Though adrenergic manifestations predominate the clinical feature of thyrotoxicosis buy discount sotalol 40mg on-line, circulating level of catecholamines are normal purchase sotalol cheap online. These adrenergic symptoms are due to increased β1-adrenergic receptor number discount 40mg sotalol overnight delivery, affinity order on line sotalol, and/or augmented post- receptor signaling mediated through thyroid hormone excess. Tremor in patients with thyrotoxicosis is fine, involuntary, and commonly involve hands, tongue, and eyelids. Tremor in thryotoxicosis is due to increased sensitivity 10 Thyrotoxicosis 217 and/or expression of β2-adrenergic receptors on small muscles at these sites. This is evidenced by the rapid resolution of tremor after initiation of β-blockers. The monosymptomatic presentations of thyrotoxicosis include “lone” atrial fibrillation, pyrexia of unknown origin, malabsorption syndrome, hypokalemic or hyperkalemic periodic paralysis, and apathetic hyperthyroidism. Children may present with attention-deficit hyperactivity disorder and tall stature. Rarely hyperpigmentation, gynecomastia, and pruritus with hives can be a presenting manifestation. Apathetic hyperthyroidism is characterized by absence of classical adrenergic manifestations like sweating, palpitations, and tremors, despite thyrotoxicosis. Patients usually present with monosymptomatic manifestations like general- ized weakness, unexplained weight loss, “lone” atrial fibrillation, or congestive cardiac failure. Therefore, in clinical practice, a high index of suspicion is required to diagnose apathetic hyperthyroidism. The disorder is usually seen in males and occurs in 10–15% of older patients with hyperthyroidism. Adrenergic manifestations are “masked” due to age-related autonomic neuropathy and relative tissue resistance to thyroid hormone. Patients with thyrotoxicosis commonly have increased appetite, but patients with thyrotoxic cardiomyopathy, apathetic hyperthyroidism, and thyrotoxicosis- induced hypercalcemia may have loss of appetite. Examination of the hand in a patient with thyrotoxicosis offers very useful infor- mation and can help in differential diagnosis. Tachycardia, tremors, palmar ery- thema, warm and moist hands are characteristic findings in thyrotoxicosis. Patients with anxiety neurosis can have many of these features; however the pres- ence of cold and moist hands differentiate it from thyrotoxicosis. These manifes- tations in thyrotoxicosis are due to increased basal metabolic rate, enhanced adrenergic activity, and relative hyperestrogenemia. Rarely knuckle hyperpigmentation, vitiligo, and thyroid-associated dermopathy can be seen on the dorsum of the hands. Sinus tachycardia is invariably present in patients with thyrotoxicosis, both at rest (90%) and during sleep. Other common arrhythmias include atrial fibrilla- tion (2–15%) and supraventricular tachycardias. Ventricular arrhythmias are 218 10 Thyrotoxicosis extremely rare and if present suggest coexisting hypokalemia or underlying cardiac disease. Congestive cardiac failure is commonly seen in elderly patients with atrial fibrillation or in those with underlying heart disease. Occasionally, younger patients may also present with heart failure even in the absence of rhythm disorders or preexisting heart disease. This is due to thyrotoxic cardio- myopathy which is usually reversible with the achievement of euthyroid state. Lastly, patients with preexisting coronary artery disease may have worsening of their symptoms with the onset of thyrotoxicosis. In patients with thyrotoxicosis, supraventricular arrhythmias like sinus tachy- cardia (>90%) and atrial fibrillation (5–15%) are more common than atrial pre- mature beats, atrial flutter, and paroxysmal atrial tachycardia, whereas ventricular premature contractions and other ventricular arrhythmias are rare. The predominance of atrial arrhythmias is due to the effect of thyroid hormones on atrial ion channels and atrial enlargement related to volume expansion. The most common cause of bradycardia in patients with thyrotoxicosis is the use of β-blockers. Rarely, sick sinus syndrome has been reported in association with thyrotoxicosis, which is reversible on achievement of euthyroidism. Thyrotoxicosis is classically associated with systolic hypertension, decreased diastolic blood pressure, and wide pulse pressure. Systolic hypertension is due to increased cardiac output and augmented myocardial contractility. Decreased diastolic blood pressure is due to peripheral vasodilatation, which occurs as a result of direct effect of thyroid hormones on vasculature and increased nitric oxide production. Peripheral vasodilatation is an adaptive response to enhanced thermogenesis to dissipate heat. The unusual cardiac manifestations of thyrotoxicosis, particularly seen in Graves’ disease, are mitral valve prolapse, sick sinus syndrome, pulmonary hypertension, rate-related cardiomyopathy, and pleuro-pericardial friction rub (Means–Lerman scratch). Most of these are reversible with adequate and inten- sive treatment in early stages of the disease. Weight loss is the usual feature of thyrotoxicosis, seen in 85% of patients, but weight gain may be seen in 2% of patients. Young individuals with 10 Thyrotoxicosis 219 thyrotoxicosis, patients with mild thyrotoxicosis, those receiving glucocorti- coids for coexisting thyroid-associated orbitopathy, and patients with conges- tive cardiac failure may present with weight gain. The effect of thyroid hormone excess on body composition includes reduction in lean body mass, fat mass, and bone mineral density. Weight loss in patients with thyrotoxicosis is predominantly due to a decrease in lean body mass, fol- lowed by decrease in fat mass. With attainment of euthyroid state, there is restoration of body composition to normal. Patients with thyrotoxicosis may have glucose intolerance, which is attributed to increased intestinal absorption of glucose, enhanced hepatic gluconeogenesis, rapid clearance of insulin, and possibly insulin resistance at receptor level. Hepatic glucose output is increased due to elevated levels of counter-regulatory hormones like glucagon and catecholamines and high levels of lactate (Cori’s cycle) due to increased anaerobic glycolysis. On the contrary, patients with Graves’ disease may present with hypoglycemia which usually occurs after treatment with methima- zole, as it acts as a hapten and induces anti-insulin antibodies. Mild hepatic dysfunction is not uncommon in thyrotoxicosis and is seen in 20–30% of patients. The hepatic damage is due to relative hypoxia and commonly manifests as transaminitis. However, severe thyrotoxicosis may lead to advanced hepatic dysfunction due to centrilobular hepatic necrosis (“water- shed zone” of liver), and can present as hyperbilirubinemia and transaminitis. Other causes of hepatic dysfunction in patients with thyrotoxicosis are concur- rent autoimmune hepatitis, congestive hepatomegaly, and rarely use of antithy- roid drugs or pulse methylprednisolone therapy for treatment of thyroid-associated orbitopathy. Propylthiouracil and methylprednisolone result in hepatocellular dysfunction, while carbimazole and methimazole leads to cholestatic jaundice. Gynecomastia is present in one-third of patients with hyperthyroidism and is more commonly observed in elderly individuals. This occurs due to the direct stimulatory effect of T4 on aromatase resulting in increased estradiol levels. Menstrual irregularities are present in 20–60% of women with thyrotoxicosis and manifests as oligomenorrhea, hypomenorrhea, polymenorrhea, or rarely amenor- rhea. In addition, 5–6% of women with thyrotoxicosis have infertility, and there is an increased risk of fetal loss due to luteal phase defects and catabolic state. Men with thyrotoxicosis can present with decreased libido, erectile dysfunction, gynecomastia, and infertility. These manifestations are due to normal/decreased free testosterone in the presence of increased free estradiol levels. Further, the sperm count may be normal or slightly reduced, but motility is consistently decreased (oligoasthenospermia) leading to infertil- ity. The unusual manifestations of thyrotoxicosis are enlisted in the table given below. Unusual manifestations Remarks Apathetic hyperthyroidism Elderly subjects (age-related neuropathy) Sinus bradycardia Use of β-blockers, sick sinus syndrome Pyrexia of unknown origin Subacute thyroiditis, Graves’ disease Weight gain Young patient, mild thyrotoxicosis Isolated thyroid-associated orbitopathy May precede hyperthyroidism Isolated thyroid-associated dermopathy May precede hyperthyroidism/orbitopathy Periodic paralysis Hypokalemia or hyperkalemia Rhabdomyolysis Severe thyrotoxicosis Fracture Fibrous dysplasia (McCune Albright syndrome) Osteoporosis Hypercalcemia Severe bone resorption Hypoglycemia Autoimmune, use of methimazole Gynecomastia Altered T/E2 ratio Hyperpigmentation Increased cortisol turnover Lymphadenopathy, thymic hyperplasia, Lymphoreticular hyperplasia due to autoimmunity and hepatosplenomegaly 10 Thyrotoxicosis 221 27. Differentiating features among the three common causes of thyrotoxicosis are summarized in the table given below. Diffuse toxic goiter, infiltrative orbitopathy, and infiltrative dermopathy consti- tute the classical triad of Graves’ disease. Diffuse toxic goiter is the most com- mon clinical manifestation; however, goiter may not be present in 4% of patients.

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A spatiotemporal evaluation of the contribution of the dorsal mesenchymal protrusion to cardiac development buy 40mg sotalol free shipping. Isl1 expression at the venous pole identifies a novel role for the second heart field in cardiac development discount sotalol 40 mg with amex. Development of the Arterial Pole of the Heart Malformations of the arterial pole of the heart sotalol 40 mg without prescription, encompassing the ventricular outlets and arterial trunks with their valves order sotalol in india, constitute almost one-third of all cardiac malformations, and are often incompatible P. These malformations are markedly diverse, combining abnormalities in ventriculoarterial connections and septation, along with valvar and vascular defects. This strongly suggests an intimate association of distinct morphogenetic and molecular pathways in the formation of the outflow tract. Studies on the morphogenesis and septation of the outflow tract in experimental animals have revealed an important role for the mesenchymal tissues derived from the two distinct cellular populations, the secondary heart field and the cardiac neural crest (255,256). The involvement of different mesenchymal tissues of different origin in the development of the cardiac outflow tract correlates well with the great variety of malformations of the arterial pole, as demonstrated in many studies using animal models. Arrows point to the persisting myocardial connections between the atrial and ventricular walls. The epicardium and the development of the atrioventricular junction in the murine heart. This process requires a variety of environmental signals to specify and then to drive delamination of the future neural crest cells from the neural tube (257). Delamination of the neural crest cells from the neuroectoderm is regulated by Wnt-signaling, with Wnt1 expression turning off soon after the cells have left the neural tube. After delamination, the neural crest cells migrate widely throughout the body participating in the development of many organs, including the cranial ganglia, peripheral nervous system, adrenal glands, and melanocytes. The migratory path and ultimate fate of these cells depends on their relative position of origin along the craniocaudal axis. A subregion of the cranial neural crest extending from the level of the midotic placode to the third somite has been named the cardiac neural crest, because of its role in cardiovascular development (259,260,261). The cells of the cardiac neural crest migrate to the third, fourth, and sixth pairs of pharyngeal arches, and from there into the heart (Fig. After arrival at the target location, the cardiac neural crest cells differentiate into mesenchymal and smooth muscle cells, which then contribute to the septation of the outflow tract, formation of the separate walls of the intrapericardial arterial trunks, or develop into the cardiac parasympathetic ganglia of the heart (259). The cardiac neural crest–derived smooth muscle cells within the caudal pharyngeal arches support the development of the aortic arch arteries. Neural crest–derived cells also influence the normal formation of the arterial valve leaflets, as abnormal semilunar valve structure was reported in the animal model of neural crest ablation (262,263,264). The cardiac neural crest–derived cells are also responsible for modulating the signaling in the caudal pharynx, including the secondary heart field. The disruption of the cardiac neural crest in numerous studies, either by physical P. Interestingly, similar malformations of the arterial pole of the heart are frequently observed in patients with 22q11-microdeletion syndrome (265), and this observation was even a reason to call this syndrome a crestopathy (266). A: Shows a left lateral view of a human embryo of about 26 days of development with well-established pharyngeal arches and their arteries, which are clearly visualized by the presence of the red erythrocytes. Role of cardiac neural crest in the development of the caudal pharyngeal arches, the cardiac outflow and disease. It is expressed in the mesenchymal tissues of the outflow tract in the developing human heart (269). Another important and well-investigated transcription factor, Pax3, is expressed in the dorsal neural tube and in the neural crest cells. The so-called Splotch mouse mutant lacks the Pax3 gene, and has been studied extensively. Mice homozygous for the Splotch mutation have a complete cardiac neural crest–ablation phenotype. It has been demonstrated that Pax3 is not necessary for migration of the cardiac neural crest cells, but it may play a role in the initial expansion of the cardiac neural crest population (272,273,274). Formation and Septation of the Cardiac Outflow Tract Within the definitive outflow tracts, three distinct components can be distinguished: a distal component composed by the intrapericardial arterial trunks, a middle component consisting of the arterial valves and their supporting sinuses, and a proximal component, the ventricular outflow tracts. This demarcation describes more accurately the nature of the cardiac arterial pole, as opposed to the traditional and often confusing division in “conus” and “truncus,” which has been adapted from terminology of the comparative anatomy (275). The arterial pole in the developing heart does not possess such readily discernible morphologic entities. It is possible, nonetheless, to consider the developing outflow tract and its extrapericardial continuation as a tripartite structure, which considerably facilitates the description and understanding of its morphogenesis. Thus, subsequent to its formation, the most proximal part of the developing outflow tract and its myocardializing cushions form the ventricular outflow tracts. The distal part of the myocardial outflow tract and its mesenchymal cushions develop into the roots of the great arteries and arterial valves and the developing arterial trunks acquire their own intrapericardial walls (275). The arterial pole of the developing heart undergoes extensive changes in a relatively short period of time. First, the tubular myocardial outflow tract with a single lumen is formed by continuous addition of secondary heart field–derived cardiomyocytes to the arterial pole of the heart (84,85,86). As discussed above, Tbx1 is a central transcriptional regulator of the secondary heart field and is necessary for proper development of cardiac outflow tract myocardium (94,276,277). The secreted morphogen Shh activates forkhead-containing transcription factors, which directly regulate Tbx1, by which its expression is maintained in the secondary heart field progenitors (278,279). In line with this, mice lacking Shh, Foxc1 and Foxc2, and Tbx1 share similar cardiac outflow tract defects (279,280). Disruption of the secondary heart field development by mutation of Tbx1 or Fgf8 results in outflow tract defects overlapping those observed with neural crest ablation, including persistent arterial trunk, alignment defects of the outflow tracts, and ventricular septal defects (281,282,283). The above described reciprocal interactions between the cells derived from the secondary heart field and from the cardiac neural crest in the outflow tract are likely essential for normal migration, differentiation, and proliferation of the cells contributing to the formation and septation of the outflow tract. The left- and right-sided panels in (A) are slightly modified reproductions of the orthotopic gold-labeling experiment of a neural crest graft transplantation in an early mouse embryo, which demonstrates that neural crest–derived cells (arrows) migrate along the pharyngeal arches. Induction of the neural crest cells is followed by their migration, positioning, and differentiation. The putative positive and negative interactions between different genes, transcription factors, and signaling molecules regulating migration and survival of the cardiac neural crest cells are omitted from this scheme as current knowledge is largely incomplete and sometimes controversial. The panels in (B) show the fate of the cardiac neural crest–derived cells during the development of the outflow tract. Cardiac neural crest of the mouse embryo: axial level of origin, migratory pathway and cell autonomy of the splotch mutant effect. It is, however, a highly dynamic structure, with differentiating cells continuously added distally from the pharyngeal mesoderm (39,87,255), and with cells seemingly “disappearing” proximally by differentiation into right ventricular myocardial cells (82,132). Interestingly, the myocardial component of the outflow tract, although temporarily retaining Islet1 expression, displays hardly any proliferation at all development stages (269,284). The lumen of the outflow tract is lined by endocardial cells expressing connexin 40, similar to the arterial endothelium, but in contrast to the rest of endocardium. The space between the myocardial wall and the endocardium of the tubular outflow tract is initially filled with cardiac jelly, which becomes populated by endocardially derived mesenchymal cells. During the 5th and 6th weeks of the human development, the outflow tract becomes relatively shorter. In experimental animals, this shortening has been shown to be dependent on an apoptosis, or programmed death of the cardiomyocytes of the outflow tract wall (285). During these stages, the mesenchyme within its proximal part becomes more densely populated, forming a pair of cushions (Fig. These cushions fuse with one another, dividing the lumen into slightly spirally oriented aortic and pulmonary P. The most distal end of the outflow tract lumen can be considered then as an aortopulmonary foramen, which dorsally is bordered by the neural crest–derived pharyngeal mesenchyme (289). This mesenchyme protrudes into the lumen of the distal outflow tract between the origins of the symmetric sixth and fourth pairs of aortic arches and can be considered as the first sign of aortopulmonary septation (Fig. The protruding dorsal wall of the aortic sac fulfills the function of aortopulmonary septation, as demonstrated by the labeling studies in chicken embryos, where the initial septation of the distal outflow tract involves intrapericardial migration of peribranchial mesenchyme along the sixth aortic arches (290). A recent study of the Ripply3-deficient mice underscores the importance and sufficiency of such a migration. These mice display complete absence of the third and fourth aortic arches, but have separated intrapericardial arterial trunks, along with normally formed sixth arches (291). A pair of endocardially derived mesenchymal cushions also forms within the distal part of the outflow tract, which become heavily populated by neural crest–derived cells (Fig. Subsequent to the fusion of these cushions and protrusion of the aortopulmonary septum, the lumen of the distal outflow tract is divided into a pulmonary channel extending leftward from the midline, and an aortic channel positioned to the right. Importantly, the spiral orientation of the future pulmonary trunk and ascending aorta already at this stage reflects the definitive postnatal topographic relations (Fig.

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The fnal adult height is usu- ally within the target height range and fertility is normal safe 40mg sotalol. A 15-year-old boy presented with poor development of secondary sexual char- acteristics and short stature discount 40 mg sotalol. This is because of poor spine growth due to delay in exposure to gonadal steroids buy 40 mg sotalol free shipping. The commonly used regi- men is testosterone enanthate or cypionate 50–100 mg intramuscularly every 236 7 Delayed Puberty month for a period of 3 months sotalol 40mg with mastercard. With this therapy, there is an increase in testicu- lar volume by 3–4 ml in 6–9 months, progressive appearance of secondary sexual characteristics, and acceleration of growth velocity from 4 cm/year to 9–10 cm/year. If testicu- lar enlargement does not occur within 3 months after discontinuation of testos- terone therapy, another short course of testosterone may be administered. Normal puberty is a slow and progressive process which is completed over a period of 2–5 years; therefore, pubertal development should be accomplished slowly over a period of 2–5 years. Normal pubertal development is orchestrated by synergistic actions of gonado- tropins. Exogenous testosterone therapy leads to gynecomastia due to aromatization of testosterone to estradiol in adipose tis- sues. Circulating estradiol levels may not necessarily be elevated in all patients because local aromatase activity in the breast tissue also contributes to gynecomastia. The index patient developed gynecomastia after initiation of testosterone therapy. Testosterone-mediated gynecomastia is frequently painful because of rapid enlargement of breast. Treatment strategies include reduction in either dose and/or frequency of testosterone administration or use of selec- tive estrogen receptor modulators/aromatase inhibitors. Selective estrogen receptor modulators like tamoxifen have been widely used in the treatment of peripubertal gynecomastia and are most effective in those with recent-onset gynecomastia. There are anecdotal case reports regarding use of aromatase inhibitors like anastrozole for the treatment of testosterone-mediated gyne- comastia. Although the most common agent used to induce virilization is testosterone, it does not initiate spermatogenesis. However, it is not clear whether to initiate combined gonadotropin therapy, at induction of puberty or when fertility is desired. It has been shown that early use of combined therapy (at 15–20 years) is more effective for initiation of spermatogenesis, as compared to its use in older subjects (at 25–30 years). Various formulations of testosterone are available including oral, intramuscular, transdermal, buccal, and nasal spray; however, 240 7 Delayed Puberty intramuscular preparations of testosterone like enanthate, propionate, or cypi- onate are preferred for induction of puberty because of the vast experience with their use. Therapy is initiated at a dose of 50–100 mg monthly, and the dose is gradually increased by 50 mg, every six months. Therapy is initiated at a low dose to minimize the risk of priapism, aggressive behavior, and acne and to prevent premature closure of epiphysis. Once a dose of 100–150 mg is reached, the frequency of administration can be increased to fortnightly. The adult replacement dose of testosterone is 200–250 mg intramuscularly every 2–3 weeks. After initiation of therapy, boys should be monitored for growth and progression of pubertal development. Monitoring of serum testosterone levels is not recommended during induction of puberty because of wide variation in reference range of serum testosterone during pubertal development in healthy boys. However, monitoring of serum testosterone should be performed once the adult replacement dose is initiated, with a target to maintain serum testosterone in the mid-normal adult range. In addi- tion, there is extensive experience of pubertal induction with intramuscular tes- tosterone therapy as compared to other modalities. However, therapy with testosterone only induces virilization and does not initiate spermatogenesis. Further, testosterone therapy is associated with adverse effects like priapism, acne, aggressive behavior, mood disorders, and gynecomastia. Therapy with intramuscular preparations is associated with supraphysiological levels of serum testosterone in the initial few days, followed by low levels before the next injection, resulting in wide swings in the concentration of serum testoster- one, which manifests as disturbing fuctuations in sexual function, energy level, and mood. In normal men, intratesticular testosterone concentration is 100- to 200-folds higher than serum testosterone levels. Assisted reproduc- tive technologies may be considered in those who fail to achieve spermatogen- esis despite optimal therapy. Pubertal induction with estrogen is preferred because of oral route of administration and once-daily dosing. Many prepara- tions of estrogen are commercially available; however, preparations contain- ing 17β-estradiol are preferred, because it is the predominant estrogen in premenopausal women. Progesterone should be added once breakthrough bleed occurs or after at least 2 years of estrogen therapy. Later, the treatment should be maintained with estrogen and proges- terone cyclically. Does the presence of gynecomastia differentiate between hypogonadotropic hypogonadism and hypergonadotropic hypogonadism during adolescence? Although gynecomastia is considered as a typical feature of hypergo- nadotropic hypogonadism (particularly Klinefelter’s syndrome), 30–40% of patients with hypogonadotropic hypogonadism can also have gynecomastia. However, detection of low-grade mosa- icism in a male without any phenotypic features does not merit a diagnosis of Klinefelter’s syndrome. The prevalence of congenital malformations (skeletal and cardiac anomalies), learning disabilities, and mental retardation are more in patients with higher-grade chromosomal aneu- ploidies. How to differentiate between hypogonadotropic hypogonadism and hypergo- nadotropic hypogonadism? The presence of anosmia, synkinesia, midline defects, skeletal anomalies, cryptorchidism, micropenis, small soft testes, and eunuchoidal proportions points to the diagnosis of hypogonadotropic hypogonadism (idiopathic), 7 Delayed Puberty 243 whereas long-leggedness, small frm testes, gynecomastia, learning disabilities, and moderate degree of spontaneous virilization suggest the diagnosis of hyper- gonadotropic hypogonadism (Klinefelter’s syndrome). The clinical features which suggest a diagnosis of Klinefelter’s syndrome in early childhood include long-leggedness, docile behavior, developmental delay in speech, and learning disabilities. How to explain the variability in phenotypic manifestations in patients with Klinefelter’s syndrome? However, it has been shown that testicular degenerative process is rela- tively slower in these subjects. Skewed inactivation of X chromosome was also considered as a cause for variability in phenotypic manifestations; how- ever, this hypothesis has been refuted in recent studies. In addition, patients with mosaic Klinefelter’s syndrome may also have variable phenotypic mani- festations (Fig. The degenerative process continues during childhood and accelerates during ado- lescence. Seminiferous Sertoli Serum tubules cells Germ cells Leydig cells testosterone Fetus Normal Normal Reduced Normal – Mini- Normal Normal Reduced Normal Reduced puberty Childhood Normal Normal Reduced – – Puberty Hyalinization Reduced Reduced Pseudohypertrophy Initially and fbrosis normal, later decline Adulthood Hyalinization Reduced Reduced/ Pseudohypertrophy Reduced and fbrosis absent 69. The onset of puberty is nor- mal in most patients with Klinefelter’s syndrome, but majority have incomplete development of pubertal events. However, the rise in serum testos- terone is accompanied with accelerated hyalinization and fbrosis of seminifer- ous tubules and degeneration of Sertoli cells. The cause for accelerated testicular damage during puberty is not clear; however, elevated levels of gonadotropins, increased intratesticular estradiol levels, and alteration in intratesticular testos- terone/estradiol ratio have been implicated. Patients with Klinefelter’s syndrome are at high risk for the development of breast cancer, lung cancer, mediastinal germ cell tumors, and non-Hodgkin’s lymphoma. The risk for breast cancer is increased by 50-fold, while that of mediastinal germ cell tumors is 500-fold. Although the exact mechanism for increased cancer risk is not clear, the most likely explanation is overdosage of genes present in X chromosome which are not lyonized. In addition, abnormal estradiol/testosterone ratio may also contribute to the development of breast cancer. What are the peculiarities of germ cell tumors associated with Klinefelter’s syndrome? It is also recommended that patients with mediastinal/intracranial germinoma should undergo karyotype analysis. However, even with these newer tech- nologies, the live birth rates vary from 20 to 46 %. In addition, there is a higher risk of autosomal abnormalities in chromosome 13, 18, and 21.

Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure order sotalol 40mg with visa. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials purchase generic sotalol line. Cardiac resynchronization therapy for pediatric patients with heart failure and congenital heart disease: a reappraisal of results generic sotalol 40 mg fast delivery. Cardiac resynchronization therapy (and multisite pacing) in pediatrics and congenital heart disease: five years experience in a single institution buy sotalol 40 mg lowest price. Cardiac resynchronisation therapy in paediatric and congenital heart disease: differential effects in various anatomical and functional substrates. Classic-pattern dyssynchrony and electrical activation delays in pediatric dilated cardiomyopathy. Evaluation of mechanical dyssynchrony in children with idiopathic dilated cardiomyopathy and associated clinical outcomes. Advanced heart failure treated with continuous-flow left ventricular assist device. Left ventricular assist device in Duchenne cardiomyopathy: Can we change the natural history of cardiac disease? The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric heart transplantation report–2014; focus theme: retransplantation. Indications for heart transplantation in pediatric heart disease: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young; the Councils on Clinical Cardiology, Cardiovascular Nursing, and Cardiovascular Surgery and Anesthesia; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Waiting list mortality among children listed for heart transplantation in the United States. Long-term outcomes of dilated cardiomyopathy diagnosed during childhood: results from a national population-based study of childhood cardiomyopathy. Recovery of echocardiographic function in children with idiopathic dilated cardiomyopathy: results from the pediatric cardiomyopathy registry. Competing risks for death and cardiac transplantation in children with dilated cardiomyopathy: results from the pediatric cardiomyopathy registry. The impact of changing medical therapy on transplantation-free survival in pediatric dilated cardiomyopathy. New mechanistic and therapeutic targets for pediatric heart failure: report from a National Heart, Lung, and Blood Institute working group. Newburger The survival of children with congenital heart disease has improved dramatically over the past four decades. As a result, the number of adults with congenital heart disease is now believed to exceed the number of children (1,2,3,4). As mortality has declined, neurologic and developmental morbidities in survivors have come increasingly into focus. Poor school performance and the resultant need for educational support across the developmental span from kindergarten through 12th grade may have considerable personal and societal costs. Furthermore, the increasing number of adults with congenital heart disease has highlighted the consequences of neurodevelopmental impairments for employability and mental health (5). Neurodevelopmental disabilities can derive from innate or genetic factors, from aberrant fetal circulation, from the physiology and sequelae of congenital heart disease itself (e. Particularly in congenital heart disease, it can be difficult to separate developmental outcomes for a particular diagnosis and its genetic underpinnings from consequences of surgical and transcatheter procedures used in its management. It is likely that central nervous system effects of congenital heart disease are cumulative and affected by the complex interaction of genetic, preoperative, intraoperative, and postoperative factors (6,7). In this chapter, we review variables that contribute to neurodevelopmental outcomes in children after heart surgery and summarize findings related to long-term neurodevelopmental outcomes for more common, complex congenital heart malformations. Genetic Abnormalities Genetic abnormalities may cause both congenital heart defects and abnormalities of central nervous system structure and function. Children with genetic syndromes have much worse neurodevelopmental outcome than those without recognizable syndromes (8,9). Furthermore, it is suspected that genetic factors may independently underlie delayed development, either through a primary effect on the central nervous system or by affecting host susceptibility and resiliency, even in some patients without a recognizable constellation of congenital abnormalities. Specific types of congenital heart defects may be associated with different chromosomal abnormalities with varying molecular pathways that impact central nervous system structure and function. Mutations causing congenital heart defects may be associated with specific neurodevelopmental profiles. For example, although the clinical phenotype associated with 22q11 microdeletion is variable (18), a reasonably consistent neurodevelopmental profile has emerged. In adults with velocardiofacial syndrome, specific deficits have been reported in visual– spatial ability, problem solving and planning (executive functions), abstract social thinking, and attentiveness (23,25,26). Finally, some genetic mutations that cause structural heart defects are associated with psychiatric illness, including, the 22q11 microdeletion (19,23,28,29,30,31,32). In adults with 22q11 microdeletion, the prevalence of late-onset psychosis, most commonly schizophrenia and schizo-affective disorders, is 10% to 20% (21,33,34). With advances in research on genetic causes of congenital heart disease, it is likely that an increasing number of genetic and epigenetic abnormalities will be linked to neurologic and developmental outcomes in congenital heart disease patients. Brain Anatomy, Pathology, and Neuroimaging Cerebral dysgenesis has been reported in autopsy series to occur in 10% to 29% of children with congenital heart disease and may include such features as microdysgenesis, incomplete operculization, microcephaly, and agenesis of the corpus callosum (7,35,36,37,38). The cause of cerebral dysgenesis may be related to genetic factors or to abnormalities of fetal cerebrovascular hemodynamics caused by the particular congenital heart defect. Fetuses with congenital heart disease and with low cerebral-to-placental resistance ratios (<1) have smaller head circumferences than normal (41). Multiple studies have demonstrated an association of smaller brains and congenital heart disease (41,43,44,45). In addition to cerebral dysgenesis, infarction may be seen on histopathologic examination of the brains of infants and children with congenital heart disease. Thromboembolic events related to cardiac catheterization, cardiac surgery, or endocarditis may cause focal infarction. Decreased cerebral perfusion, related to hypotension, hypoperfusion, or cardiac arrest, is associated with a diffuse pattern of cerebral injury (46). Although a spectrum of gray matter lesions was evident, cerebral white matter damage, composed of either periventricular leukomalacia or diffuse white matter gliosis, was the most significant finding. Neonates were more likely than infants to have periventricular leukoencephalopathy, reflecting the vulnerability of the immature (premyelinating) white matter to hypoxic–ischemic injury. Otherwise, the timing and type of surgery were unrelated to the pattern and severity of overall brain injury. The Total Maturation Scoring System developed by Childs to measure brain maturation in premature infants incorporates information related to myelination, cortical infolding, glial cell migration bands, and the presence of germinal matrix tissue (49). Moreover, preoperative cerebral lactate peaks were elevated in more than half of infants evaluated by magnetic resonance spectroscopy. In the early postoperative period, 48% of infants had new periventricular leukoencephalopathy, 19% had new infarcts, and 33% had new parenchymal hemorrhage. However, cerebral atrophy was detected in two, old infarct in one, and new infarct in one subject. Lower scores on developmental assessments were not associated with the presence of new postoperative white matter injury but did correlate with preoperative white matter injury and brain immaturity (54). Changes in central nervous system structure may underlie neurocognitive abnormalities in children with congenital heart disease. For example, worse performance in math problem solving and numerical operations was correlated with reduced left parietal fractional anisotropy. In a mixed group of congenital heart disease adolescents, compared to controls, brain volume was reduced, and the extent of brain volume reduction was significantly associated with scores on tests of cognition, executive function, and motor function (56). Perioperative Risk Factors Prospective studies of central nervous system protection and injury have mainly focused on risk factors related to cardiac surgery and the perioperative period. The intense attention to perioperative risk factors is likely related to the ability of investigators to study the brain during this high-risk period, which includes planned brain ischemia–reperfusion injury with use of hypothermic cardiopulmonary bypass and total circulatory arrest techniques. Furthermore, perioperative management strategies can be tested in randomized clinical trials. Perioperative Monitoring Approaches As investigators have sought to optimize neurodevelopmental outcomes by modifying surgical and medical perioperative approaches, one limiting factor has been difficulty in identifying early predictive markers of longer- term developmental outcomes. However, some centers have adopted perioperative monitoring strategies that include continuous electroencephalogram, near- infrared spectroscopy, and/or transcranial Doppler ultrasound (51,57,58). Clinical adoption of these monitoring techniques has outpaced establishment of definitive evidence for their clinical benefit. Further study of this technique, other perioperative monitoring approaches and additional potential early markers are needed to better understand how late outcomes can be predicted in newborns and infants undergoing cardiac surgery. Nonetheless, a great deal has been learned since the 1990s related to perioperative risk factors of central nervous system insults for children with congenital heart disease.

J. Alima. Saint Anselm College.

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