Ronald V. Lacro

Pattern of Malformations in the Children of Women Treated with Carbamazepine during Pregnancy

In an attempt to determine whether and to what extent carbamazepine is teratogenic, we evaluated eight children whom we identified retrospectively as having had prenatal exposure to carbamazepine alone or in combination with a variety of anticonvulsants other than phenytoin. In addition, in a prospective study, we documented the outcome of the pregnancies of 72 women who contacted us early in pregnancy because they were concerned about the potential teratogenicity of carbamazepine. A pattern of malformation, the principal features of which are minor craniofacial defects and fingernail hypoplasia, and of developmental delay was identified in the eight children retrospectively ascertained to have been exposed to carbamazepine in utero; this pattern was subsequently confirmed through the evaluation of 48 children born alive to the women in the prospective study. That carbamazepine itself is teratogenic is indicated by the incidence of craniofacial defects (11 percent), fingernail hypoplasia (26 percent), and developmental delay (20 percent) in the 35 live-born children of the women in the prospective study who were exposed prenatally to carbamazepine alone. The similarity between the children exposed prenatally to carbamazepine and those with the fetal hydantoin syndrome is probably related to the fact that both drugs are metabolized through the arene oxide pathway and raises the possibility that it is the epoxide intermediate rather than the specific drug itself that is the teratogenic agent.

Pulmonary Artery Hypertension in Formerly Premature Infants With Bronchopulmonary Dysplasia : Clinical Features and Outcomes in the Surfactant Era

BACKGROUND. Although abnormal pulmonary vascular structure and function in preterm infants with bronchopulmonary dysplasia may predispose infants to pulmonary artery hypertension, little is known about the characteristics and outcomes of bronchopulmonary dysplasia-associated pulmonary artery hypertension in the surfactant era. METHODS. We studied 42 premature infants (<32 weeks of gestation) with bronchopulmonary dysplasia who were diagnosed as having pulmonary artery hypertension ≥2 months after birth, between 1998 and 2006, at a median age of 4.8 months. Pulmonary artery hypertension was graded through echocardiography for all patients; 13 patients also underwent cardiac catheterization. RESULTS. Eighteen (43%) of 42 patients had severe pulmonary artery hypertension (systemic or suprasystemic right ventricular pressure). Among 13 patients who underwent catheterization, the mean pulmonary artery pressure was 43 ± 8 mmHg and the pulmonary vascular resistance index was 9.9 ± 2.8 Wood units. In 12 patients, pulmonary artery pressure and pulmonary vascular resistance improved with 100% oxygen and 80 ppm inhaled nitric oxide but remained elevated. The pulmonary vascular resistance index decreased to 7.9 ± 3.8 Wood units in 100% oxygen and to 6.4 ± 3.1 Wood units with the addition of nitric oxide. Sixteen patients (38%) died during the follow-up period. Estimated survival rates were 64% ± 8% at 6 months and 53% ± 11% at 2 years after diagnosis of pulmonary artery hypertension. In multivariate analyses, severe pulmonary artery hypertension and small birth weight for gestational age were associated with worse survival rates. Among 26 survivors (median follow-up period: 9.8 months), pulmonary artery hypertension was improved, relative to its most severe level, in 24 patients (89%). CONCLUSION. Premature infants with bronchopulmonary dysplasia and severe pulmonary artery hypertension are at high risk of death, particularly during the first 6 months after diagnosis of pulmonary artery hypertension.

Atenolol versus Losartan in Children and Young Adults With Marfan's Syndrome

BACKGROUND Aortic-root dissection is the leading cause of death in Marfans syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfans syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (±SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS Among children and young adults with Marfans syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).

Expression of dihydropyridine receptor (Ca2+ channel) and calsequestrin genes in the myocardium of patients with end-stage heart failure.

Cytoplasmic free calcium ions (Ca2+) play a central role in excitation-contraction coupling of cardiac muscle. Abnormal Ca2+ handling has been implicated in systolic and diastolic dysfunction in patients with end-stage heart failure. The current study tests the hypothesis that expression of genes encoding proteins regulating myocardial Ca2+ homeostasis is altered in human heart failure. We analyzed RNA isolated from the left ventricular (LV) myocardium of 30 cardiac transplant recipients with end-stage heart failure (HF) and five organ donors (normal control), using cDNA probes specific for the cardiac dihydropyridine (DHP) receptor (the alpha 1 subunit of the DHP-sensitive Ca2+ channel) and cardiac calsequestrin of sarcoplasmic reticulum (SR). In addition, abundance of DHP binding sites was assessed by ligand binding techniques (n = 6 each for the patients and normal controls). There was no difference in the level of cardiac calsequestrin mRNA between the HF patients and normal controls. In contrast, the level of mRNA encoding the DHP receptor was decreased by 47% (P less than 0.001) in the LV myocardium from the patients with HF compared to the normal controls. The number of DHP binding sites was decreased by 35-48%. As reported previously, expression of the SR Ca(2+)-ATPase mRNA was also diminished by 50% (P less than 0.001) in the HF group. These data suggest that expression of the genes encoding the cardiac DHP receptor and SR Ca(2+)-ATPase is reduced in the LV myocardium from patients with HF. Altered expression of these genes may be related to abnormal Ca2+ handling in the failing myocardium, contributing to LV systolic and diastolic dysfunction in patients with end-stage heart failure.

Clinical Approach to Genetic Cardiomyopathy in Children

BACKGROUND Cardiomyopathy (CM) remains one of the leading cardiac causes of death in children, although in the majority of cases, the cause is unknown. To have an impact on morbidity and mortality, attention must shift to etiology-specific treatments. The diagnostic evaluation of children with CM of genetic origin is complicated by the large number of rare genetic causes, the broad range of clinical presentations, and the array of specialized diagnostic tests and biochemical assays. METHODS AND RESULTS We present a multidisciplinary diagnostic approach to pediatric CM of genetic etiology. We specify criteria for abnormal left ventricular systolic performance and structure that suggest CM based on established normal echocardiographic measurements and list other indications to consider an evaluation for CM. We provide a differential diagnosis of genetic conditions associated with CM, classified as inborn errors of metabolism, malformation syndromes, neuromuscular diseases, and familial isolated CM disorders. A diagnostic strategy is offered that is based on the clinical presentation: biochemical abnormalities, encephalopathy, dysmorphic features or multiple malformations, neuromuscular disease, apparently isolated CM, and pathological specimen findings. Adjunctive treatment measures are recommended for severely ill patients in whom a metabolic cause of CM is suspected. A protocol is provided for the evaluation of moribund patients. CONCLUSIONS In summary, we hope to assist pediatric cardiologists and other subspecialists in the evaluation of children with CM for a possible genetic cause using a presentation-based approach. This should increase the percentage of children with CM for whom a diagnosis can be established, with important implications for treatment, prognosis, and genetic counseling.

Sudden death in Williams syndrome: Report of ten cases☆☆☆★

Williams syndrome (WS) is a recognizable pattern of malformation with mental retardation, mild growth deficiency, characteristic facies and temperament, and cardiovascular disease. Sudden death is a recognized complication of WS; however, it is thought to be rare. The clinical features of 10 children with WS who died suddenly are reported here, doubling the number of unexpected deaths reported in the literature. We suggest that sudden death is a more common complication than has been assumed previously. Pathologic findings on the seven autopsy cases implicate two anatomic abnormalities that predispose individuals with WS to sudden death: coronary artery stenosis and severe biventricular outflow tract obstruction. The mechanisms for sudden death for both anatomic subgroups include myocardial ischemia, decreased cardiac output, and arrhythmia. We believe these observations warrant the development of strategies for monitoring patients with WS in an attempt to identify those at increased risk of sudden death.

The umbilical cord twist: Origin direction, and relevance

The purpose of this study was to evaluate the origin, direction, and relevance of the umbilical cord twist. We initially hypothesized that the direction of the helix or twist of the human umbilical cord at birth correlated with the eventual handedness of the child. Among 2801 singleton placentas in this study, only 5% had no twist, and the left twist outnumbered the right twist by 7 to 1, a ratio that is strikingly similar to the predominance of right-handed persons to non-right-handed persons in the general population. Forty-five 3- and 4-year-old children with previously documented cord twists were evaluated with respect to hand preference and performance. The direction of the cord twist was independent of the handedness of the child as well as the mother. We have documented an increased incidence of absent twist and right twist in association with single umbilical artery, suggesting that the impetus for the cord twist is independent on hemodynamic forces in the umbilical cord itself. We further document an increased incidence of absent twist among intrauterine fetal deaths and twins, suggesting that decreased fetal movement can impede the forces leading to normal twisting of the umbilical cord. Absence of cord twist may be associated with adverse prognosis.

Increased Vertebral Artery Tortuosity Index Is Associated With Adverse Outcomes in Children and Young Adults With Connective Tissue Disorders

Background— Arterial tortuosity is described as a common and distinctive feature of Loeys-Dietz syndrome (LDS), yet reports on arterial tortuosity are based on qualitative observations and none have investigated an association between tortuosity and cardiovascular outcomes in LDS or other connective tissue disorders. Methods and Results— We performed a retrospective analysis of 90 patients ⩽50 years of age with Marfan syndrome, LDS, Ehlers-Danlos syndrome, or nonspecific connective tissue disorder who underwent thoracic contrast-enhanced magnetic resonance angiography. Controls (n=30) underwent magnetic resonance imaging to exclude arrhythmogenic right ventricular dysplasia. Using a volume-rendered angiogram, vertebral arteries were measured along the curvature of the vessel (actual length) and linearly (straight length), and distance factor was calculated: [(actual/straight length−1)×100]. Each subjects maximum distance factor was designated the Vertebral Tortuosity Index (VTI). The VTI was compared among diagnostic groups and among patients with cardiac surgery, dissection, and death. Median age at magnetic resonance imaging was 19.6 years (range 0.2 to 50.1). VTI interrater reliability was excellent (intraclass correlation coefficient =0.987). The VTI was higher in Marfan syndrome (n=57, median 26; interquartile range 10 to 49) and LDS (n=13, median 58; interquartile range 18 to 92) compared with controls (median 4.5; interquartile range 3 to 6; P<0.001 for both). Higher VTI was associated with younger age at surgery even when controlling for root size (adjusted P=0.002). Vertebral tortuosity index ≥50 was associated with earlier age at dissection and death compared with VTI <50 (P=0.001 versus P<0.001). We found no difference in age at surgery, dissection, or death in Marfan syndrome compared with LDS. Conclusion— Arterial tortuosity measured by magnetic resonance angiography is a reproducible marker of adverse cardiovascular outcomes in connective tissue disorders.

Cardiovascular malformations: changes in prevalence and birth status, 1972-1990.

Through an ongoing hospital-based active malformation surveillance program, we identified cardiovascular malformations (CVMs) in 3.3 per 1,000 liveborn and stillborn infants, and fetuses from pregnancies terminated electively during a 15-year period. We excluded the children of mothers who had planned delivery elsewhere, but were transferred for care of anomalies that had been detected in prenatal screening. Birth status changed markedly during the study with a significant increase in elective terminations of fetuses with a CVM from 0 to 22% (P < 0.01 based on a test for trend). The proportion of liveborn infants with CVMs decreased from 90% to 73% (P < 0.01); the frequency of stillbirths did not change. During the study period, there was a significant increase in the prevalence of CVMs in all births (P < 0.01) and elective terminations (P < 0.01). The increase in liveborn prevalence was not statistically significant (P = 0.08). Stillborn prevalence was unchanged. The number of mothers having prenatal ultrasonography (P < 0.01 for trend) and amniocentesis (P < 0.01 for trend) increased steadily. There were significant increases in the proportion of mothers having any ultrasound examination (P < 0.01 for trend), the number of initial ultrasound examinations occurring in the second trimester (P < 0.01 for trend), and the proportion of mothers having amniocentesis (P < 0.01 for trend). There was a significant increasing trend in the proportion of mothers who were 35 years and older (10% in 1972-1974, 26% in 1988-1990, P < 0.01). This hospital-based active surveillance program suggests that more frequent elective terminations had a significant effect on overall birth prevalence of CVMs. This trend would not have been detected by most other surveillance systems which determine prevalence of common birth defects from birth certificates and other forms of administrative reporting, and exclude elective terminations of pregnancy.

Performant Mutation Identification Using Targeted Next‐Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes

At least 14 causative genes have been identified for both syndromic and nonsyndromic forms of thoracic aortic aneurysm/dissection (TAA), an important cause of death in the industrialized world. Molecular confirmation of the diagnosis is increasingly important for gene‐tailored patient management but consecutive, conventional molecular TAA gene screening is expensive and labor‐intensive. To circumvent these problems, we developed a TAA gene panel for next‐generation sequencing of 14 TAA genes. After validation, we applied the assay to 100 Marfan patients. We identified 90 FBN1 mutations, 44 of which were novel. In addition, Multiplex ligation‐dependent probe amplification identified large deletions in six of the remaining samples, whereas false‐negative results were excluded by Sanger sequencing of FBN1, TGFBR1, and TGFBR2 in the last four samples. Subsequently, we screened 55 syndromic and nonsyndromic TAA patients. We identified causal mutations in 15 patients (27%), one in each of the six following genes: ACTA2, COL3A1, TGFBR1, MYLK, SMAD3, SLC2A10 (homozygous), two in NOTCH1, and seven in FBN1. We conclude that our approach for TAA genetic testing overcomes the intrinsic hurdles of consecutive Sanger sequencing of all candidate genes and provides a powerful tool for the elaboration of clinical phenotypes assigned to different genes.