A Scandinavian case of skin fragility, alopecia and cardiomyopathy caused by DSP mutations.

Congenital skin fragility is a heterogeneous disorder with epidermolysis bullosa and various skin infections as the leading causes. However, even rare diseases must be considered in the differential diagnosis of neonatal skin blistering, including some genetic syndromes with extracutaneous involvement. One such syndrome is ectodermal dysplasia due to deficiency of desmoplakin, a desmosomal protein essential for cellular cohesion in both epithelia and cardiac tissues. Desmoplakin is encoded by the DSP gene, which is localized on chromosome 6p24. Both dominant and recessive mutations in this gene have been reported to cause skin fragility and keratinization defects. We report a child born with a fragile epidermis, alopecia, thick nails, and focal hyperkeratoses on the digits and knees. She was found to have a deficiency of desmoplakin caused by compound heterozygous DSP mutations. She has gradually developed signs of a left ventricular cardiomyopathy.

Noninvasive peripheral perfusion index as a possible tool for screening for critical left heart obstruction.

AIM: Peripheral perfusion index (PPI) has been suggested as a possible method to detect illness causing circulatory embarrassment. We aimed to establish the normal range of this index in healthy newborns, and compare it with newborns with duct-dependent systemic circulation. DESIGN: We conducted a case-control study. SETTING: Our study population comprised 10,000 prospectively recruited newborns from Västra Götaland, Sweden. PATIENTS: A total of 10,000 normal newborns and 9 infants with duct-dependent systemic circulation (left heart obstructive disease [LHOD] group) participated in the study. METHODS: We conducted single pre- and postductal measurements of PPI with a new generation pulse oximeter (Masimo Radical SET) before discharge from hospital. RESULTS: PPI values between 1 and 120 h of age show an asymmetrical, non-normal distribution with median PPI value of 1.70 and interquartile range of 1.18-2.50. The 5th percentile = 0.70 and 95th percentile = 4.50. All infants in the LHOD group had either pre- or postductal PPI below the interquartile range, and 5 of 9 (56%) were below the 5th percentile cut-off of 0.70 (p < 0.0001, Fisher's exact test). A PPI value <0.70 gave an odds ratio for LHOD of 23.75 (95% CI 6.36-88.74). CONCLUSION: PPI values lower than 0.70 may indicate illness and a value <0.50 (1st percentile) indicates definite underperfusion. PPI values might be a useful additional tool for early detection of LHOD.

A cohort study of neurodevelopmental outcome in children with DiGeorge syndrome following cardiac surgery.

AIMS: To examine whether the learning difficulties seen in a proportion of children with DGS are secondary to cardiac pathology and treatment, or a feature of the DGS phenotype. METHODS: Cohort study of all patients with DGS and coexisting cardiac lesions within a region. Ten children with 22q11 deletion were assigned two controls each, matched for age, sex, cardiac lesion, and preoperative hemodynamic status but without DGS. The neurodevelopmental status was evaluated with the Ruth Griffiths test for babies and young children. RESULTS: Children with the 22q11 deletion showed a wide range of developmental quotient (DQ; mean 71, 95% CI 47 to 95) and subscale scores, but these as a group were significantly lower than those of the control group (DQ 113, 95% CI 108 to 118). Four of the DGS children had DQs below 60. Hypocalcaemia, prolonged postoperative ventilation, and abnormal neurology perioperatively were associated with a low DQ. CONCLUSIONS: A proportion of children with DGS have a very poor developmental outcome following cardiac surgery. This outcome is not attributable to the cardiac condition and its treatment alone, but represents either a pre-existing component of the syndrome or an interaction between the syndrome and its treatment.

Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis.

Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known contractile protein disease genes are not found in up to one-third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in PRKAG2, encoding the gamma(2) subunit of AMP-activated protein kinase (AMPK), in two families with severe HCM and aberrant conduction from atria to ventricles in some affected individuals (pre-excitation or Wolff-Parkinson-White syndrome). The mutations, one missense and one in-frame single codon insertion, occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, we propose that these data substantiate energy compromise as a unifying pathogenic mechanism in all forms of HCM. This conclusion should radically redirect thinking about this disorder and also, by establishing energy depletion as a cause of myocardial dysfunction, should be relevant to the acquired forms of heart muscle disease that HCM models.

A simple method for assessing the regression or progression of ventricular hypertrophy in the growing child and adult: the value of left ventricular wall-to-cavity ratios.

AIMS: To establish the normal range of diastolic and systolic left ventricular wall-to-cavity ratios. METHODS AND RESULTS: Two hundred and sixty-two normal subjects (age 0-40 years), 15 children with valvar aortic stenosis and 11 childhood athletes were studied with M-mode echocardiography. Values of diastolic septum-to-cavity ratio and diastolic left ventricular wall-to-cavity ratio were not influenced by sex nor, in adults, by height, weight or body surface area. There were slight age variations from 0-15 years of age, but not in adults from 15-40 years of age. Values of diastolic left ventricular wall-to-cavity ratio in neonates were 0.18 (95% confidence limits 0.17-0.19); in 3-5 year olds 0.16 (0.15-0.16); and in adults 0.18 (0.17-0.19). In valvar aortic stenosis there is a positive correlation between the Doppler-estimated pressure gradient and the degree of left ventricular hypertrophy, as expressed by both diastolic and systolic left ventricular wall-to-cavity ratio (r = 0.90;P < 0.00001 and r = 0.85;P = 0.00006 respectively). CONCLUSIONS: Diastolic septum and left ventricular wall-to-cavity ratios accurately differentiate physiological from pathological left ventricular hypertrophy in the growing child. Because these ratios are independent of sex and body size, they may also be more sensitive than absolute wall thickness in the detection of abnormal left ventricular hypertrophy in adults.

Recommendations of the British Paediatric Cardiac Association for therapeutic cardiac catheterisation in congenital cardiac disease.

The aims of these recommendations are to improve the outcome for patients after, and to provide acceptable standards of practice of therapeutic cardiac catheterisation performed to treat congenital cardiac disease. The scope of the recommendations includes all interventional procedures, recognising that for some congenital malformations, surgical treatment is equally as effective as, or occasionally preferable to, interventional treatment. The limitations of the recommendations are that, at present, no data are available which compare the results of interventional treatment with surgery, and certainly none which evaluate the numbers and types of procedures that need to be performed for the maintenance of skills. Thus, there is a recognised need to collect comprehensive data with which these recommendations could be reviewed in the future, and re-written as evidence-based guidelines. Such a review will have to take into account the methods of collection of data, their effectiveness, and the latest developments in technology. The present recommendations should, therefore, be considered as consensus statements, and as describing accepted practice, which could be used as a basis for ensuring and improving the quality of future care.

Diagnosis of hypertrophic cardiomyopathy and screening for the phenotype suggestive of gene carriage in familial disease: a simple echocardiographic procedure.

OBJECTIVES: To design a new echocardiographic method of screening for hypertrophic cardiomyopathy applicable to children and adults, with a low false positive rate in athletes. SETTING: Regional centre of cardiology, Oxford, UK. METHODS: Forty one patients with hypertrophic cardiomyopathy, 66 first degree relatives from families with familial hypertrophic cardiomyopathy, 262 normal subjects, and 32 athletes were studied by long axis M mode and cross sectional echocardiography to determine the frequency distribution of diastolic and systolic ratios of cardiac wall thickness to cavity diameter. RESULTS: The best screening measure for hypertrophic cardiomyopathy is diastolic septum to cavity ratio, where a value of > 0.26 yielded a 100% disease detection rate at all ages with 0% false positives in the ordinary population. In comparison, the conventional screening tool of diastolic septum to posterior left ventricular wall ratio of > 1.5 yielded a detection rate of only 75%, for a false positive rate of 2%. In first degree relatives, a septum to cavity ratio > 0.26 yielded a 100% detection rate for an abnormal phenotype suggestive of carriage of a mutation for hypertrophic cardiomyopathy with no obvious false positives. Conventional screening showed a detection rate of only 44%. Athletes with physiological cardiac hypertrophy showed only a 6% false positive rate with diastolic septum to cavity ratio, and could be differentiated from subjects with hypertrophic cardiomyopathy by the absence of hypercontractility shown by a normal systolic left ventricular wall to cavity ratio (cut off < 0.63; 0% false positives). CONCLUSIONS: M mode echocardiographic measurement of the septum to cavity ratio provides a good screening test for hypertrophic cardiomyopathy at all ages. Combining this measurement with systolic left ventricular wall to cavity ratio improves the accuracy further.

A cohort study of childhood hypertrophic cardiomyopathy: improved survival following high-dose beta-adrenoceptor antagonist treatment.

OBJECTIVES: The study analyzed factors, including treatment, affecting disease-related death in patients with hypertrophic cardiomyopathy (HCM) presenting in childhood. BACKGROUND: Previous smaller studies suggest that mortality is higher in patients with HCM presenting in childhood compared with presentation in adulthood, but these studies have all originated from selected patient populations in tertiary referral centers, and reported no significant protection by treatment. METHODS: Retrospective comparisons of mortality were done in total cohort of patients presenting to three regional centers of pediatric cardiology. There were 66 patients (25 with Noonan's syndrome) with HCM presenting at age <19 years; mean follow-up was 12.0 years. RESULTS: Among risk factors for death were congestive heart failure (p = 0.008), large electrocardiogram voltages (Sokolow-Lyon index p = 0.0003), and degree of septal (p = 0.004) and left ventricular (p = 0.028) hypertrophy expressed as percent of 95th centile value. The only treatment that significantly reduced the risk of death on multifactorial analysis of variance was high-dose beta-adrenoceptor antagonist therapy (propranolol 5 to 23 mg/kg/day or equivalent; p = 0.0001). Nineteen out of 40 patients managed conventionally (no treatment, 0.8 to 4 mg/kg of propranolol, or verapamil) died, median survival 15.8 years, with no deaths among 26 patients on high-dose beta-blockers (p = 0.0004); survival proportions at 10 years were 0.65 (95% confidence interval 0.49-0.80) and 1.0, respectively (p = 0.0015). Survival time analysis shows better survival in the high-dose beta-blocker group compared with the "no specific therapy" group (p = 0.0009) and with the conventional-dose beta-blocker group (p = 0.002). Hazard ratio analysis suggests that high-dose beta-blocker therapy produces a 5-10-fold reduction in the risk of disease-related death. CONCLUSIONS: High-dose beta-blocker therapy improves survival in childhood HCM.

A comparison of MRI and echocardiography in hypertrophic cardiomyopathy.

This study compares MRI and echocardiography as imaging modalities in hypertrophic cardiomyopathy, with particular reference to measurement of left ventricular wall thickness and mass. 10 subjects underwent echocardiography and MRI. Contiguous 10 mm short axis 35 degrees flip angle cine gradient recalled echo MR images were acquired from the apex to the base of the left ventricle at 1.5 tesla. Standard M-mode and cross-sectional echocardiographic views of the left ventricle were obtained. Excellent agreement between measurements occurred with MRI and M-mode echocardiographic assessment of the thickness of the anterior interventricular septum (95% limits of agreement -1.5 to +1.5 mm). Other comparisons of MRI vs M-mode echocardiographic measurements had the following limits of agreement: posterior free wall -3.3 to +2.9 mm; end-diastolic dimension -5 to +8 mm, left ventricular mass -291 to +55.5 g. Comparing MRI with cross-sectional echocardiographic measurements, the limits of agreement were: anterior interventricular septum -2.4 to +1.7 mm, posterior interventricular septum -2.4 to +2.9 mm, posterior free wall -3.4 to +2.5 mm, anterior free wall -2.4 to +1.7 mm, end-diastolic dimension -4.1 to +8 mm. MRI estimates of LVM in systole vs diastole showed good agreement with 95% limits of agreement of -20 to +17 g, with excellent interobserver variability in diastole (-9 to +5 g) and in systole (-7 to +12 g). In conclusion, MRI is superior to echocardiography for the quantification of ventricular mass in the abnormal left ventricle because it does not make invalid geometrical assumptions. Comparisons of wall thickness show greater discrepancy with increasing distance from the echocardiographic transducer. This study suggests that sequential echocardiography could rationalize the need for MRI in left ventricular hypertrophy. A change in anterior septal thickness of > or = 3 mm on echocardiography merits a further MRI study.

Middle aortic syndrome in a boy with arteriohepatic dysplasia (Alagille syndrome).

Middle aortic syndrome is increasingly recognized as a cause of hypertension in adolescents and young adults. Alagille syndrome is a genetic disorder characterized by hepatic, eye, and bony abnormalities. Cardiovascular lesions occur in most of the patients, but narrowing of the abdominal aorta has not been previously recorded. We present an unusual association between middle aortic syndrome and Alagille syndrome, with a similar vascular lesion seen in two generations.

Infant Ross procedure for recurrent aortic stenosis.

A male infant underwent an open aortic valvotomy during the second day of life. Aortic stenosis recurred and at the age of eight weeks he underwent a pulmonary autograft aortic root replacement (Ross procedure). The pulmonary autograft procedure is a valuable option in this circumstance.

Effects of oxygen and nitric oxide in oxygen on pulmonary arterial pressures of children with congenital cardiac defects.

Inhaled nitric oxide is a specific pulmonary vasodilator. This study was undertaken to assess the effect on pulmonary arterial pressure of administering 100% oxygen compared with nitric oxide in oxygen. Thirteen mechanically ventilated children undergoing routine cardiac catheterization for the investigation of congenital heart disease were studied. Pulmonary arterial pressures were measured during inhalation of 30% oxygen (baseline), 100% oxygen, and nitric oxide (40 parts per million) in oxygen. In addition, in six children the pulmonary/systemic blood flow ratio and pulmonary vascular resistance were calculated using oxygen content, an assumed value for oxygen uptake, and the Fick principle. Results were compared using analysis of variance and the Wilcoxon signed-rank test. Pulmonary arterial pressure decreased from a mean value of 29.5 mmHg (SD 15.1) to 25.6 mmHg (SD 9.3), p = 0.048, after increasing the inspired oxygen fraction from 0.3 to 1.0. The addition of nitric oxide caused a further reduction to 22.9 mmHg (SD 7.9), p = 0.0001. There was no change in systemic arterial pressure or heart rate during the study period, but a small increase occurred in the mean methemoglobin level (1.1% to 1.3%) p = 0.039. Changes in the pulmonary/systemic blood flow ratio and pulmonary vascular resistance (n = 6) were not significant. Nitric oxide in oxygen appears to be a more potent pulmonary vasodilator than oxygen alone in pediatric patients with congenital cardiac defects.

Reduction by beta-adrenoceptor blockade of hypoxia-induced right heart hypertrophy in the rat.

1. The study was undertaken to assess the role of beta-adrenoceptors in the induction of compensatory cardiac hypertrophy in an in vivo model. 2. In the rat, exposure to severe hypoxia (6% inspired oxygen for 8 h day) caused a 51% increase in right heart weight and a 75% increase in haematocrit. 3. The hypoxia-induced right ventricular hypertrophic response was reduced by 65% by oral treatment with a high dose of the non-selective beta-adrenoceptor antagonist, propranolol (80 mg kg-1 body weight); the drug treatment caused only a minor reduction (6%) in secondary polycythaemia. 4. With a less severe degree of hypoxia (7% inspired oxygen) there was only minimal secondary polycythaemia (+15%), and a lesser degree of compensatory right ventricular hypertrophy in untreated rats (+33%). 5. Treatment with the beta 1-adrenoceptor antagonist, atenolol, in a dose of 80 mg kg-1 body weight abolished right ventricular hypertrophy in response to 7% inspired oxygen, without affecting haematocrit and caused a small reduction in the ratio of heart weight to body weight in normoxic rats. 6. The results show that the effect of propranolol on hypoxic right ventricular hypertrophy is not secondary to any effect on secondary polycythaemia as has previously been suggested and that a marked reduction of compensatory cardiac hypertrophy can be obtained by a beta 1-selective adrenoceptor antagonist. Thus these findings support the view that noradrenaline released from cardiac sympathetic nerve terminals exerts a trophic effect on myocardial cells and demonstrates that in vivo, this trophic effect can be reduced by beta 1-adrenoceptor blockade.

Reduction by oral propranolol treatment of left ventricular hypertrophy secondary to pressure-overload in the rat.

1. Studies on cardiac myocyte cell cultures have postulated a role for alpha 1-adrenoceptors and mechanical stretch in the induction of cellular changes thought to be important in compensatory cardiac hypertrophy. However, in vivo work suggests that beta-adrenoceptors are important and the present study was designed to analyse the effect of propranolol on the cardiac hypertrophy caused by a pressure-overload in a way that takes account of the effects of propranolol on the work load itself. 2. The compensatory cardiac hypertrophy that develops in response to experimental coarctation of the aorta was studied in the rat. Pressure gradients and total cardiac work load (expressed as rate x pressure product) were assessed, and the relationship between increasing cardiac work load and the resulting left ventricular hypertrophy was established in a control group and compared with left ventricular hypertrophy in a group treated with a high dose of oral propranolol (80 mg kg-1 body weight). 3. In the rats with mean pressure gradients over the coarctation in the range of 15-31 mmHg, the animals on control diet showed a 38% increase in left ventricular weight/body weight ratio (LV ratio) and a 30% increase in heart weight/body weight ratio (heart ratio), whereas rats given high dose oral propranolol-treatment showed increases of only 13% and 9%, respectively. 4. In a second series of rats with a wider range of pressure gradients, the regression lines of LV ratio versus mean pressure gradient, and of LV ratio versus cardiac work, were different in the two groups with a slope that was only half as steep in the propranolol-treated rats as in the controls. Thus, for the same increment in cardiac work load, the degree of compensatory cardiac hypertrophy in propranolol-treated rats was half that observed in controls. 5. The reduction in compensatory cardiac hypertrophy was not associated with an increase in incidence of congestive heart failure and the propranolol-treated rats were able to sustain equally high (or higher) degrees of pressure over-load as controls did. 6. It is concluded that propranolol treatment approximately halves the compensatory cardiac hypertrophy occurring in response to a left ventricular pressure over-load by a mechanism independent of its effect on cardiac work load. This finding provides further support for the view that noradrenaline released from sympathetic nerve terminals in the heart exerts a trophic effect on cardiac myocytes, and that the sympathetic nervous system may be the final common pathway in many forms of compensatory cardiac hypertrophy. In contrast to in vitro models, this effect appears to be largely mediated via beta-adrenoceptors in the intact animal.

The post-angiocardiography urogram in children: should it be abandoned?

This study examines the value of the urogram radiograph taken after angiocardiography, in children with suspected congenital heart disease, to screen for co-existent urinary tract abnormalities. A retrospective audit of post-angiocardiography urograms over a three year period 1990 to 1993 is presented. 184 urograms obtained in 166 children were reviewed (86 males; mean age 18.1 months). Twenty-five urograms (13.6%) were obtained in cases where the urinary tract had previously been investigated. These urograms contributed no additional information. Image quality was suboptimal in 62 examinations (33.7%), due to gas, faeces or poor opacification, and two lesions were undetected on suboptimal radiographs. Urinary tract abnormalities were detected in 17 patients (10.2%). These lesions were also detectable at sonography. We suggest that routine post-angiocardiography urograms can be abandoned in favour of sonographic screening of the urinary tract in children with congenital heart disease.