmonary disease help focus the differential diagnosis, as do findings relevant to the jugular venous pressure and waveforms, the arterial pulses, other heart sounds, the lungs, the abdomen, the skin, and the extremities. In many instances, laboratory studies, an ECG, and/or a chest x-ray may have been obtained earlier and may contain valuable information. A patient with suspected infective endocarditis, for example, may have a murmur in the setting of fever, chills, anorexia, fatigue, dyspnea, splenomegaly, petechiae, and positive blood cultures. A new systolic murmur in a patient with a marked fall in blood pressure after a recent MI suggests myocardial rupture. By contrast, an isolated grade 1 or 2 mid-systolic murmur at the left sternal border in a healthy, active, and asymptomatic young

InternalMed_Harrison

or absence of a third heart sound (S3). Accurate characterization of cardiac murmurs provides important insight into the natural history of many valvular and congenital heart lesions. Finally, the important role played by the physical examination in enhancing the clinician-patient relationship cannot be overestimated. THE GENERAL PHYSICAL EXAMINATION Any examination begins with an assessment of the general appear-ance of the patient, with notation of age, posture, demeanor, and 267 SEC Tion 2 DiAgnoSiS oF CARDiovASCulAR DiSoRDERS overall health status. Is the patient in pain or resting quietly, dyspneic or diaphoretic? Does the patient choose to avoid certain body positions to reduce or eliminate pain, as might be the case with suspected acute pericarditis? Are there clues indicating that dyspnea may have a pulmonary cause, such as a barrel chest deformity with an increased anterior-posterior diameter, tachypnea, and pursed-lip breathing? Skin pallor, cyanosis, and jaundice can be

Aortic Stenosis -- History and Physical

The acquired aortic stenosis manifests with exertional dyspnea, syncope, angina, and, ultimately, heart failure. [17] [18] Typically, symptoms begin at the age of 50 to 70 years in patients with the bicuspid aortic valve and in greater than 70 years in patients with tri-leaflet valve calcific stenosis. Patients progressively experience a gradual decrease in exercise tolerance, dyspnea on exertion, and fatigue. Severe exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, and pulmonary edema show various degrees of pulmonary venous hypertension. Angina results from the combination of the need for increased oxygen in hypertrophied myocardium and reduction of oxygen delivery secondary to the excessive compression of coronary vessels. Syncope is caused by the decrease in cerebral perfusion occurring during exertion when the arterial pressure declines due to systemic vasodilation and an inadequate increase in cardiac output related to stenosis. It is also due to the malfunction of the baroreceptor mechanism in severe aortic stenosis. Non-cardiac symptoms include gastrointestinal (GI) bleeding and cerebral emboli. GI bleeding is observed in patients with severe aortic stenosis and is often associated with angiodysplasia or other vascular malformations. It manifests from shear stress-induced platelet aggregation and reduction in the von Willebrand factor. [19] Cerebral emboli occur due to microthrombi formation on thickened bicuspid valves. There is also an observed increase in the risk of infective endocarditis in patients with aortic valve disease, especially with a bicuspid valve. On examination, carotid upstroke can be observed on palpation. A slow-rising, late-peaking, and a low-amplitude carotid impulse, pulsus parvus et tardus, is an expected finding in severe aortic stenosis and, when present, is specific to aortic stenosis. On auscultation, the second heart sound may lack a split and can be heard as a single sound during inspiration. It can also become paradoxical when the closure of the aortic valve gets delayed than the pulmonic valve. A mid-systolic ejection murmur, heard best over the right second intercostal space, with radiation into the right neck. However, high-frequency components may radiate to the apex in calcified aortic valves, and this phenomenon is called the Gallavardin phenomenon. The murmur becomes softer in LV failure and when there is a fall of stroke volume.

Acquired Immune Deficiency Syndrome -- History and Physical -- Cardiac System [8]

HIV infection and ART likely contribute to increased cardiovascular disease in patients. Common presenting symptoms may include chest pain, shortness of breath, or fatigue. The examination should proceed as one would when assessing for acute coronary syndrome or valvular disease, palpating for chest wall pain, observing for jugular venous distension and peripheral edema, and auscultating for abnormal heart sounds, murmurs, or evidence of pulmonary edema. Cardiovascular AIDS-related illnesses could include purulent pericarditis or cardiac tamponade caused by Mycobacterium tuberculosis . If these conditions are suspected, observing for Beck’s triad of low blood pressure, jugular venous distension, and muffled heart sounds may confirm a compressive pericardial effusion.

Diagnostic Challenges in Chronic Constrictive Pericarditis.

Chronic constrictive pericarditis (CCP) is a disease that has multiple possible causes and is associated with variable clinical findings, depending on its severity. It develops insidiously, and in many cases, particularly in developed countries, no antecedent diagnosis can be found. These cases are termed idiopathic. Tuberculosis is the leading cause of constrictive pericarditis in developing nations but represents only a small minority in developed countries. Here the authors describe two different case reports where tuberculosis was the probable cause of CCP. A 21-year-old man born in Cape Verde living in Europe for 4 years and a 24-year-old man born in Guiné Bissau were both admitted due to intense precordial pain and syncope after exertion. Interestingly both had fatigability, dyspnea, chest discomfort and palpitations on exertion, as well as progressive involuntary weight loss and decubitus cough. On physical examination they had tachycardia, jaundice, cachexia, elevated jugular venous pressure, hepatomegaly and ascites. Both electrocardiograms showed prominent P waves and chest X-ray showed bilateral pulmonary interstitial infiltrates and enlargement of the right cavities. Analytically, elevated bilirubin, leukopenia and thrombocytopenia was also found in both. Echocardiography revealed findings, in both cases, compatible with CCP including less common signs as annulus reversus and annulus paradoxus. Thoraco-abdomino-pelvic CT from both patients revealed chronic liver disease with congestion, pleural effusion, pericardial calcifications, ascites and massive mediastinal and abdominal adenopathies. Blood cultures and IGRA test were negative. However, given the presumptive diagnosis of tuberculosis (TB), anti-TB therapy was started. Despite the diagnosis of "end-stage" CCP with very high operative risk multidisciplinary team decided after informed consent, to perform total anterior pericardiectomy, that occurred without complications. Pericardial and mediastinal biopsies, pericardial/pleural fluid cultures/ immune-phenotyping were inconclusive. Anti- tuberculosis therapy was maintained. After surgery, the patients had a remarkable clinical improvement (NYHA I) that persisted in 6- month follow-up. These two case reports illustrate that despite the markedly elevated operative risk of pericardiectomy in "end-stage" forms of disease after patients informed consent must be a considered option. The other point to consider is that, despite rare, tuberculosis still is a possible diagnosis to consider in CCP in Portugal.

Acute pericarditis

Corticosteroids are usually used in those cases that are clearly refractory to NSAIDs and colchicine and a specific cause has not been found. Systemic corticosteroids are usually reserved for those with autoimmune disease. Prognosis One of the most feared complications of acute pericarditis is cardiac tamponade. Cardiac tamponade is accumulation of enough fluid in the pericardial space --- pericardial effusion --- to cause serious obstruction to the inflow of blood to the heart. Signs of cardiac tamponade include distended neck veins, muffled heart sounds when listening with a stethoscope, and low blood pressure (together known as Beck's triad). This condition can be fatal if not immediately treated.

Pericarditis as a presenting sign of infective endocarditis: two case reports and review of the literature.

Pericarditis as a presenting sign of infective endocarditis is rare. Here we describe 2 cases and an additional 19 cases of pericarditis as a presenting sign of infective endocarditis reported during the last 40 y. 71% of patients were young males (mean age 43.2 y). The most commonly reported underlying conditions were diabetes mellitus type 2 (5 patients, 24%), and substance or alcohol abuse (4 patients, 19%). The native aortic valve was the most frequently involved valve. The most common symptoms were fever, cough or dyspnoea, and chest pain. Overt tamponade was diagnosed in 47% of the patients. However, pulsus paradoxus and pericardial friction rub were rare. A heart murmur was heard in 12 patients (57%). Staphylococcus aureus was the most commonly isolated pathogen concomitantly from blood and pericardial fluid. 16 patients (76%) were operated. Six underwent a pericardial procedure, 5 underwent valve replacement, 4 both, and 1 patient was operated for pseudoaneurysm. Mortality rates were 60% and 31% of patients treated with antibiotics alone versus antibiotics and surgical intervention, respectively. In patients presenting with pericarditis with or without cardiac tamponade, the possibility of infective endocarditis should be considered. Optimal therapy should consist of antibiotics and surgical intervention.

An important thing to keep in mind when considering pulsus paradoxus while discerning between pericardial and non-pericardial disease is the following: pulsus paradoxus in non-pericardial disease will usually manifest with a drop in systolic and diastolic pressures. This is in contrast to pericardial disease in which the drop is mainly in systolic pressure, diastolic pressure is usually minimally affected, and thus pulse pressure will be narrower.

Fibrinous Pericarditis -- History and Physical

Other critical clinical signs to be aware of are signs of tamponade such as raised jugular venous pressure (JVP), muffled heart sounds, and decreased blood pressure. If pericardial tamponade is concerned, checking for a pulsus paradoxus is recommended. It is defined as a drop of systolic blood pressure by more than 10 mm hg during inspiration.

InternalMed_Harrison

Suspected severe valve disease in symptomatic patients—dyspnea, angina, heart failure, syncope Infective endocarditis with need for cardiac surgery Asymptomatic patients with aortic regurgitation and cardiac enlargement or Prior to cardiac surgery in patients with suspected coronary artery disease New onset with angina or suspected undiagnosed coronary artery disease New-onset cardiomyopathy of uncertain cause or suspected to be due to coronary artery disease Prior to surgical correction, when symptoms or noninvasive testing suggests coronary disease Symptomatic patients with suspected cardiac tamponade or constrictive pericarditis Hypertrophic cardiomyopathy with angina Diseases of the aorta when knowledge of coronary artery involvement is necessary for management

Postpericardiotomy syndrome

Complications Complications include pericarditis, pericardial effusion, pleuritis, pulmonary infiltration, and very rarely pericardial tamponade. Of these cardiac tamponade is the most life-threatening complication. The pericardial fluid increases intra-pericardial pressure therefore preventing complete expansion of the atria and the ventricles upon the diastole. This causes equilibration of the pressure in all four heart chambers, and results in the common findings of the tamponade which are pulsus paradoxus, Beck's triad of hypotension, muffled heart sounds, and raised jugular venous pressure, as well as EKG or Holter monitor findings such as electrical alternans. Physically the patients who progress to severe pericardial tamponade obtundate, become mentally altered, and lethargic. If left untreated, severe decrease in cardiac output, vascular collapse, and hypoperfusion of body including the brain results in death.

Combined multiple-valve procedures. Factors influencing the early and late results.

The early and late results were retrospectively evaluated in 57 cases of double or triple valve replacement or repair performed in 1970-1983. The causes of the valvular lesions were rheumatic fever (43 cases), bacterial endocarditis (6), syphilis (1) and unknown (7 cases). The preoperative NYHA classification was III in 29 patients and IV in 28, due mainly to dyspnea of effort. Cardiomegaly (mean radiologic volume 880 cm3/m2) and atrial fibrillation were the dominant clinical findings. Surgery was on emergency indications in five cases. Cold cardioplegia combined with external cardiac cooling has been used for myocardial protection since 1977. The valve replacements were 56 aortic, 50 mitral and 2 tricuspid. In addition there were three closed and two open mitral commissurotomies, two mitral plastic repairs, three tricuspid valve anuloplasties (DeVega) and one aortic anuloplasty. Follow-up (0.3-13, mean 3.5 years) was supplemented with a check-up including two-dimensional echophonocardiography and hematologic tests. The operative mortality (10/57 patients) fell from 26% in 1970-1976 to 12% in 1977-1983. The causes of death were low cardiac output in preoperatively ill patients (5), myocardial infarction (2), technical failure (2) and sepsis (1 case). There were 11 late deaths (6.7/100 patient-years of observation), the commonest cause (5 patients) being congestive heart failure. The respective incidences of thromboembolism, paravalvular leak and postoperative endocarditis were 2.1, 4.2 and 2.1 episodes/100 patient-years.(ABSTRACT TRUNCATED AT 250 WORDS)

Pericarditis

Complications Pericarditis can progress to pericardial effusion and eventually cardiac tamponade. This can be seen in people who are experiencing the classic signs of pericarditis but then show signs of relief, and progress to show signs of cardiac tamponade which include decreased alertness and lethargy, pulsus paradoxus (decrease of at least 10 mmHg of the systolic blood pressure upon inspiration), low blood pressure (due to decreased cardiac index), (jugular vein distention from right sided heart failure and fluid overload), distant heart sounds on auscultation, and equilibration of all the diastolic blood pressures on cardiac catheterization due to the constriction of the pericardium by the fluid.

Myopericarditis -- History and Physical

Early symptoms included precordial chest pain, fatigue, dyspnea, palpitations, and fever. Patients may give symptoms suggestive of a viral prodrome (a runny nose, arthralgia, low-grade fever) 1 to 2 weeks preceding the presentation. In predominant pericardial involvement, they can describe the pain as sharp, worse with a cough or inspiration and relieved by sitting forward. If there is significant myocardial involvement, there may be a continuous pain, and sometimes, it is hard to differentiate from myocardial ischemia pain, especially in people with cardiovascular risk factors. They may also have predominant heart failure symptoms such as shortness of breath, orthopnea, pedal edema, and fatigue. Rare symptoms include arrhythmias, syncope, and sudden cardiac arrest. Physical examination findings can be variable, but common findings may include fever, pericardial friction rub and features of heart failure. Look for other signs of systemic illness which may contribute to the etiology.

Pericardial effusion

Patients with concern for cardiac tamponade may present with abnormal vitals and what's classically known as the Beck's triad, which consists of hypotension (low blood pressure), jugular venous distension and distant heart sounds. Though these are the classical findings; all three occur simultaneously in only a minority of patients. Patients presenting with cardiac tamponade may also be evaluated for pulsus paradoxus. Pulsus paradoxus is a phenomenon in which systolic blood pressure drops by 10 mmHg or more during inspiration. In cardiac tamponade, the pressure within the pericardium is significantly higher, hence decreasing the compliance of the chambers (the capacity to expand/ conform to volume changes). During inspiration, right ventricle filling in increased, which causes the Interventricular septum to bulge into the left ventricle, hence leading to reduced left ventricular filling and consequently reduced stroke volume and low systolic blood pressure. Exams

Jugular venous pressure

Prominent 'x' descent Cardiac tamponade Slow 'y' descent Tricuspid stenosis Cardiac tamponade Prominent & deep 'y' descent Constrictive pericarditis Parodoxical JVP (Kussmaul's sign: JVP rises with inspiration, drops with expiration) Pericardial effusion Constrictive pericarditis Pericardial tamponade

Rheumatic Heart Disease -- History and Physical

Carditis is the most serious presentation of rheumatic fever. The symptoms and signs of carditis are dependent on the areas of the heart involved, which include the pericardium, myocardium, or heart valves. The presentation of a pericardial friction rub on auscultation leans toward the diagnosis of pericarditis. The presence of signs of congestive heart failure points toward a diagnosis of myocarditis, which includes but is not limited to lower extremity edema, shortness of breath with exertion or rest, abdominal distension, or inability to lay flat due to shortness of breath (orthopnea). Myocarditis in the absence of valvular disease is unlikely to be rheumatic in origin. Therefore, an apical systolic or basal diastolic murmur should be auscultated on physical exam. Mitral regurgitation is the most common valvular lesion, which is an apical pan-systolic murmur on auscultation. [8] Aortic regurgitation is less common. If patients have a known history of rheumatic heart disease, a change in the character of the murmur or the presence of a new murmur on auscultation leads to the diagnosis of acute rheumatic heart fever. Rheumatic heart disease predominantly affects the left-sided cardiac valves. [8] The tricuspid valve and rarely pulmonary valve can be affected, but very unlikely without mitral valve involvement.

InternalMed_Harrison

Echocardiography should be performed in patients with a history of cardiac disease or if abnormalities are found on physical examination or the ECG. Echocardiographic diagnoses that may be responsible for syncope include aortic stenosis, hyper-trophic cardiomyopathy, cardiac tumors, aortic dissection, and pericardial tamponade. Echocardiography also has a role in risk stratification based on the left ventricular ejection fraction. Treadmill exercise testing with ECG and blood pressure monitoring should be performed in patients who have experienced syncope during or shortly after exercise. Treadmill testing may help identify exercise-induced arrhythmias (e.g., tachycardia-related AV block) and exercise-induced exaggerated vasodilation.

Tricuspid Valve Endocarditis -- History and Physical

History and physical exam are essential towards making an adequate diagnosis in cases of TVIE. Establishing diagnosis can be more difficult in these cases because presentation can often be subacute or present with absence of typical IE features. Peripheral phenomenon such as splinter hemorrhages is less common, as is a cardiac murmur. However, clinicians must always be aware of potential complications of this disease process that are manifested by the various embolic phenomenon. Characteristics, which should lead clinicians to consider TVIE, include: Fever Chills Anorexia Weight loss Fatigue Malaise Arthralgia Dyspnea on exertion A cough Pleuritic pain Abdominal Pain

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PART 2 Cardinal Manifestations and Presentation of Diseases Vital Signs Significant tachycardia and hypotension are indicative of important hemodynamic consequences of the underlying cause of chest discomfort and should prompt a rapid survey for the most severe conditions, such as acute MI with cardiogenic shock, massive pulmonary embolism, pericarditis with tamponade, or tension pneumothorax. Acute aortic emergencies usually present with severe hypertension but may be associated with profound hypotension when there is coronary arterial compromise or dissection into the pericardium. Sinus tachycardia is an important manifestation of submassive pulmonary embolism. Tachypnea and hypoxemia point toward a pulmonary cause. The presence of low-grade fever is nonspecific because it may occur with MI and with thromboembolism in addition to infection.

Pulsus paradoxus

Causes Pulsus paradoxus can be caused by several physiologic mechanisms. Anatomically, these can be grouped into: cardiac causes, pulmonary causes and non-pulmonary and non-cardiac causes. Considered physiologically, PP is caused by: decreased right heart functional reserve, e.g. myocardial infarction and tamponade, right ventricular inflow or outflow obstruction, e.g. superior vena cava obstruction and pulmonary embolism, and decreased blood to the left heart due to lung hyperinflation (e.g. asthma, COPD) and anaphylactic shock. List of causes Cardiac: constrictive pericarditis. One study found that pulsus paradoxus occurs in less than 20% of patients with constrictive pericarditis. pericardial effusion, including cardiac tamponade cardiogenic shock Pulmonary: pulmonary embolism tension pneumothorax asthma (especially with severe asthma exacerbations) chronic obstructive pulmonary disease


This question may be a little more difficult, as the clinical case presented to us is very vague. An adolescent with pubertal delay and short stature; nothing more. With this information, she could have several genetic pathologies, but this is the MIR and we are told that the patient does not have an intellectual disability. In the MIR, an adolescent with pubertal delay and short stature should be a Turner until proven otherwise (there were two questions in 2017). Therefore, if that is our first diagnostic suspicion, the HABITUAL test (as the statement says) for diagnosis should be a conventional karyotype (formula: 45, X0). A Turner can also be diagnosed with a FISH (there would only be one signal for the X instead of the two that females usually have) or with an array. However, both array and NGS are usually reserved for patients with non-obvious clinical pictures, intellectual disability, or suspicion of a genetic syndrome that requires these specific tests (for example, an array to diagnose a 22q11 deletion syndrome or an NGS panel to diagnose a Noonan syndrome).

15-year-old female presenting with delayed menarche and short stature. She does not have intellectual disability. Which of the following genetic tests would be routinely used for the diagnosis of this patient:

Genetic testing in pediatric endocrine pathology.

In genetic endocrine diseases, genetic testing is necessary for a precise diagnosis, which will provide a better knowledge of the evolution and prognosis and also indicate the adequate therapy, targeting the precise etiopathogenesis of the disease. Genetic testing in endocrinology is often based on classical cytogenetic techniques, molecular cytogenetic analysis or molecular biology techniques. Genetic testing in disorders of sex development includes the karyotype and SRY gene analysis and depending on the presence of associated clinical signs and on the observations at paraclinical examination, these tests will be followed by chromosomal array techniques and NGS sequencing. In short stature, the decision to perform a genetic test is taken depending on clinical, paraclinical and imaging signs. In case of a short stature associated with a low weight/length for gestational age, genetic testing is proposed to evaluate a Russell-Silver syndrome or if the short stature is associated with other clinical signs (e.g. intellectual disability), chromosomal analysis by microarray is proposed. If the short stature is disproportionate, it is indicated to perform a next generation sequencing (NGS) of a panel of genes involved in skeletal dysplasia. If an endocrine cause for short stature is observed at the hormonal evaluation, it is indicated to test a panel of genes involved in these pathways. In genetic obesity, depending on clinical signs associated to obesity, it will be a more targeted genetic testing. If obesity is associated with intellectual disability or other nonspecific neurological changes, a chromosomal analysis by microarray will be indicated. If monogenic obesity is suspected, NGS testing will be indicated (as genes panel or whole exome or genome analysis). Genetic testing in endocrine diseases brings an etiological diagnosis, but a favorable cost-benefit ratio derives from an adequate indication of these tests, generally proposed in expert centers for rare endocrine diseases.

XXXY syndrome

Diagnosis Diagnosis of 48,XXXY is usually done by a standard karyotype. A karyotype is a chromosomal analysis in which a full set of chromosomes can be seen for an individual. The presence of the additional 2 X chromosomes on the karyotype are indicative of XXXY syndrome. Another way to diagnosis 48,XXXY is by chromosomal microarray showing the presence of extra X chromosomes. Chromosomal microarray (CMA) is used to detect extra or missing chromosomal segments or whole chromosomes. CMA uses microchip-based testing to analyze many pieces of DNA. Males with 48,XXXY are diagnosed anywhere from before birth to adulthood as a result of the range in the severity of symptoms. The age range at diagnosis is likely due to the fact that XXXY is a rare syndrome, and does not cause as extreme phenotypes as other variants of Klinefelter syndrome (such as XXXXY).

Genotype-Phenotype Analysis of 8q24.3 Duplication and 21q22.3 Deletion in a Chinese Patient and Literature Review.

Copy number variants (CNVs) are responsible for many patients with short stature of unknown etiology. This study aims to analyze clinical phenotypes and identify pathogenic CNVs in a patient with short stature, intellectual disability, craniofacial deformities, and anal imperforation. G-banded karyotyping and chromosomal microarray analysis (CMA) was used on the patient to identify pathogenic causes. Fluorescence in situ hybridization (FISH) was applied to explore the abnormal genetic origin. Literatures were searched using identified CNVs as keywords in the PubMed database to perform genotype-phenotype analysis. Cytogenetic analysis revealed a normal karyotype 46,XY. CMA detected a 6.1 Mb duplication at 8q24.3 and a 3.6 Mb deletion at 21q22.3. FISH confirmed that the abnormal chromosomes were inherited from paternal balanced translocation. We compared phenotypes of our patient with 6 patients with 8q24.3 duplication and 7 cases with 21q22.3 deletion respectively. A novel 8q24.3 duplication and 21q22.3 deletion was identified in a Chinese patient. Genotype-phenotype analysis demonstrated that patients with 8q24.3 duplication and 21q22.3 deletion had specific facial features, intellectual disability, short stature, and multiple malformations.

[Genetic and prenatal diagnosis of a pregnant women with mental retardation].

To conduct genetic testing and prenatal diagnosis for a pregnant women with growth retardation, severe mental retardation, and a history of adverse pregnancies. G-banded chromosome analysis, fluorescence in situ hybridization (FISH), and whole genome DNA microarray were used to analyze the patient and her fetus. The women was found to be a chimera containing two cell lines with 47 and 46 chromosomes, respectively. Both have involved deletion of 18q21.2q23. FISH analysis suggested that the cell line containing 47 chromosomes has harbored a chromosome marker derived from chromosome 15. The marker has contained chromosome 15p involving the SNRPN locus and part of 15q, which gave rise to a karyotype of 47,XX,del18q21.3,+ish mar D15Z1+ SNRPN+[82]/46,XX,del18q21.3[18]. Whole genome DNA microarray confirmed that a 3.044 Mb fragment from 15q11.2q12 was duplicated, which involved NIPA1, SNRPN and other 17 OMIM genes. Duplication of this region has been characterized by low mental retardation, autism, developmental delay. Meanwhile, there was a 17.992 Mb deletion at 18q21.33q23, which contained 39 OMIM genes including TNFRSF11A and PHLPP1. This fragment was characterized by mental retardation, developmental delay, short stature, and cleft palate. Whole genome microarray analysis confirmed that there was a 17.9 Mb deletion at 18q21.33q23, which has been implemented with mental retardation, general growth retardation, short stature, and cleft palate. After genetic counseling, the family decided to terminate the pregnancy at 21st week. Combined chromosome karyotyping, FISH, and whole genome DNA microarray can determine the origin of marker chromosomes and facilitate delineation of its correlation with the clinical phenotype.

Inconsistency of Karyotyping and Array Comparative Genomic Hybridization (aCGH) in a Mosaic Turner Syndrome Case.

<bPurpose</b  Turner syndrome is a sex chromosomal aberration where majority of the patients have 45,X karyotype, while several patients are mosaic involving 45,X/46,XX; 46,X,i(Xq); and other variants. Cytogenetic analysis, karyotyping, is considered to be the "gold standard" to detect numerical and structural chromosomal abnormalities. In the recent years, alternative approaches, such as array comparative genomic hybridization (aCGH), have been widely used in genetic analysis to detect numerical abnormalities as well as unbalanced structural rearrangements. In this study, we report the use of karyotyping as well as aCGH in detecting a possible Turner syndrome variant. <bMethods</b  An apparent 16-year-old female was clinically diagnosed as Turner syndrome with premature ovarian failure and short stature. The genetic diagnosis was performed for the patient and the parents by karyotyping analysis. aCGH was also performed for the patient. <bMain Findings</b  Cytogenetic analysis of the patient was performed showing variant Turner syndrome (46,X,i(X)(q10)[26]/46,X,del(X)(q11.2)[11]/45,X[8]/46,XX[5]). The patient's aCGH result revealed that she has a deletion of 57,252kb of Xp22.33-p11.21 region; arr[GRCh37] Xp22.33-p11.21 (310,932-57,563-078)X1. Both aCGH and fluorescence in situ hybridization (FISH) results suggested that <ishort stature Homeobox-containing</i ( <iSHOX</i ) gene, which is located on Xp22.33, was deleted, though FISH result indicated that this was in a mosaic pattern. <bConclusion</b  In the recent years, aCGH has become the preferred method in detecting numerical abnormalities and unbalanced chromosomal rearrangements. However, its use is hindered by its failure of detecting mosaicism, especially low-level partial mosaicism. Therefore, although the resolution of the aCGH is higher, the cytogenetic investigation is still the first in line to detect mosaicism.

22q13 deletion syndrome

Diagnosis and management Clinical genetics and genetic testing Genetic testing is necessary to confirm the diagnosis of PMS. A prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small to detect with this method. Chromosomal microarray should be ordered in children with suspected developmental delays or ASD. Most cases will be identified by microarray; however, small variations in genes might be missed. The falling cost for whole exome sequencing may replace DNA microarray technology for candidate gene evaluation. Biological parents should be tested with fluorescence in situ hybridization (FISH) to rule out balanced translocations or inversions. Balanced translocation in a parent increases the risk for recurrence and heritability within families (figure 3).

Elective genetic and genomic testing

Genetic testing for a variety of disorders has seen many advances starting with cytogenetics to evaluate human chromosomes for aneuploidy and other chromosome abnormalities. The development of molecular cytogenetics involving techniques such as fluorescence in situ hybridization (FISH) followed, permitting the detection of more subtle changes in the karyotype. Techniques to determine the precise sequence of nucleotides in DNA by DNA sequencing, notably Sanger sequencing was developed in the 1970s. In the 1980s the DNA microarray appeared, permitting laboratories to find copy number variants associated with disease that are below the level of detection of cytogenetics but too large to be detected by DNA sequencing. In recent years the development of high-throughput or next-generation sequencing has dramatically lowered the cost of DNA sequencing permitting laboratories to evaluate all 20,000 genes of the human genome at once through exome sequencing and whole genome sequencing. A

22q13 deletion syndrome

Prototypical terminal deletion of 22q13 can be uncovered by karyotype analysis, but many terminal and interstitial deletions are too small. The availability of DNA microarray technology for revealing multiple genetic problems simultaneously has been the diagnostic tool of choice. The falling cost for the whole exome sequencing and, eventually, whole genome sequencing, may replace DNA microarray technology for candidate evaluation. However, fluorescence in situ hybridization (FISH) tests remain valuable for diagnosing cases of mosaicism (mosaic genetics) and chromosomal rearrangements (e.g., ring chromosome, unbalanced chromosomal translocation). Although early researchers sought a monogenic (single gene genetic disorder) explanation, recent studies have not supported that hypothesis (see Etiology). Signs and symptoms

Chromosome abnormalities in Indonesian patients with short stature.

Short stature is associated with several disorders including wide variations of chromosomal disorders and single gene disorders. The objective of this report is to present the cytogenetic findings in Indonesian patients with short stature. G-banding and interphase/metaphase FISH were performed on short stature patients with and without other clinical features who were referred by clinicians all over Indonesia to our laboratory during the year 2003-2009. The results of chromosomal analysis of ninety seven patients (mean age: 10.7 years old) were collected. The group of patients with other clinical features showed sex chromosome abnormalities in 45% (18/40) and autosomal abnormalities in 10% (4/40), whereas those with short stature only, 42.1% (24/57) had sex chromosome abnormalities and 1.75% (1/57) had autosomal abnormalities. The autosomal chromosomal abnormalities involved mostly subtelomeric regions. Results discrepancies between karyotype and FISH were found in 10 patients, including detection of low-level monosomy X mosaicism in 6 patients with normal karyotype, and detection of mosaic aneuploidy chromosome 18 in 1 patient with 45,XX,rob(13;14)(q10;q10).Statistical analysis showed no significant association between the groups and the type of chromosomal abnormalities. Chromosome abnormalities account for about 50% of the short stature patients. Wide variations of both sex and autosomal chromosomes abnormalities were detected in the study. Since three out of five patients had autosomal structural abnormalities involving the subtelomeric regions, thus in the future, subtelomeric FISH or even a more sensitive method such as genomic/SNP microarray is needed to confirm deletions of subtelomeric regions of chromosome 9, 11 and 18. Low-level mosaicism in normal karyotype patients indicates interphase FISH need to be routinely carried out in short stature patients as an adjunct to karyotyping.

18p-

Genetics 18p- describes a deletion of the short arm of chromosome 18. About half of the people with deletions have a breakpoint at the centromere. Those with it are said to have centromeric 18p-, and those without are said to have non-centromeric 18p-. Diagnosis Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of 18p- is usually made via a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible via amniocentesis of chorionic villus sampling. MRI In some children without "classic" holoprosencephaly, microforms of holoprosencephaly may be noted on MRI, including missing olfactory tracts and bulbs and absent or hypoplastic corpus callosum. Treatment

Distal 18q-

Diagnosis Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of distal 18q- is usually made from a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible using amniocentesis or chorionic villus sampling. Treatment At present, treatment for distal 18q- is symptomatic, meaning the focus is on treating the signs and symptoms of the conditions as they arise. To ensure early diagnosis and treatment, people with distal 18q- are suggested to undergo routine screenings for thyroid, hearing, and vision problems. History

Clinical Profiles and Genetic Spectra of 814 Chinese Children With Short Stature.

Data and studies based on exome sequencing for the genetic evaluation of short stature are limited, and more large-scale studies are warranted. Some factors increase the likelihood of a monogenic cause of short stature, including skeletal dysplasia, severe short stature, and small for gestational age (SGA) without catch-up growth. However, whether these factors can serve as predictors of molecular diagnosis remains unknown. We aimed to explore the diagnostic efficiency of the associated risk factors and their exome sequences for screening. We defined and applied factors that increased the likelihood of monogenic causes of short stature in diagnostic genetic tests based on next-generation sequencing (NGS) in 814 patients with short stature and at least 1 other factor. Pathogenic/likely pathogenic (P/LP) variants in genes, copy number variations, and chromosomal abnormalities were identified in 361 patients. We found P/LP variants among 111 genes, and RASopathies comprised the most important etiology. Short stature combined with other phenotypes significantly increased the likelihood of a monogenic cause, including skeletal dysplasia, facial dysmorphism, and intellectual disability, compared with simple severe short stature (<-3 SD scores). We report novel candidate pathogenic genes, KMT2C for unequivocal growth hormone insensitivity and GATA6 for SGA. Our study identified the diagnostic characteristics of NGS in short stature with different risk factors. Our study provides novel insights into the current understanding of the etiology of short stature in patients with different phenotypes.

[Diagnosis of a case with partial 9p trisomy by next generation sequencing].

To explore the genetic cause for a child featuring growth and mental retardation. Following conventional karyotyping analysis of the trio family, next generation sequencing (NGS) was carried out to explore the origin of the supernumerary marker chromosome. Fluorescence in situ hybridization (FISH) was used to confirm the result. The karyotypes of both parents were normal, while the proband was found to be 47,XX,+mar. NGS showed that the supernumerary marker has originated from chromosome 9p13.1p24.3 with a size of 39.77 Mb. FISH has confirmed the above finding. The 9p13.1-p24.3 trisomy probably underlies the abnormal phenotypes of the child. Cytogenetic analysis combined with NGS and FISH can provide accurate diagnosis for such disorders.

SYNGAP1-related intellectual disability

The majority of mutations are considered de novo, however cases of inheritance from both somatic mosaic and germ-line mosaic parents have been reported. Diagnosis Diagnosis is based on genetic testing, with the recommended testing approach being Chromosomal Microarray Analysis followed by an Intellectual Disability multigene panel or Whole Exome Sequencing. A diagnosis is established following the identification of a heterozygous pathogenic (or likely pathogenic) point mutation of the SYNGAP1 gene (present in approximately 89% of patients), a micro deletion of chromosome 6 incorporating SYNGAP1 (approximately 11% of patients), or a balanced translocation disrupting SYNGAP1. EEG monitoring frequently shows generalized epilepsy, predominantly in the occipital regions. Seizure onset usually occurs around 2 years of age. MRI is usually normal.

Case Report: Genetic Analysis of a Small Supernumerary Marker Chromosome in a Unique Case of Mosaic Turner Syndrome.

The aim of this study was to explore the source and morphology of a small supernumerary marker chromosome (sSMC) from karyotype analysis of a patient with a unique case of mosaic Turner syndrome. The study findings will provide technical reference and genetic counseling for similar cases. A female patient with 46,X,+mar karyotype was diagnosed by genetic karyotype analysis. Genetic methods including fluorescence <iin situ</i hybridization (FISH) and copy number variation sequencing (CNV-seq) based on low-depth whole-genome sequencing were used to explore the source and morphology of sSMC. FISH technology showed that 56.5% of the cells were X and 43.5% of the cells were XY. CNV-seq detection found that the sSMC was chrY, implying that the patient's karyotype was mos 45,X[58.6%]/46,XY[41.4%]. Retrospective karyotype analysis indicated that the female patient's sSMC was inherited from her father's small chrY. Customized FISH probe of Yq12 microdeletion was positive, indicating that the sSMC was a del(Y)(q12). Based on the results of genetic diagnosis, the specialist doctor gave a comprehensive genetic consultation and ordered regular follow-up examinations. The findings of the current study showed that the chromosome description of the unique Turner case was mos 45,X[56.5%]/46,X,del(Y)(q12)[43.5%]. FISH technology played a key role in diagnosis of mosaicism. The terminal deletion of mosaic chrY provided a scientific and an accurate explanation for masculinity failure and abnormal sexual development of the current case.

A unique combination of 17pter trisomy and 21qter monosomy in a boy with developmental delay, severe intellectual disability, growth retardation and dysmorphisms.

Microduplication at 17p13.3 and microdeletion at 21q22 are both rare chromosomal aberrations. The presence of both genomic imbalances in one patient has not been previously reported in literature. In this study, we performed a molecular diagnostic testing with a whole genome microarray on a 3-year-old boy with developmental delay, mental retardation and multiple malformations. A routine G-banding karyotype analysis was performed using peripheral lymphocytes. Chromosome microarray analysis (CMA) was done using Affymetrix CytoScan™ HD array. Genomic imbalances were further confirmed by multiple ligation-dependent probe amplification (MLPA). The result of karyotyping was normal but CMA detected a 9.8 Mb microduplication at 17p13.3-13.1 (chr17: 1-9,875,545) and a 2.8 Mb microdeletion involving 21q22.3-qter (chr21: 45,239,077-48,097,372). The imbalances were due to a balanced translocation present in patient's mother. The patient was characterized with short stature, profound developmental delay, non-verbal, intellectual disability as well as craniofacial dysmorphism, subtle brain structural anomaly and sparse scalp hair. This is the first patient reported with a combination of a microduplication at 17p13.3-13.1 and a microdeletion at 21q22.3-qter. Both genomic imbalances were undetected by conventional karyotyping but were delineated with CMA test. Synergistic effect from the two rare genomic imbalances is likely responsible for the severe clinical phenotypes observed in this patient.

The Case with Short Stature and Intellectual Disability Caused by a Novel 2q12 Duplication.

Copy number variation (CNV) is a kind of malfunction of DNA polymerase to produce extra genetic material which leads to more number of repeats in genes. The CNVs have been associated with different clinical phenotypes such as learning disabilities, short stature, and intellectual disability. The chromosomal microarray analysis is an effective diagnostic method for identifying new CNVs and understanding their clinical effects. In this case report, a variation that has not been reported previously in the literature is presented. This case report will contribute to increasing the knowledge. The CNV (arr [hg19] 2q12.1q12.3 (103,368,824-107,946,062) x3) detected in the index case was also detected in her father and male sibling. Key Words: DNA, Copy number variation, Chromosomal duplication, Intellectual disabilities.

Partial and complete trisomy 14 mosaicism: clinical follow-up, cytogenetic and molecular analysis.

Trisomy 14 mosaicism is a rare chromosomal abnormality. It is associated with multiple congenital anomalies. We report a 15 year-old female with an unusual karyotype with three cell lines: 47,XX,+mar/47,XX,+14/46,XX. At six months old she had short stature, cleft palate, hyperpigmented linear spots in arms and legs and developmental delay. At present, she has mild facial dysmorphism and moderate mental retardation. Cytogenetic analysis was performed in peripheral blood lymphocytes and in the light and dark skin following standard methods. DNAarray - Oligo 180 k was carried out using Agilent Technologies and FISH analysis was accomplished using DNA BACs probes to confirm the result obtained by DNAarray. Methylation-Specific PCR (MS-PCR) of the MEG3 promoter and microsatellite analysis were performed. Microarray analysis confirmed partial trisomy 14 mosaicism; the marker chromosome was found to be from chromosome 14, the result was confirmed with FISH. Methylation (14q32.3) and microsatellite (14q11-14q32.33) analysis were carried out and UPD was discarded. The global result was: mos 47,XX,+del(14)(q11.2)[45]/47,XX,+14[10]/46,XX[45]. This is a unique case because of the coexistence of two abnormal cell lines, including one with +14 and another with +del(14)(q11.2). To our knowledge, only three patients have been reported with trisomy 14 and another abnormal cell line. The array analysis identified the marker chromosome and characterized the breakpoint. The del(14)(q11.2) does not seem to be related to any particular phenotypic characteristic of the patient; the clinical features of our patient observed until now, can be attributed to trisomy 14 mosaicism. Nevertheless, we cannot discard the manifestation of new symptoms related to her karyotype in the future.

Karyotyping and prenatal diagnosis of 47,XX,+ 8[67]/46,XX [13] Mosaicism: case report and literature review.

Trisomy 8 mosaicism has a wide phenotypic variability, ranging from mild dysmorphic features to severe malformations. This report concluded a female pregnant woman with trisomy 8 mosaicism, and carefully cytogenetic diagnoses were performed to give her prenatal diagnostic information. This report also provides more knowledge about trisomy 8 mosaicism and the prenatal diagnostic for clinicians. In this present study, we reported one case of pregnancy woman with trisomy 8 mosaicism. Noninvasive prenatal testing prompted an abnormal Z-score, but further three dimension color ultrasound result suggested a single live fetus with no abnormality. The phenotypic of the pregnant woman was normal. Based on our results, there were no abnormal initial myeloid cells (< 10<sup- 4</sup), which suggested that the patient had no blood diseases. The peripheral blood karyotype of the patient was 47,XX,+ 8[67]/46,XX [13], and karyotype of amniotic fluid was 46, XX. The next generation sequencing (NGS) result suggested that the proportions of trisomy 8 in different tissues were obviously different; and 0% in amniotic fluid. Last, the chromosomes of the patient and her baby were confirmed using chromosome microarray analysis (CMA), and the results were arr[GRCh37](8) × 3,11p15.5p13(230750-33,455,733) × 2 hmz and normal. This pregnancy woman was trisomy 8 mosaicism, but the phenotypic was normal, and also the fetus was normal. Carefully cytogenetic diagnoses should be performed for prenatal diagnose.

Genotype-first approach

Genotype-first assessment is becoming the standard approach for clinical diagnosis of complex heterogeneous diseases. Microduplication and microdeletion syndromes have a range of characteristics, including intellectual disability and developmental delay, which vary in severity making patients with these syndromes very difficult to diagnose. Since the development of next-generation sequencing technologies, clinicians have been able to use a genotype-first approach to group these patients based on their microdeletion or duplication and document the disease features present in these groups. Chromosomal microarray analysis, in particular, is being used clinically to assist in diagnosing patients with microdeletion and microdulplication syndromes. In diseases, such as Autism spectrum disorder (ASD), where differentiating patients into disease subtype groups based on phenotype is challenging, genotype-first studies allow the classification of patients into subtypes based on their genetics.

[Reflection of a case misdiagnosed as trisomy 21 syndrome by G-banded chromosomal karyotyping analysis].

To emphasize the clinical significance of copy number variations (CNVs) detection by describing a case misdiagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. A girl with obesity and short stature was diagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. Considering the discrepancy of her karyotype with her phenotype, genomic CNVs was detected by next-generation sequencing and the result was verified by quantitative PCR (qPCR). A microduplication of 16p11.2: 29 642 339-29 775 631 (133.292 kb) was detected. qPCR assay for QPRT and SPN located in the duplicated region confirmed the finding of CNVs assay. Meanwhile, her parents did not present similar duplication in 16p11.2. The 16p11.2 microduplication was a novel genomic structural variation in the girl, though it may not be associated with her clinical manifestations. Chromosomal microarray or next-generation sequencing-based CNVs detection can accurately determine the origin of small supernumerary marker chromosome and reduce the chance of misdiagnosis.

[Genotypic and phenotypic analysis of a patient with de novo partial monosomy 18p and partial trisomy 18q].

To explore the genetic cause for a patient with intellectual disability, short stature and multiple congenital anomalies, and to correlate the result with the clinical phenotype. Routine karyotyping analysis was carried out on GTG-banded metaphase chromosomes. Single nucleotide polymorphism (SNP) microarray was used to detect microdeletions or microduplications in the patient. Fluorescence in situ hybridization (FISH) was used to ascertain the origin of aberrant chromosomes. The karyotype of the patient was 46,XY,der(18), while both of his parents had a normal karyotype. SNP array identified a 1.23 Mb deletion at 18p11.32-pter (chr18: 136 227-1 370 501, hg19) and a 33.76 Mb duplication at 18q21.1-qter (chr18: 44 250 359-78 013 728, hg19) in the patient. Above finding was confirmed by dual-color FISH with one color for 18p and another for 18q. The patient presented with some common features of 18p deletion and 18q duplication including intellectual disability and growth retardation, in addition with some features of 18p deletion including pectus excavatum, short stature and growth hormone (GH) deficiency. The patient showed progressive improvement of stature with GH therapy. Comparison of patients with previously reported dup(18q)+del(18p) recombinations suggested that, even for patients with similar breakpoints, their phenotypes have ranged from normal to severe and there were no consistent findings. As aberrations involving double chromosomal segments often result in phenotypic variability, it has been difficult to correlate the genotype of our patient with his phenotype.

[Application of chromosomal microarray analysis for the diagnosis of children with intellectual disability/developmental delay and a normal karytype].

To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of children with intellectual disability/developmental delay (ID/DD) but a normal karytype. Peripheral blood samples from 92 ID/DD patients were analyzed with CMA using Affymetrix CytoScan 750K arrays. The results were analyzed by ChAS v3.0 software. Eighteen cases (19.57%) were detected with abnormalities by CMA, among which 10 cases were diagnosed with microdeletion/microduplication syndromes. These included 2 Williams-Beuren syndromes, 2 Angelman syndromes, 2 Russell-Silver syndromes, 1 Smith-Magenis syndromes, 1 Wolf-Hirschhorn syndromes, 1 15q26 overgrowth syndrome and 1 Xq28 (MECP2) duplication syndrome. In addition, 8 cases were diagnosed with pathogenic copy number variations (pCNV). CMA can significantly improve the diagnostic rate for patients with ID/DD, which is of great value for the treatment of such children and guidance of reproduction for their parents. Therefore, CMA should become the first-line diagnostic test for patients with ID/DD.

A novel 1p33p32.2 deletion involving SCP2, ORC1, and DAB1 genes in a patient with craniofacial dysplasia, short stature, developmental delay, and leukoencephalopathy: A case report.

Microdeletion syndromes occur from deletion of 5Mb of a chromosome in approximately 5% of patients with unexplained intellectual disability. Interstitial microdeletions at bands 1p33 and 1p32.2 of the short arm of chromosome 1 are rare and have not been previously reported in relation to disease. We present a case of a 39-month boy with Pierre Robin sequence, development delay/intellectual disability, growth retardation, short stature, leukoencephalopathy, craniofacial dysplasia, and speech delay. The child was referred to the Child health care department in October 2014 for his delayed language development and aggravated aggression. Molecular diagnostic testing with G-band karyotyping was normal but clinical microarray analysis detected a 10 Mb microdeletion at 1p33p32.2. The patient received rehabilitation. Three candidate genes were pinpointed to the deleted area, including ORC1, SCP2, and DAB1. Phenotype-genotype analysis suggested that these three genes are likely to be responsible for the main phenotypes observed in the patient, such as microcephaly, growth retardation, short stature, leukoencephalopathy, and development delay/intellectual disability. The spectrum of phenotypes this case presented with are likely to be caused by 1p33p32.2 deletion which could represent a new microdeletion syndrome.

[Clinical and genetic analysis of a rare case with mosaic partial trisomy 5p syndrome].

To determine the size and origin of a small supernumerary marker chromosome (sSMC) identified in a patient featuring developmental retardation. High-throughput sequencing for copy number variation (CNV-seq) was carried out to delineate the sSMC identified upon G-banded chromosomal karyotyping. The genotype-phenotype correlation was explored by database retrieval and literature analysis. The patient was found to have a karyotype of mos 47,XX,+mar[36]/46,XX[23]. CNV-seq has identified a 18 Mb duplication at 5p14.1-p12 (hg19: 27,399,261-46,083,784)x2.6 with a mosaicism rate of approximately 60%. Patients with mosaic partial trisomy 5p may have extensive clinical manifestations, and the ratio of trisomy 5p cells is correlated with clinical severity of this syndrome.

A Rare, Recurrent, De Novo 14q32.2q32.31 Microdeletion of 1.1 Mb in a 20-Year-Old Female Patient with a Maternal UPD(14)-Like Phenotype and Intellectual Disability.

We present a 20-year-old female patient from Indonesia with intellectual disability (ID), proportionate short stature, motor delay, feeding problems, microcephaly, facial dysmorphism, and precocious puberty who was previously screened normal for conventional karyotyping, fragile X testing, and subtelomeric MLPA analysis. Subsequent genome wide array analysis was performed on DNA from blood and revealed a 1.1 Mb deletion in 14q32.2q32.31 (chr14:100,388,343-101,506,214; hg19). Subsequent carrier testing in the parents by array showed that the deletion had occurred de novo in the patient and that her paternal 14q32 allele was deleted. The deleted region encompasses the DLK1/GTL2 imprinted gene cluster which is consistent with the maternal UPD(14)-like phenotype of the patient. This rare, recurrent microdeletion was recently shown not to be mediated by low copy repeats, but by expanded TGG repeats, flanking the 14q32.2q32.21 deletion boundaries, a novel mechanism of recurrent genomic rearrangement. This is another example how the application of high resolution genome wide testing provides an accurate genetic diagnosis, thereby improving the care for patients and optimizing the counselling for family.

A case of 46,XX dysgenesis and marked tall stature; the need for caution in interpreting array comparative genomic hybridization (CGH).

Gonadal dysgenesis with an apparently normal 46,XX karyotype is a rare cause of hypergonadotrophic hypogonadism. Tall stature is not a widely recognized association. A 15-year-old girl presented with primary amenorrhoea. Examination showed a non-dysmorphic girl of normal intellect with no breast development (Tanner stage B1P4A1) who was tall compared with her parents: height standard deviation score (SDS) +1.56 vs. midparental height of +0.23 SDS, and slim build (weight -0.13 SDS). Investigations showed a 46,XX karyotype, elevated gonadotropins (FSH 119 and LH 33.7 IU/L), serum estradiol <5 pmol/L, uterine length 3.75 cm with cylindrical shape, and absent ovaries on ultrasound. Initially, a 364055-bp deletion on Xp21.2 was reported on array CGH. However, repeat analysis using BlueGnome CytoChip ISCA 4x180k v2.0 array was normal. With oral ethinyl estradiol induction puberty progressed to B4P4A2 but aged 18.4 years, the patient was remarkably tall with height SDS +2.88, weight SDS +0.97. Caution is needed in interpreting small changes with array CGH, particularly with the older assays. We postulate that the genetic change causing 46,XX gonadal dysgenesis in our patient may have also resulted in unsuppressed somatic growth. More critical height assessment, including parental height measurement, of future patients with 46,XX gonadal dysgenesis is recommended in order to determine whether or not a true association with tall stature may be present in certain cases.

A 13-year-old girl with 18p deletion syndrome presenting Turner syndrome-like clinical features of short stature, short webbed neck, low posterior hair line, puffy eyelids and increased carrying angle of the elbows.

We report a 13-year-old girl with 18p deletion syndrome presenting Turner syndrome-like clinical features. A 13-year-old girl was referred for genetic counseling of Turner syndrome-like clinical features of short stature, short webbed neck, low posterior hair line, puffy eyelids and increased carrying angle of the elbows. The girl also had mild intellectual disability, psychomotor developmental delay, speech disorder, high-arched palate, hypertelorism and mid-face hypoplasia. Cytogenetic analysis of the girl revealed a karyotype of 46,XX,del(18) (p11.2). The parental karyotypes were normal. Array comparative genomic hybridization analysis on the DNA extracted from the peripheral blood revealed a 13.93-Mb deletion of 18p11.32-p11.21 or arr 18p11.32p11.21 (148,993-14,081,858) × 1.0 [GRCh37 (hg19)] encompassing 52 Online Mendelian Inheritance in Man (OMIM) genes including USP14, TYMS, SMCHD1, TGIF1, LAMA1, TWSG1, GNAL and PTPN2. Polymorphic DNA marker analysis revealed a maternal origin of the deletion. Females with Turner syndrome-like clinical features in association with intellectual disability, facial dysmorphism and psychomotor developmental delay should be suspected of having chromosome deletion syndromes.

Tetrasomy 18p Case Report.

Tetrasomy 18p is a rare disorder. It is known to affect about 250 families worldwide. Tetrasomy 18p is also the most common type of isochromosome. Here we report a de novo tetrasomy 18p. The copy number variation of the patient was detected by microarray. Whether the abnormal gene was inherited from the parents was detected by karyotype analysis. Then the source of the chromosome was located by fluorescence in situ hybridization. Finally, we used MLPA technology to validate the results of patient testing. Microarray detection found that patients with 18p11.32p11.21 had duplication, with a copy number of four, which was tetrasomy 18 syndrome. The karyotype results showed 48,XY,+2mar?. Chromosome 18 telomere probe FISH experimental results: 48,XY,+i(18)(p10),+mar.ish. MLPA results showed that the number of chromosome 18 short arm copies is increased. Karyotype analysis results of his mother were 47,XX,+mar. Microarray results showed normal. Karyotype results of his father were normal. This case is de novo case, the patient's marker chromosome may be inherited from his mother, which does not rule out the influence of his mother's marker chromosome on his isochromosome 18.

Novel contiguous gene deletion in peruvian girl with Trichothiodystrophy type 4 and glutaric aciduria type 3.

Trichothiodystrophy type 4 is a rare autosomal recessive and ectodermal disorder, characterized by dry, brittle, sparse and sulfur-deficient hair and other features like intellectual disability, ichthyotic skin and short stature, caused by a homozygous mutation in MPLKIP gene. Glutaric aciduria type 3 is caused by a homozygous mutation in SUGCT gene with no distinctive phenotype. Both genes are localized on chromosome 7 (7p14). We report an 8-year-old female with short stature, microcephaly, development delay, intellectual disability and hair characterized for dark, short, coarse, sparse and brittle associated to classical trichorrhexis microscopy pattern. Chromosome microarray analysis showed a 125 kb homozygous pathogenic deletion, which includes genes MPLKIP and SUGCT, not described before. This is the first case described in Peru of a novel contiguous gene deletion of Trichothiodystrophy type 4 and Glutaric aciduria type 3 performed by chromosome microarray analysis, highlighting the contribution and importance of molecular technologies on diagnosis of rare genetic conditions.

The phenotype and rhGH treatment response of ring Chromosome 15 Syndrome: Case report and literature review.

Ring chromosome 15 [r (15)] is an uncommon finding with various clinical manifestations. A common phenotype for these patients has not been established and data on the efficacy of recombinant human growth hormone (rhGH) treatment in patients with r (15) syndrome are limited. One short stature patient in our hospital with r (15) syndrome by whole exome sequencing (WES) and karyotype examination was included. All published r (15) syndrome cases as of March 15, 2021, were searched, and their clinical information was recorded and summarized. One 11.5-year-old female with prenatal and postnatal growth retardation, ventricular septal defect, intellectual disability, downward corners, short fifth metacarpal bone, scattered milk coffee spots, and a right ovarian cyst was included. Her height was 126.9 cm (-3.45 SDS). Karyotype analysis showed 46, XX, r (15). WES revealed a 4.5 Mb heterozygous deletion in the chromosome 15q26.2-q26.3 region, encompassing genes from ARRDC4 to OR4F15. Gonadotrophin-releasing hormone analogue (triptorelin) and rhGH were administered for 6 months. The height has increased 3.8 cm (+0.2SDS) and the calculated growth rate has improved from 4.7 to 7.6 cm/y. The literature review indicated the main clinical manifestations of r (15) syndrome with prenatal and postnatal growth retardation, characteristic craniofacial features, and multisystem abnormalities, and rhGH treatment is beneficial for r (15) syndrome patients with short stature. We delineate the clinical spectrum of r (15) syndrome with the identification of an additional individual and rhGH treatment is beneficial for r (15) syndrome patients with short stature.

Obstentrics_Williams

This technique may be used for rapid identiication of a speciic chromosome abnormality and for veriication of suspected microdeletion or duplication syndromes, such as the 22q 11.2 microdeletion described earlier (p. 260). Because of its 1-to 2-day turnaround time, FISH is often selected for cases in which indings may alter pregnancy management. To perform FISH, cells are ixed onto a glass slide, and fluorescent-labeled probes are hybridized to the ixed chromosomes (Figs. 13-11 and 13-12). Each probe is a DNA sequence that is complementary to a region of the chromosome or gene being investigated. If the DNA sequence is present, hybridization is detected as a bright signal visible by microscopy. The number of signals indicates the number of chromosomes or genes of that type in the cell being analyzed. Findings are probe-speciic. Namely, FISH does not provide information on the entire chromosomal complement but merely the chromosomal or gene region of interest.