Clinical and molecular analysis of RASopathies in a group of Turkish patients.

The 'RASopathies' are a group of disorders sharing many clinical features and a common pathophysiology. In this study, we aimed to clinically evaluate a group of Turkish patients and elucidate the underlying genetic etiology. Thirty-one patients with a clinical diagnosis of one of the RASopathy syndromes were included in the study. Of these, 26 (83.8%) had a clinical diagnosis of Noonan syndrome, whereas 5 had a clinical diagnosis of either Costello, LEOPARD or cardio-facio-cutaneous syndromes. Twenty of 31 (64.5%) patients were found to be mutation positive. Mutations in PTPN11, SOS1 and SHOC2 genes were detected in patients with Noonan syndrome (57.6%). Mutations in MEK1, PTPN11, BRAF and HRAS genes were detected in the remaining. Pulmonary stenosis was the most common (61.5%) cardiac anomaly. Among Noonan syndrome patients with a confirmed mutation, mild intellectual disability tended to be more common in patients with PTPN11 mutation than in those with SOS1 mutation. Hematologic evaluation revealed coagulation defects in three Noonan syndrome patients with a mutation. This is currently the largest clinical and molecular study in Turkish RASopathy patients. Our findings indicate that molecular epidemiology and genotype-phenotype correlations in RASopathies are relatively independent from the ethnic population background.

A prenatally sonographically diagnosed conotruncal anomaly with mosaic type trisomy 21 and 22q11.2 microdeletion/DiGeorge syndrome.

A prenatally sonographically diagnosed conotruncal anomaly with mosaic type trisomy 21 and 22q11.2 microdeletion/DiGeorge syndrome: We report a prenatally sonographically diagnosed conotruncal and urogenital anomaly. Postnatally, the patient presented with seizures, hypocalcemia, hypoparathyroidism and thymic aplasia and diagnosed as DiGeorge syndrome. Echocardiography showed malalignment VSD, supravalvular pulmonary stenosis and overriding aorta. Chromosome and FISH studies showed the association of mosaic type trisomy 21 and 22q11.2 microdeletion. The present patient is the second case of mosaic type of Down syndrome associated with 22q11.2 microdeletion. In addition the patient also had clinical and laboratory features of DiGeorge syndrome.

A multidisciplinary approach to the management of individuals with fragile X syndrome.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Since the identification of the responsible gene (FMR1) and its protein (FMRP), there has been enormous progress in both clinical and pathogenetic research on the neurobehavioural aspects of the condition. However, studies regarding other medical problems anticipated in individuals with FXS are limited. A multidisciplinary study evaluating various causes of morbidity in the same group has not been published yet. METHODS: Twenty-four boys with FXS full mutation were recruited out of a larger group of 103 diagnosed in one centre over the past 10 years. Ear nose and throat, eye and cardiac examinations were performed in addition to routine cognitive, behavioural, neurological and speech and language assessments. RESULTS: The average IQ score was 49.8 +/- 20 (range 25-90). There were four patients (18%) with IQ above 70. Using DSM-IV, attention deficit hyperactivity disorder was diagnosed in five boys out of 22 examined (23%), while 32% were diagnosed with pervasive developmental disorder. The seizure frequency was 17%. A psychiatric disorder was diagnosed in six out of eight boys with electroencephalogram abnormalities (75%). Minimal conductive hearing loss was found in five (5/22) patients. There was significant delay in both expressive and receptive language skills. Ocular findings were refractive errors (13%) and strabismus (4.4%). Mitral valve prolapsus (MVP) was observed in 3/22 (13.7%) patients and aortic annulus dilatation was present in 2/22 (9%) patients. CONCLUSIONS: Frequency of psychiatric diagnoses made with DSM-IV were in parallel to those reported in the literature. Comorbidity of seizures and psychiatric disorders was noteworthy. The percentage of 'high-functioning' full mutation males supports the previous observations. Ear nose and throat and eye examination revealed remarkably lower prevalence of abnormal findings than reported. MVP was slightly less frequent compared with the single study in the literature. Age at the time of examination had an effect on the outcome of cardiac evaluation. These findings will guide us in future management of the group of patients followed in our institution. The protocol applied provides an applicable outline for multidisciplinary institutional settings dealing with individuals with FXS.

Severe hemolytic anemia after repair of primum septal defect and cleft mitral valve.

Two cases are described in which severe mechanical hemolytic anemia developed after surgical repair of primum atrial septal defect (ASD) and cleft mitral valve. In both cases there was residual mitral regurgitation after repair. Moderate mitral regurgitation and collision of the regurgitant jet with the teflon patch used for repair of the primum ASD were detected by color-Doppler echocardiography imaging. Laboratory tests showed normochromic normocytic anemia, increased indirect serum bilirubin, decreased plasma haptoglobin and hemoglobinuria. The peripheral blood smear contained numerous fragmented red cells. Following another surgical correction of the mitral valve (repair or mitral valve replacement), there was no more hemolysis. The two presented cases show that foreign materials in association with localized intracardiac turbulence may cause severe hemolysis.

Comparison of mid-term clinical experience with steroid-eluting active and passive fixation ventricular electrodes in children.

Although active fixation ventricular leads seem to have advantages over passive fixation leads, this study compares the follow-up results of active and passive fixation leads in children. We evaluated the implantation and follow-up data of 41 children with active (Accufix II DEC, group 1) (n = 20) or passive (Membrane E, group 2) (n = 21) fixation, steroid-eluting ventricular leads. All but one of the patients in group 1 completed the 12-month follow-up. The mean follow-up period in group 2 was 10.4 +/- 2.9 months (range 3-12 months, median 12 months). In both groups the mean pacing threshold was measured as 0.51 +/- 0.09 V versus 0.48 +/- 0.15 V (P > 0.05) at 0.5-ms pulse width, mean R wave amplitude as 9.9 +/- 2.5 mV versus 9.4 +/- 3.2 mV (P > 0.05), and mean impedance as 557 +/- 92 omega versus 664 +/- 160 omega (P < 0.05), respectively, at implantation. After the first week of pacing, mean threshold values in group 1 were significantly lower than those of group 2 (P < 0.01 and P < 0.05, respectively). During the follow-up period, lead impedance measurements did not show a significant difference between the two groups. In one patient from group 1, the lead (by unscrewing) was removed easily because of pacemaker pocket infection. No lead dislodgement or helix deformation occurred in group 1. Nevertheless, in one patient from group 2, the lead was extracted at 4-month postimplantation because of lead displacement. We conclude that the steroid-eluting active fixation lead (Accufix II DEC) have advantages of easier implantation and lower acute and chronic stimulation thresholds compared to the passive fixation lead (Membrane E). Therefore, Accufix II DEC is superior to Membrane E, and it is a better first choice in children with an implanted single chamber ventricular pacemaker.

Torsade de pointes associated with encephalitis.

Torsade de pointes is a polymorphic ventricular tachycardia. Causes of torsade de pointes are well described. Although intracranial disease can produce dramatic electrocardiographic (ECG) changes, we are not aware of previous cases with torsade de pointes and encephalitis. We report a case with encephalitis who developed torsade de pointes, and was treated with temporary ventricular pacing and magnesium infusion.

Comparison of normal sinus rhythm and pacing rate in children with minute ventilation single chamber rate adaptive permanent pacemakers.

Rate adaptive pacemakers are used to achieve a better cardiac performance during exercise by increasing the heart rate and cardiac output. The ideal rate adaptive sensor should be able to mimic sinus node modulation under various degrees of exercise and other metabolic needs. Minute ventilation sensing has proven to be one of the most accurate sensor systems. In this study, alterations in sinus rhythm and pacing rates during daily life conditions in 11 children (median age 11 years, range 6-14 years) with minute ventilation single chamber pacemakers were investigated. Correlation of sinus rhythm with pacing rates was assessed. ECG records were obtained from 24-hour Holter monitoring. Average rates of five consecutive P waves and pace waves were determined every half hour. The average of the two values was then used to determine hourly rates. Correlation coefficients between the sinus rhythm and pacing rates were calculated. In nine patients, pacing rates correlated well to sinus rhythm (range 0.6793-0.9558, P < 0.001 and P < 0.05), whereas in two cases correlation was not sufficient (P > 0.05). Most of the patients, in whom rate response factor (RRF) measurements during peak exercise by treadmill with chronotropic assessment exercise protocol were performed and pacemakers were programmed to these parameters, had more appropriate ventricular rates compared to spontaneous sinus rates. In these patients mean RRF value was 15.3 +/- 2.7 (range 12-20, median 15). This study shows that during daily activities minute ventilation rate adaptive pacemakers can achieve pacing rates well correlated to sinus rhythm that reflects the physiological heart rate in children.

Echocardiographic assessment of left and right ventricular diastolic functions in children with dilated cardiomyopathy.

We evaluated left and right ventricular diastolic functions by pulsed Doppler echocardiography in 16 children with dilated cardiomyopathy and in 20 healthy age-matched control subjects. The cardiomyopathy group demonstrated an abnormal relaxation pattern of the left ventricle. In the cardiomyopathy group compared to normal subjects, peak early filling velocities (43.3 +/- 11 cm/s versus 60.4 +/- 11 cms/s, p < 0.01), the corresponding velocity-time integrals (3.3 +/- 1.4 cm versus 4.6 +/- 1.2 cm, p < 0.01) and the ratio of peak early filling velocity to late filling velocity (1.22 +/- 0.47 versus 1.49 +/- 0.23, p < 0.05) were significantly lower whereas isovolumic relaxation time was significantly longer (58.9 +/- 19.8 ms versus 49.7 +/- 8.9 ms, p < 0.05). In addition, right ventricular diastolic filling was also impaired in children with dilated cardiomyopathy. Peak early filling velocities (41 +/- 7.9 cm/s versus 47.5 +/- 8.8 cm/s, p < 0.05) and the corresponding velocity time integrals (3.0 +/- 1.0 cm versus 3.87 +/- 1.1 cm, p < 0.05) were significantly decreased, while isovolumic relaxation time was significantly increased (60.6 +/- 16.3 ms versus 52.2 +/- 12.8 ms, p < 0.05) in the cardiomyopathy group. The study suggests that abnormalities of both right and left ventricular diastolic function may occur, and should be searched for, in pediatric patients with dilated cardiomyopathy.

Balloon dilation of stenotic nonvalved conduits after Fontan operation.

The Fontan operation is used to supply a ventriculo-arterial connection in patients with tricuspid atresia. An important complication is the obstruction of the conduit that may necessitate reoperation. In these patients balloon dilation of the conduit stenosis has been advocated as a method to relieve the obstruction and postpone surgical replacement. While there are several reports about the balloon dilation of stenotic valved conduits, we do not have enough information about the results of balloon dilation of nonvalved conduits. We performed successful balloon dilations in two patients with tricuspid atresia who underwent the Fontan operation and had stenotic nonvalved conduits. In the first patient, the stenosis was relieved but recurred. A second balloon dilation procedure was performed, and the patient has been symptom free for one year. In the second patient, the stenosis was relieved but recurred. Our preliminary results suggest that balloon dilation is an efficient method to relieve the obstruction in stenotic nonvalved conduits and can be repeated successfully if the stenosis recurs.

Bruce treadmill test in healthy Turkish children: endurance time, heart rate, blood pressure and electrocardiographic changes.

Heart rate, systolic and diastolic blood pressure and electrocardiographic changes were studied in 80 healthy children during treadmill exercise with Bruce protocol. Mean duration of exercise in boys increased from 10.01 +/- 1.61 minutes at age four to six years with a mean body surface area of 0.75 +/- 0.06 m2, to 17.86 +/- 2.66 minutes at age 13 to 15 years with a mean body surface area of 1.48 +/- 0.10 m2. Mean endurance time in girls increased from 11.06 +/- 1.92 minutes at age four to six years with a mean body surface area of 0.76 +/- 0.08 m2, to 15.69 +/- 2.23 minutes at age 13 to 15 years with a mean body surface area of 1.41 +/- 0.07 m2. Mean maximal heart rate was 193.38 +/- 10.89 beats/minute in boys and 196.78 +/- 10.99 beats/minute in girls. The maximum level of systolic blood pressure attained at peak exercise was lower in girls. Although data of healthy Turkish children including mean endurance time, heart rate and blood pressure responses to exercise were consistent with the results from several countries using the Bruce protocol, mean maximal heart rates for all groups were slightly higher than those obtained with the Balke protocol. The data obtained from this study offers age- and size-appropriate normal data in both sexes in healthy Turkish children and may be used as reference values during treadmill exercise.

Beneficial effects of 1-year captopril therapy in children with chronic aortic regurgitation who have no symptoms.

OBJECTIVE: This prospective study was performed to assess the effects of 1 year of angiotensin-converting enzyme inhibition with captopril in 20 children (mean age 14.3+/-2.3 years) with asymptomatic chronic aortic regurgitation. METHODS AND RESULTS: At 12 months patients receiving captopril had a significant reduction in left ventricular end-diastolic and end-systolic dimensions (57+/-9.3 vs 51+/-9.5 mm, p < 0.001; 35.4+/-6.1 vs 32+/-6.8 mm, p < 0.001), end-diastolic and end-systolic volume indexes (111+/-36 vs 94+/-29 ml/m2, p < 0.001; 35+/-13 vs 30+/-12 ml/m2, p < 0.001, respectively), and mass index (138+/-37 vs 109+/-32 gm/m2, p < 0.0001) determined by two-dimensional echocardiography. Meridian (p < 0.01) and circumferential (p < 0.0001) wall stresses also decreased significantly with therapy. Significant reduction (27.8%, p < 0.0001) was achieved in regurgitant fraction with captopril. CONCLUSIONS: These data show that the long-term therapy with angiotensin-converting enzyme inhibitors is able to reverse left ventricular dilation and hypertrophy and suggest that such therapy has the potential to favorably influence the natural history of the disease in children.

Role of adenosine in the diagnosis and treatment of tachyarrhythmias in pediatric patients.

Tachyarrhythmias are common rhythm disturbances in infants and children. Despite the availability of diagnostic criteria arrhythmias are sometimes commonly misdiagnosed. Recent reports suggest that an endogenous purine nucleoside, adenosine, has a diagnostic effect in narrow QRS complex tachycardias, in addition to terminating supraventricular tachycardia involving the atrioventricular node. This report reviews the authors' experience with the use of adenosine for diagnosis of narrow and wide complex tachyarrhythmias in children. Adenosine was administered to 43 patients with several types of tachyarrhythmias (mean age, 8.3 +/- 5.24 years). Nineteen patients had structural or acquired heart disease. Of the 43 patients there were 28 (65%) several different types of narrow QRS complex tachycardia and 14 (33%) ventricular arrhythmias. One patient (2%) had long QT. Adenosine terminated supraventricular tachycardia, in 11 of 12 patients (92%), ventricular tachycardia in five of eight patients (63%), and transiently terminated premature ventricular contractions in two of six patients (33%). The diagnostic ability of adenosine was perfect in eight supraventricular tachycardia. In these eight cases the tachycardia mechanism was unclear before the administration of adenosine, which demonstrated three cases of sinus tachycardia, three of atrial flutter, one of atrial fibrillation and one of atrial fibrilloflutter. Confirmation of the primary diagnosis by adenosine was perfect in five tachyarrhythmias including three cases of atrial flutter, one of atrial fibrillation and one of ectopic atrial tachycardia. The average effective dose of adenosine was 212 micrograms/kg (range, 100-400 micrograms/kg). There were no serious side-effects except transient dyspnea, chest pain and flushing. These findings demonstrate adenosine to be helpful and safe in the diagnosis of tachyarrhythmias.

The role of serotonin re-uptake inhibitors in preventing recurrent unexplained childhood syncope -- a preliminary report.

UNLABELLED: To assess the efficacy of a serotonin re-uptake inhibitor, sertraline hydrochloride, in preventing recurrent neurocardiogenic syncope, we studied 15 patients (10 female; mean age 12.9 +/- 2 years) with positive head-upright tilt test and resistant to standard pharmacotherapy, atenolol or disopyramide. The patients were given 50 mg oral sertraline hydrochloride daily for 6 weeks. Intolerance to the drug was seen in 3 patients and 2 had syncopal episodes during the therapy. A head-upright tilt table test was then repeated in 10 patients. Six were tilt negative and asymptomatic over a mean follow up period of 7 +/- 3 months while four remained tilt positive: two experienced marked hypotension and bradycardia, characterized as mixed type syncope, and two had cardiac asystole, lasting > 10 s, during tilting, thereby exhibiting a cardio-inhibitory response. CONCLUSION: Sertraline hydrochloride may be useful in preventing recurrent neurocardiogenic syncope resistant to standard pharmacotherapy but careful clinical studies are essential before such a treatment strategy can be recommended since serious asystole could develop.

Calpain-3 deficiency causes a mild muscular dystrophy in childhood.

Among our 20 families with LGMD2, 10 were documented to have muscle-specific calcium-activated neutral protease 3 (calpain-3) deficiency. Consanguinity was present in all. The current ages of the index cases were between 12 and 23 years, and there were additional nine members affected. Clinically, the patients showed mild courses; none of the cases below age 30 lost autonomy so far. The dystrophy is mainly proximal and atrophic with calf enlargement and scapular wasting in some. In three cases walking was delayed. Creatine kinase levels were at least 10 times elevated. All obligate carriers had normal creatine kinase levels. Five families shared the same 551 delA frameshift mutation. In four of these families there was the same core haplotype, whereas one was distinct suggesting an independent origin. Calpain-3 deficiency in general is a mild muscular dystrophy during childhood.

Long-term clinical experience with a steroid-eluting active fixation ventricular electrode in children.

In this study, the first study performed in pediatric patients, we assessed the safety and efficacy of a steroid-eluting active fixation ventricular electrode in 18 children. Our study shows that steroid-eluting active fixation leads are safe and effective in children, and suggests that these leads with their easy implantation and low chronic threshold values may be considered as the first choice in this age group.

Comparison of sensitivity and specificity of tilt protocols with and without isoproterenol in children with unexplained syncope.

Head-up tilt testing with or without isoproterenol is extensively used in the evaluation of patients with unexplained syncope. However, sensitivity and specificity of tilt protocols with and without isoproterenol have not been clarified in children, due to lack of age matched control subjects. This study was designed to assess and to compare the sensitivity and specificity of tilting alone and tilting in conjunction with isoproterenol. Thirty children with unexplained syncope (group I) and 15 age-matched control subjects (control group I) underwent successive 60 degrees head-up tilts for 10 minutes during infusions of 0.02, 0.04, and 0.06 microgram/kg/min of isoproterenol, after a baseline tilt to 60 degrees for 25 minutes. Also, 35 children (group II) with unexplained syncope and 15 healthy control subjects (control group II) were evaluated by head-up tilt to 60 degrees for 45 minutes without an infusion of isoproterenol. In response to tilt protocol with graded isoproterenol, 23 (76.6%) of the patients in group I and 2 of the 15 (13.3%) control subjects developed syncope. Accordingly, the sensitivity of tilt testing with isoproterenol was 76.6%, and its specificity was 86.7%. Tilt testing without isoproterenol was positive in 17 (48.5%) of the patients in group II but in only 1 of the 15 (6.6%) control subjects. Thus, sensitivity and specificity of tilt testing without isoproterenol were 48.5% and 93.4%, respectively. The mean heart rate and systolic blood pressure decreased significantly (P < 0.001) in all tilt positive patients during syncope. In conclusion, the head-up tilt test is a valuable diagnostic test in the evaluation of children with unexplained syncope, and isoproterenol is likely to increase the sensitivity of the test without decreasing its specificity.