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Background Prader-Willi syndrome (PWS), is a genetically determined neurodevelopmental disorder, associated with intellectual disabilities and a high incidence of obesity, diabetes mellitus, and respiratory disorders. We hypothesised that COVID-19, a viral infection which more severely affects people with these conditions, would, in people with PWS, present atypically and result in severe outcomes. Method A structured on-line questionnaire was piloted with parents and professionals at the International Prader-Willi Syndrome Organization (IPWSO) and promoted internationally through their global network. Family members/other carers were asked to complete if someone they cared for with PWS was strongly suspected or confirmed as having COVID-19. Results Over 1 year of the pandemic 72 responses were received, 47 adults, 25 children. The following underlying conditions were present: 16 people with PWS were overweight and 18 obese, five had diabetes mellitus and 18 sleep apnoea. Main presenting symptoms were raised temperature, fatigue/daytime sleepiness, dry cough, headache/pain, and feeling unwell, with illnesses generally lasting less than a week. Length of illness was not significantly related to age, BMI, sex, or genetic subtype. No one was ventilated or in an intensive care unit or died, one person was in hospital for four days needing oxygen. Conclusions Contrary to our hypothesis, the PWS cohort had asymptomatic infection or mild illness. A possible explanation, supported by anecdotal evidence from parents and professional carers, is that people with PWS have a degree of innate immunity to viral infections. However, likely selection effects and a relatively low number of responses means that further evidence is needed to test this hypothesis.

Klippel–Trenaunay syndrome (KTS) is a rare, sporadic, complex malformation characterized by the clinical triad of (1) capillary malformations (port wine stain); (2) soft tissue and bone hypertrophy or, occasionally, hypotrophy of usually one lower limb; and (3) atypical, mostly lateral varicosity. KTS is a mixed vascular malformation, with predominant capillary, venous and lymphatic components, without significant arteriovenous shunting. Management is largely conservative and the extent of diagnostic evaluation is determined by the planned treatment. Compression is the hallmark of conservative management; laser can be used to treat port wine stains. Imaging before vascular interventions must confirm venous anatomy and deep venous drainage. Techniques for ablation of superficial veins and malformations are individualized and may include sclerotherapy with alcohol or foam, endovenous thermal ablation or, as used most frequently in our practice, surgical stripping and phlebectomy. Intraoperative use of tourniquet will decrease bleeding, selective use of an inferior vena cava filter will prevent pulmonary embolism. A multidisciplinary approach to management of KTS is warranted.

A laboratory study was conducted to evaluate the potential for secondary organic aerosol formation from emissions from automotive exhaust. The goal was to determine to what extent photochemical oxidation products of these hydrocarbons contribute to secondary organic aerosol (SOA) and how well their formation is described by recently developed models for SOA formation. The quality of a surrogate was tested by comparing its reactivity with that from irradiations of authentic automobile exhaust. Experiments for secondary particle formation using the surrogate were conducted in a fixed volume reactor operated in a dynamic mode. The mass concentration of the aerosol was determined from measurements of organic carbon collected on quartz filters and was corrected for the presence of hydrogen, nitrogen, and oxygen atoms in the organic species. A functional group analysis of the aerosol made by Fourier transform infrared (FTIR) spectroscopy indicated

A laboratory study was carried out to investigate the formation of polyketones in secondary organic aerosol from photooxidation of the aromatic hydrocarbon toluene, a major constituent of automobile exhaust. The laboratory experiments consisted of irradiating toluene/propylene/NO x /air mixtures in a smog chamber operated in the dynamic mode and collecting submicron secondary organic aerosol samples on Zefluor filters and on stainless steel disks in a low pressure cascade impactor. Carbonyl oxidation products in methanol extracts of the filters were derivatized using O-(2,3,4,5,6,-pentafluorobenzyl)-hydroxylamine, and the oxime derivatives were detected with a positive chemical ionization gas chromatography ion trap mass spectroscopy (GC-ITMS) system. Infrared spectra of the cascade impactor samples were used to determine the chemical functional group concentrations of the aerosol. The results of the GC-ITMS and infrared spectral analyses were consistent with the formation of multifunctional oxygenates, i...

Laboratory experiments were conducted to investigate the deposition to aqueous media of the gas phase oxidation products of the following hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs): HCFC-22 (CClF2H), HFC-41 (CH3F), HCFC-123 (CCl2HCF3), HCFC-124 (CClFHCF3), HFC-125 (CF3CF2H), HFC-134a (CF3CFH2), HCFC-141b (CCl2FCH3), HCFC-142b (CClF2CH3), and HFC-152a (CF2HCH3). Single component experiments were conducted were the oxidation products CF3CFO, COF2, CF3C(O)Cl were exposed under laminar flow conditions to alkaline, acidic, and neutral solutions in a aluminum exposure trough. The anionic composition of the exposure solutions were used to determine the effective deposition velocity. Exposures to neutral solutions were also conducted for irradiated HFC and HCFC/Cl2/air mixtures. The combined single component and irradiated mixture experiments were used to measure the effective deposition velocities of C(O)F2, C(O)FCl, HFC(O), CF(O)OOCF(O), CF3CCl(O), CF3CF(O). The deposition velocities differed by as much as a factor of two with the largest velocities found for C(O)F2 and CF3CF(O). The data were insufficient to determine the extent to which gas and liquid phase resistance controlled the overall deposition. However, the data were used to estimate lower limits for the laboratory aqueous resistance and the results were found to be consistent with the recent conclusions of Wine and Chameides who reported the deposition of the oxidation products to oceans and cloudwater was sufficiently fast that there was little likelihood that the products would be transported to the stratosphere.

Data on the tropospheric degradation of proposed substitutes for ozone depleting CFCs were obtained by conducting photochemical oxidation studies of HCFCs and HFCs using long path Fourier transform infrared spectroscopy. The hydrogen abstraction reactions were initiated using Cl radicals rather than OH radicals because of the rather unreactive nature of the compounds. The experimental product yields at T = 25 ± 3°C and 700 Torr of dry air were: CHClF2 (1.11 ± 0.06 C(O)F2); CClFHCF3 (1.00 ± 0.04 CF3C(O)F); CF3CHF2 (1.09 ± 0.05 C(O)F2); CClF2CH3 (0.98 ± 0.03 C(O)F2); CHF2CH3 (1.00 ± 0.05 C(O)F2); CF3CH2F (0.16 ± 0.03 CF3CF(O), and 0.83 ± 0.22 HFC(O)), where all standard deviations are 2σ. For each compound, the critical step in determining the oxidation products was the decomposition of a halogenated alkoxy radical. For HCFC-22 and HCFC-124, the major alkoxy radical decomposition route was Cl elimination. The HFC-125 product data were consistent with CC cleavage of a two carbon alkoxy radical as the major decomposition route whereas both CC cleavage and H abstraction by O2 were significant contributors to the decomposition of the HFC-134a alkoxy radical. Secondary Cl reactions in the HCFC-142b and HFC-152a experiments prevented an unambiguous determination of the decomposition modes; the data are consistent with both CC bond scission and Cl reactions with halogenated aldehydes producing the oxidation product C(O)F2. With the exception of the HFC-134a and HFC-125 data, the proposed mechanisms can account for the major oxidation products. For HFC-134a and HFC-125, a number of product bands could not be identified. The bands are likely due to products from reactions involving the CF3O2 radical. © John Wiley & Sons, Inc.

Data on the tropospheric degradation of proposed substitutes for ozone depleting CFCs were obtained by conducting photochemical oxidation studies of HCFCs and HFCs using long path Fourier transform infrared spectroscopy. The hydrogen abstraction reactions were initiated using Cl radicals rather than OH radicals because of the rather unreactive nature of the compounds. The experimental product yields at T = 25 ± 3°C and 700 Torr of dry air were: CHClF2 (1.11 ± 0.06 C(O)F2); CClFHCF3 (1.00 ± 0.04 CF3C(O)F); CF3CHF2 (1.09 ± 0.05 C(O)F2); CClF2CH3 (0.98 ± 0.03 C(O)F2); CHF2CH3 (1.00 ± 0.05 C(O)F2); CF3CH2F (0.16 ± 0.03 CF3CF(O), and 0.83 ± 0.22 HFC(O)), where all standard deviations are 2σ. For each compound, the critical step in determining the oxidation products was the decomposition of a halogenated alkoxy radical. For HCFC-22 and HCFC-124, the major alkoxy radical decomposition route was Cl elimination. The HFC-125 product data were consistent with CC cleavage of a two carbon alkoxy radical as the major decomposition route whereas both CC cleavage and H abstraction by O2 were significant contributors to the decomposition of the HFC-134a alkoxy radical. Secondary Cl reactions in the HCFC-142b and HFC-152a experiments prevented an unambiguous determination of the decomposition modes; the data are consistent with both CC bond scission and Cl reactions with halogenated aldehydes producing the oxidation product C(O)F2. With the exception of the HFC-134a and HFC-125 data, the proposed mechanisms can account for the major oxidation products. For HFC-134a and HFC-125, a number of product bands could not be identified. The bands are likely due to products from reactions involving the CF3O2 radical. © John Wiley & Sons, Inc.

Oxidation reactions of the proposed CFC substitutes HCFC-123 (CF3CHCl2) and HCFC-141b (CFCl2CH3) have been studied in the laboratory using long-path Fourier transform infrared spectroscopy. The air oxidation of the HCFCs was initiated by the photolysis of Cl2 forming Cl atoms that abstract H atoms from the HCFC. CF3C(O)Cl was the only carbon containing compound observed in the infrared spectrum of the products of the HCFC-123/Cl2 irradiations and its yield was approximately one. The product data are consistent with formation of CF3C(O)Cl by Cl elimination of the intermediate halogenated alkoxy radical CF3CCl2O. The Cl-initiated oxidation of HCFC-141b led to the formation of CO and C(O)FCl. The product data are consistent with a 1 : 1 relationship between C(O)FCl formed and HCFC-141b reacted. Product data were compatible with both decomposition by cleavage of the C−C bond of the radical CFCl2CH2O leading to the prompt generation of C(O)FCl and reaction of the radical with O2 forming the two carbon halogenated aldehyde CFCl2CH(O), which in the presence of Cl was likely oxidized to C(O)FCl. An approximate method was developed in which the ratio was extracted from analysis of the time evolution of HCFC-141b, C(O)FCl, and CO. The data suggest that the contributions are comparable.

About 1% of individuals with autism or types of pervasive developmental disorder have a duplication of the 15q11-q13 region. These abnormalities can be detected by routine G-banded chromosome study, showing an extra marker chromosome, or demonstrated by fluorescence in situ hybridization (FISH) analysis, revealing an interstitial duplication. We report here the molecular, cytogenetic, clinical and neuropsychiatric evaluations of a family in whom 3 of 4 siblings inherited an interstitial duplication of 15q11-q13. This duplication was inherited from their mother who also had a maternally derived duplication. Affected family members had apraxia of speech, phonological awareness deficits, developmental language disorder, dyslexia, as well as limb apraxia but did not have any dysmorphic clinical features. The observations in this family suggest that the phenotypic manifestations of proximal 15q duplications may also involve language-based learning disabilities.

A 5-year-old asymptomatic boy was found incidentally, on a chest radiograph, to have gross cardiomegaly; further evaluation by echocardiography showed a giant right atrial aneurysm. The patient underwent successful surgical reduction of the right atrium, closure of an atrial septal defect, and tricuspid valve repair. These measures were taken to prevent thrombus formation in the right atrium, prevent paradoxical embolism, and lower the risk of atrial arrhythmias. The morphologic features of the resected atrial tissue showed paper-thin wall with a central aneurysm and focal endocardial fibrosis consistent with a diagnosis of idiopathic dilatation of the right atrium. (Tex Heart Inst J 2001; 28:301–3)

The Angelman (AS) and Prader-Willi syndromes (PWS) are clinically distinct neurobehavioural syndromes resulting from loss of maternal (AS) or paternal contributions (PWS) of imprinted genes within the chromosomal 15q11-q13 region. The molecular diagnosis of both syndromes can be made by a variety of techniques, including DNA methylation, DNA polymorphism and molecular cytogenetic analyses. DNA methylation analysis at three major loci (ZNF127, PW71 and 5' SNRPN) has been successfully used for the postnatal diagnosis of AS and PWS. Methylation analysis, in contrast to other techniques, can reliably be used to diagnose all three major molecular classes (deletion, uniparental disomy and imprinting mutation) of PWS, and three of the four major classes of AS. In this study we demonstrate that methylation analysis can also be successfully used in prenatal diagnosis, by examining specimens obtained from amniocentesis and chorionic villus sampling. Correct prenatal diagnoses were obtained in 24 out of 24 samples using the 5' SNRPN locus; 4 out of 15 using the ZNF127 locus; and 10 out of 18 using the PW71 locus. Therefore, our data indicate that although the DNA methylation imprints of ZNF127 and 5' SNRPN arise in the germline and are present in brain, only 5' SNRPN maintains the imprint in tissues suitable for the prenatal diagnosis of AS and PWS.

Neurofibromatosis type 1 (NF1) is a dominant disorder caused by mutations in the NF1 gene; approximately 100 NF1 gene mutations have been published. The CpG C-to-T transition is a frequent mutation mechanism in genetic disorders. To estimate its frequency in NF1, we employed a PCR-restriction digestion method to examine 17 CpGs in 65 patients, and also screened for a CpG nonsense transition (R1947X) that occurs in 1-2% of patients. The analysis revealed disease-related CpG C-to-T transitions (including a nonsense mutation that may be as frequent as R1947X) as well as a benign variant and another mutation at a CpG. Four patients showed CpG mutations in analysis of 18 sites (17 surveyed by restriction digest, plus the R1947X assay), including three C-to-T transitions and one C-to-G transversion. These 18 sites represent one-fifth of the 91 CpGs at which a C-to-T transition would result in a nonsense or nonconservative missense mutation. Thus, it is feasible that the CpG mutation rate at NF1 might be similar to that seen in other disorders with a high mutation rate, and that recurrent NF1 mutations may frequently reside at CpG sites.

To review the outcome of cardiac transplantation undertaken in patients with congenital heart defects.Between November 1991 and March 1998 at our institution, cardiac transplantation was performed in 16 patients with congenital heart disease (age range, 3 to 57 years; mean, 26.1). Preoperative diagnoses included univentricular heart (N = 4); complete transposition of the great arteries (N = 3); Ebstein's anomaly (N = 2); tetralogy of Fallot (N = 2); levotransposition (N = 2); dextrocardia, corrected transposition, ventricular and atrial septal defects, and pulmonary stenosis (N = 1); double-outlet right ventricle (N = 1); and hypertrophic obstructive cardiomyopathy (N = 1). All patients had undergone from one to five previous palliative operations.Four patients required permanent pacemaker implantation during the first month postoperatively because of bradycardia; more than 2 years later, another patient required a permanent pacemaker because of sick sinus syndrome. In addition, one patient had an automatic implantable cardioverter-defibrillator. Three patients required reconstruction of cardiovascular structures with use of prosthetic material (Teflon patches or donor tissue) at the time of cardiac transplantation. Actuarial 1-, 2-, and 5-year survival was 86.2 +/- 9.1%. During the first year after transplantation, two deaths occurred--one at 41 days of putative vascular rejection and the second at 60 days of severe cellular rejection. All other patients are alive and functionally rehabilitated; the mean follow-up period has been 26.1 months (range, 2 to 89.6).Cardiac transplantation for patients with congenital heart disease can be accomplished with a low perioperative mortality and an excellent medium-term survival despite the challenges presented by the technical difficulties during invasive diagnostic procedures and at operation and the need for adherence to long-term multiple-drug therapy in this patient population.

Deficiency of methylenetetrahydrofolate reductase (MTHFR) is associated with a variable phenotype that includes mental retardation, gait abnormalities, and seizures. Many of the same clinical findings are also seen in patients with Angelman syndrome. We report on a patient with MTHFR deficiency who was initially diagnosed as having Angelman syndrome. This case illustrates that MTHFR deficiency can mimic the phenotype of Angelman syndrome and that MTHFR deficiency should be excluded in patients with manifestations of Angelman syndrome whose molecular studies of chromosome 15 are normal.

Velo-cardio-facial syndrome, DiGeorge syndrome, conotruncal anomaly face syndrome, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect are all associated with hemizygosity of 22q11. While the prevalence of the deletions in these phenotypes has been studied, the frequency of deletions in patients presenting with velopharyngeal insufficiency (VPI) is unknown. We performed fluorescence in situ hybridization for locus D22S75 within the 22q11 region on 23 patients with VPI (age range 5-42 years) followed in the Craniofacial Clinic at the University of Florida. The VPI occurred either as a condition of unknown cause (n=16) or as a condition remaining following primary cleft palate surgery (n=7). Six of sixteen patients with VPI of unknown cause and one of seven with VPI following surgery had a deletion in the region. This study documents a high frequency of 22q11 deletions in those presenting with VPI unrelated to overt cleft palate surgery and suggests that deletion testing should be considered in patients with VPI.

We report on two instances of familial recurrence of Angelman syndrome which, from pedigree analysis, appear incompatible with currently known mechanisms of inheritance of this disorder. In these two families, deletion-positive Angelman syndrome has recurred in cousins. Several established mechanisms for deletion-positive familial recurrence have been ruled out. In each family, molecular cytogenetic studies show typical chromosome 15 deletions, and DNA methylation analysis verifies the maternal origin of the deleted chromosomes in all four individuals. Since the mothers of the affected individuals in each family are not known to be related, these recurrences appear to be secondary to coincidental, de novo events. This conclusion is consistent with direct and indirect estimates of the population frequency of Angelman syndrome.

Recent studies have identified a new class of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients who have biparental inheritance, but neither the typical deletion nor uniparental disomy (UPD) or translocation. However, these patients have uniparental DNA methylation throughout 15q11-q13, and thus appear to have a mutation in the imprinting process for this region. Here we describe detailed clinical findings of five AS imprinting mutation patients (three families) and two PWS imprinting mutation patients (one new family). All these patients have essentially the classical clinical phenotype for the respective syndrome, except that the incidence of microcephaly is lower in imprinting mutation AS patients than in deletion AS patients. Furthermore, imprinting mutation AS and PWS patients do not typically have hypopigmentation, which is commonly found in patients with the usual large deletion. Molecular diagnosis of these cases is initially achieved by DNA methylation analyses of the DN34/ZNF127, PW71 (D15S63), and SNRPN loci. The latter two probes have clear advantages in the simple molecular diagnostic analysis of PWS and AS patients with an imprinting mutation, as has been found for typical deletion or UPD PWS and AS cases. With the recent finding of inherited microdeletions in PWS and AS imprinting mutation families, our studies define a new class of these two syndromes. The clinical and molecular identification of these PWS and AS patients has important genetic counseling consequences.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized predominantly by neurofibromas, café-au-lait spots, and Lisch nodules. The disease is caused by disruptive mutations of the large NF1 gene, with half of cases caused by new mutation. Less than 100 constitutional mutations have thus far been published, ranging from very large deletions to point mutations. We have pursued NF1 mutation analysis by heteroduplex analysis (HDA) and single-strand conformational polymorphism analysis (SSCP) of individual exons. We streamlined these techniques to eliminate the use of radioactivity, to apply both methods to the same PCR product, and to multiplex samples in gels. Applied simultaneously to a set of 67 unrelated NF1 patients, HDA and SSCP have thus far identified 26 mutations and/or variants in 45 of the 59 exons tested. Disease-causing mutations were found in 19% (13/67) of cases studied. Both techniques detected a variety of mutations including splice mutations, insertions, deletions, and point changes, with some overlap in the ability of each method to detect variants.

Angelman syndrome (AS) is associated with a loss of maternal genetic information, which typically occurs as a result of a deletion at 15q11-q13 or paternal uniparental disomy of chromosome 15. We report a patient with AS as a result of an unbalanced cryptic translocation whose breakpoint, at 15q11.2, falls within this region. The proband was diagnosed clinically as having Angelman syndrome, but without a detectable cytogenetic deletion, by using high-resolution G-banding. FISH detected a deletion of D15S11 (IR4-3R), with an intact GABRB3 locus. Subsequent studies of the proband's mother and sister detected a cryptic reciprocal translocation between chromosomes 14 and 15 with the breakpoint being between SNRPN and D15S10 (3- 21). The proband was found to have inherited an unbalanced form, being monosomic from 15pter through SNRPN and trisomic for 14pter to 14q11.2. DNA methylation studies showed that the proband had a paternal-only DNA methylation pattern at SNRPN, D15S63 (PW71), and ZNF127. The mother and unaffected sister, both having the balanced translocation, demonstrated normal DNA methylation patterns at all three loci. These data suggest that the gene for AS most likely lies proximal to D15S10, in contrast to the previously published position, although a less likely possibility is that the maternally inherited imprinting center acts in trans in the unaffected balanced translocation carrier sister.

In order to further our understanding of the epigenetic modifications of DNA and its role in imprinting, we examined DNA methylation patterns of human tissues of uniparental origin. We used complete hydatidiform moles (CHM), which are totally androgenetic conceptions, to examine the paternal methylation pattern in the absence of a maternal contribution and we used ovarian teratomas to represent the maternal counterpart. We carried out an analysis of DNA methylation of a gene which has been shown to contain sites which are differentially methylated in a parent-specific fashion. The gene, ZNF127, is located on chromosome 15q11-q13 in the region associated with Prader-Willi and Angelman syndromes. The parent-of-origin DNA methylation has been postulated to reflect the presence of an imprint and recent studies have confirmed that ZNF127 is differentially expressed only from the paternal chromosome. We identified a unique pattern of hyper- and hypomethylated sites in androgenetic conceptions which was nearly identical to the paternal pattern found in sperm. This may represent the paternal germ-line methylation imprint. We also studied partial hydatidiform moles, non-molar triploid conceptions, normal chorionic villi, and somatic tissue. These all demonstrated a modified DNA methylation pattern characteristic of normal chorionic villi with only limited findings of the imprint. Our results suggest that human androgenetic conceptions may provide an excellent model to analyze epigenetic DNA modifications, such as methylation, in imprinted genes. The paternal allele-specific methylation imprint will also be useful clinically to confirm the androgenetic nature of suspected molar conceptions in which parental blood samples may not be available.

Unilateral clubbing has been associated with local vascular lesions of the arm, axilla, and thoracic outlet and with hemiplegia. We describe a patient with Takayasu's arteritis, a disease that affects the aorta and its major branches, who presented with unilateral digital clubbing. A review of the literature on unilateral clubbing is included.

Congenital pulmonary vein stenosis is a rare cause of obstruction of pulmonary venous blood flow with a high mortality. Acquired pulmonary vein stenosis is an equally serious condition.Eight patients (age range, 3 months to 43 years; median age, 1.5 years) underwent surgical relief of pulmonary vein stenosis. Two had congenital pulmonary vein stenosis, 5 had pulmonary vein stenosis that was acquired after surgical treatment of total anomalous pulmonary venous connection, and 1 had pulmonary vein stenosis associated with idiopathic mediastinal fibrosis and calcification.One infant died 2 months after correction of acquired pulmonary vein stenosis. At follow-up extending to 16 years (median follow-up, 6.5 years), 6 patients are in New York Heart Association functional class I, and 1 patient is in class II.In view of the dismal natural history of untreated pulmonary vein stenosis, prompt surgical relief of the stenosis may be a rewarding undertaking.

Abnormalities of chromosome region 15q11-13 are associated with Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Differences between the methylation patterns of the region of chromosome 15q11-13 which hybridizes to the highly conserved DNA, DN34, in normal individuals and in patients with AS and PWS have been described. We report on a family in which first cousins are affected by AS and PWS as a result of a familial paracentric inversion of 15q11-q13. The results of the studies on this family demonstrate the differences in the methylation patterns in the 2 conditions and the phenomenon of genomic imprinting, whereby genetic information is expressed differently dependent on the parent of origin.

We reviewed medical records from eight patients (4 to 29 years of age) with a functional single ventricle and pulmonary microthrombosis as observed on open lung biopsy specimens. Hemodynamic assessment before biopsy revealed pulmonary hypertension (mean pulmonary artery pressure 19 to 53 mm Hg) in the seven patients tested and severely increased pulmonary arteriolar resistance (6 to 13 U.m2) in three of the five patients in whom these measurements were performed. Pulmonary blood flow varied (4 L/min per square meter in two patients and5 L/min per square meter in four patients), and the pulmonary/systemic blood flow ratio was low or normal (0.6 to 1.1) in five of six cases. Hemoglobin values were increased (16.4 to 22 gm/dl) in seven of eight patients. Lung biopsy specimens revealed thrombotic obstructive lesions in 56% (range 28% to 96%) of muscular pulmonary arteries. Coexistent medial hypertrophy was absent or mild in all but one specimen, and none had features of plexogenic pulmonary arteriopathy. Microscopic pulmonary thrombi accounted for unexpected pulmonary hypertension, precluding the Fontan operation, in five patients and unsuccessful Fontan operation in two. Clinically significant thrombi should be considered in patients with severe polycythemia (hemoglobin value20 gm/dl) and unobtainable or unreliable pulmonary blood flow or pulmonary resistance determinations.

All of the 2,401 patients with aortic stenosis (AS), pulmonary stenosis (PS), or ventricular septal defect (VSD) admitted to the First Natural History Study of Congenital Heart Defects between 1958 and 1965 were eligible for the Second Natural History Study. Most patients with severe defects were managed surgically, and most with mild defects were managed medically. Final examination in the first study was carried out 8 years after admission.For AS, the incidence rate of bacterial endocarditis (BE) was 27.1 per 10,000 person-years. The incidence rate was 15.7 per 10,000 person-years for those managed medically and 40.9 per 10,000 person-years for those managed surgically. Most patients managed surgically had severe AS, and severity was more important to the risk of BE than the method of management. For PS, only one of the 592 patients with PS experienced BE. For VSD, the incidence rate of BE was 14.5 per 10,000 person-years. Size of the VSD was not associated with risk of BE. The risk of BE before closure of the VSD was more than twice that after surgery.The incidence rate of BE was nearly 35-fold the population-based rate. The increased incidence in patients with AS after valvotomy was a function of severity of the defect and not a function of surgery. Presence of aortic regurgitation in patients with AS did not increase the risk of developing BE. Surgical closure of VSD lowered the risk of BE.

Quality of life of patients with congenital heart defects is an important aspect of the assessment of outcome of medical and surgical treatment.All participants in the Second Natural History Study of Congenital Heart Defects who completed the study questionnaire were included in this analysis. The questionnaire completed by the patients included inquiries relative to medical history, marital and family life, self-perception of well-being, insurability, and employability. The following general observations were apparent. The study cohort reported a self-perception of health status that was similar to that of the general population. Second, 35-40% of patients had not had a cardiac evaluation within the previous 10 years. Third, 16% of the patients had no health insurance, and 35.7% of the patients had no life insurance. For the patients with pulmonary stenosis and ventricular septal defect, the percent who were married was less than that of the corresponding national age- and sex-specific population. For patients with aortic stenosis, the percent married was greater than that of the general population for some age groups. The proportion of divorced or separated individuals was similar to that of the general population. For all three defects, the level of educational attainment exceeded the national average. Last, unemployment rates were similar to national averages except for women with aortic stenosis, who had a significantly higher unemployment rate than did age- and sex-matched controls.Patients initially identified with aortic stenosis, pulmonary stenosis, or ventricular septal defect in 1959-1973 have a quality of life in the mid-1980s similar to that of the general US population.

From 1958 to 1969, 462 patients (mostly children) with aortic stenosis were admitted to the First Natural History Study of Congenital Heart Defects (NHS-1) after cardiac catheterization. Most with gradients50 mm Hg were managed medically; most with gradientsor = 80 mm Hg had aortic valvotomy. Of those with gradients of 50-79 mm Hg, some were managed medically, and some were managed surgically. Most had a second cardiac catheterization at the conclusion of NHS-1. More than 15 years have elapsed since NHS-1, and most of the cohort are adults. This report (the Second Natural History Study [NHS-2]) addresses the long-term results of medical and surgical management.Of the original cohort of 462 patients, 440 were alive at completion of NHS-1. New data were obtained on 371 (80.3%) of the original cohort. Probability of 25-year survival was 92.4% for those admitted with gradients50 mm Hg and 81.0% for those with admission gradientsor = 50 mm Hg. More than half of the cardiac deaths were sudden and unexpected. Forty percent of patients managed medically during NHS-1 subsequently required surgical management. Almost 40% of operated patients required a second operation. Three percent of the original cohort subsequently had bacterial endocarditis. There was a higher-than-normal prevalence of serious arrhythmias. Of NHS-2 full participants, 92.3% were in New York Heart Association functional class I. Most patients had low Doppler mean gradients. Clinically, 46.6% had aortic valve regurgitation. The final clinical status was excellent in 29.9%, good in 22.8%, fair in 28.6%, and poor in 18.7%.Patients with gradients25 mm Hg can be followed medically; however, progressive stenosis can occur, and approximately 20% will require intervention. If the gradient isor = 50 mm Hg, there is a risk of serious arrhythmias and, possibly, sudden death. If the gradient isor = 80 mm Hg, intervention is clearly indicated; as techniques improve, delaying intervention in patients with gradients of 50-79 mm Hg may not be advantageous. Patients with gradients of 25-49 mm Hg can be followed medically with annual evaluation.

Results of the location and recruitment efforts and comparisons of responses from patients who cooperated at different levels in the Second Natural History Study of Congenital Heart Defects are included because they influenced the choice of analytic methods and are essential to the generalizability of the results to the entire study cohort. Included are examination and data collection protocols (e.g., protocol definitions, test procedures, and data editing), statistical methods (e.g., box plots, survival curves, multivariable models, and rate adjustment), participation results (e.g., proportional odds analysis, mortality, location, recruitment, and full participants, including comparison of questionnaire responses and comparison of questionnaire response and physician history), and a discussion.

From 1958 to 1969, 1,280 patients (mostly children) with ventricular septal defects (VSDs) were admitted to the First Natural History Study of Congenital Heart Defects (NHS-1) after cardiac catheterization. Most with small defects and Eisenmenger's syndrome were managed medically; most with large VSDs were managed surgically. Of those with moderate-size defects, some were managed medically, and some were managed surgically. Most had a second catheterization at the conclusion of NHS-1. More than 15 years have elapsed since NHS-1, and most of the cohort are adults. This report (Second Natural History Study) addresses the long-term results of medical and surgical management.Of an original cohort of 1,280 patients, 1,099 were alive at completion of NHS-1. New data were obtained on 976 (76.3%) of the original cohort. Probability of 25-year survival was 87%, and admission severity was the best predictor of survival. Of the 860 patients managed medically during NHS-1, 245 subsequently required surgical closure of the VSD. Only 5.5% of patients who had surgical closure required a second operation. On follow-up, there was a higher-than-normal prevalence of serious arrhythmias. Bacterial endocarditis occurred rarely. Of patients with small VSDs, 94.1% were in New York Heart Association functional class I. With the exception of those with Eisenmenger's syndrome, most patients had a final clinical status that was excellent or good.The majority of patients fared well. However, there was a higher-than-normal prevalence of serious arrhythmia and sudden death, including those with small VSDs.

The purpose of this study was to determine exercise tolerance and cardiac response to exercise for a large cohort of adult subjects with aortic stenosis, pulmonary stenosis, or ventricular septal defect participating in the Second Natural History Study of Congenital Heart Defects (NHS-2).Exercise testing was performed on 134 of 235 NHS-2 full participants with aortic stenosis, 195 of 331 NHS-2 full participants with pulmonary stenosis, and 324 of 594 NHS-2 full participants with ventricular septal defect. A Bruce treadmill exercise protocol was used. Mean exercise duration for patients with aortic stenosis, pulmonary stenosis, and ventricular septal defect was 86.5%, 94.2%, and 90.8% of predicted, respectively. For patients with aortic stenosis, there was a direct relation between echocardiographic Doppler maximum transaortic gradient and ST segment change during exercise. ST segment change during exercise was very uncommon for patients with pulmonary stenosis. For patients with ventricular septal defect, there was an association between arrhythmias noted during exercise and the presence of associated aortic insufficiency.Although exercise duration was well preserved for patients with each of the three defects, exercise tolerance was subnormal.

Knowledge of the risk of occurrence of congenital heart defects in offspring of individuals with a congenital heart defect is important for genetic counseling and understanding the etiology of congenital heart diseases.A portion of the questionnaire mailed to all patients in the Second Natural History Study of Congenital Heart Defects (NHS-2) addressed marital status, pregnancy, miscarriage, and presence or absence of congenital heart defects or other congenital malformations in first-degree relatives. Offspring were not examined as a part of the study. For male probands with aortic stenosis (AS), three of 251 offspring had congenital heart disease, whereas one of 72 offspring of female probands with AS had congenital heart disease. For patients with pulmonary stenosis (PS), three of 176 offspring of male probands had congenital heart disease, whereas eight of 205 offspring of female probands had congenital heart disease. For male probands with ventricular septal defect (VSD), 10 of 334 offspring had congenital heart defects, and 11 of 384 offspring of female probands with VSD had offspring with congenital heart defects. The prevalence rate for noncardiac congenital anomalies in offspring of probands was 2%.Based on known congenital heart defects in offspring of probands in the NHS-2, occurrence rates of congenital heart disease in children of subjects with AS, PS, and VSD were 1.2% (confidence interval [CI], 0.34-3.1%), 2.8% (CI, 1.4-5.1%), and 2.9% (CI, 1.8-4.4%), respectively.

From 1958 to 1969, 592 patients (mostly children) with pulmonary stenosis were admitted to the First Natural History Study of Congenital Heart Defects (NHS-1) after cardiac catheterization. Most with gradients50 mm Hg were managed medically; most with gradientsor = 80 mm Hg had pulmonary valvotomy. Among these with gradients of 50-79 mm Hg, some were managed medically, and some were managed surgically. Most had a second cardiac catheterization at conclusion of NHS-1. More than 15 years had elapsed since NHS-1, and most of the cohort are adults. This report (Second Natural History Study) addresses the long-term results of medical and surgical management.Of the original cohort of 592 patients, 580 were alive at completion of NHS-1. New data were obtained on 464 (78.4%) of the original cohort. Probability of 25-year survival was 95.7%. Probability of survival was less (80%) in a subgroup of patients entering NHS-112 years old with cardiomegaly. Less than 20% of patients managed medically during NHS-1 subsequently required a valvotomy. Only 4% of operated patients required a second operation. Bacterial endocarditis occurred rarely. Ninety-seven percent were in New York Heart Association class I. There was a small but higher-than-normal prevalence of serious arrhythmias. Most patients, whether medically or surgically managed, had low Doppler maximum gradients. Final clinical status was excellent or good in 83%.Probability of survival is similar to that of the general population, and the vast majority of patients are asymptomatic. If valvotomy or valvuloplasty is required in a child, reoperation is rarely necessary. Patients with gradients25 mm Hg do not experience an increase in gradient. Patients with a gradientor = 50 mm Hg should have valvotomy or valvuloplasty. Choice of management of patients with gradients of 40-49 mm Hg remains debatable.

Arrhythmias are a significant source of morbidity and mortality in patients with congenital heart defects.As part of the Second Natural History Study of Congenital Heart Defects (NHS-2), 24-hour ambulatory ECG monitoring was performed for full participants in the study. At least 15.5 hours of monitoring was required for inclusion in the analysis. This was achieved for 755 (90.6%) of the patients. Multiform premature ventricular contractions, ventricular couplets, and ventricular tachycardia were considered "serious arrhythmias." For patients with aortic stenosis, the presence of "serious arrhythmias" was associated with higher left ventricular end-diastolic pressure, presence of aortic regurgitation, male sex, and presence of prior aortic valve replacement. For patients with pulmonary stenosis, only older age on admission to NHS-1 was significantly associated with "serious arrhythmias." For patients with ventricular septal defect, the variables associated with "serious arrhythmias" were different for medically and surgically managed patients. For medically managed patients, higher mean pulmonary artery pressure on admission to NHS-1 and older age on admission to NHS-2 were associated with the presence of serious arrhythmias. For surgically managed patients, higher New York Heart Association functional class and cardiomegaly were associated with serious arrhythmias.The prevalence of arrhythmias (especially ventricular arrhythmias) was higher for patients with aortic stenosis, pulmonary stenosis, or ventricular septal defect than for an historical control population. "Serious arrhythmias" were most frequently noted in patients with aortic stenosis who also had a higher incidence of sudden death. The prevalence of "serious arrhythmias" was second highest for patients with ventricular septal defect who had the second highest incidence of sudden death.

From April 1972 to February 12, 1991, 189 patients with Ebstein's anomaly underwent repair. Ages ranged from 11 months to 64 years (median 16 years, mean 19.1 years). In 58.2%, tricuspid valve reconstruction was possible, and in 36.5%, a prosthetic valve, usually a bioprosthesis, was inserted. In 5.3%, a modified Fontan or other procedure was performed. There were 12 hospital deaths (6.3%). All 28 patients who had accessory conduction pathways (Wolff-Parkinson-White syndrome) underwent successful ablation of the pathways as part of the operative treatment. Follow-up was obtained in 151 (85.3%) patients. Of those patients followed up more than 1 year after operation, 92.9% were in New York Heart Association class I or II. There were 10 late deaths: seven cardiac (four sudden), two noncardiac, and one of an unknown cause. Postoperative Doppler echocardiographic assessment showed the atrial septum was intact in all patients and tricuspid valve function was good to excellent in most patients. Four of the 110 patients (3.6%) who underwent valve reconstruction required reoperation 1.4 to 14.1 years later. Postoperative reduction in heart size was usual, atrial arrhythmias were reduced, and late postoperative exercise testing showed a significant improvement in performance: Maximal oxygen consumption increased from a mean of 47% of predicted value before the operation to a mean of 72% after the operation. Nine patients had a total of 12 successful pregnancies with deliveries of normal children.

The reduction of dietary cholesterol and fat lowers low-density lipoprotein cholesterol (LDL-C) and reduces risk of coronary heart disease in adults. The purpose of this study was to determine the individual variability of response of serum lipid and lipoprotein levels to a low-fat, low-cholesterol diet in children with elevated LDL-C levels. Thirty-two children (2 to 16 years of age) enrolled in a diet modification program, who had LDL-C levels of at least 110 mg/dL but normal triglyceride levels for their ages, were studied. Lipid levels and dietary nutrients were analyzed at the time of admission, and final assessments were made at least 3 months after entry. There was a significant correlation, for the group as a whole, between change in LDL-C concentration and change in grams of dietary saturated fat; however, there was marked individual variability in LDL-C response. There were no significant correlations between changes in LDL-C levels and changes in either total fat, polyunsaturated fat, or cholesterol intake. It is concluded that modest decreases in dietary saturated fat coincide with a lowering of LDL-C concentration, over a short term, in many children, but the degree of lowering varies considerably from one child to another. This variability is consistent with the concept that response of serum lipid levels to dietary changes is modified by genetic, metabolic, and other, as of yet, undefined variables.

Deletions or uniparental disomy for human chromosome 15q11q13 result in Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS), depending upon the respective parental origin. Clinical and cytogenetic aspects of the two disorders are covered elsewhere in this book. Molecular studies have indicated that the extent of deletions in PWS and AS do not differ (Knoll et al, 1990). That deletions in PWS occurred predominantly on the paternal chromosome 15 was first demonstrated using cytogenetic polymorphisms (Butler et al, 1986), and we now know that all cases are paternal in origin (Nicholls et al, 1989a; Nicholls et al, 1989b; Butler, 1990). In contrast, deletions in AS always occur on the maternal chromosome 15 (Knoll et al, 1989).

Because we have observed a relatively large number of tricuspid atresia patients with a short P-R interval and slurring of the initial QRS pattern suggesting preexcitation, we conducted a retrospective study to determine the frequency of this electrocardiographic pattern and whether or not this represented the presence of a true atrioventricular bypass tract. Three pediatric cardiologists reviewed the surface electrocardiograms of 183 consecutive tricuspid atresia patients who had been evaluated at the Mayo Clinic between 1980 and 1986. The patients' ages ranged from 4 months to 21 years; the male-to-female ratio was 5:4. The criteria for preexcitation included 1) a P-R segment0.10 sec, 2) a QRS complex0.10 sec, and 3) slurring of the upstroke of the QRS complex ("delta wave"). Of the 183 patients, 22 (12%) had P-R segments0.10 sec, 9 of whom fulfilled the criteria for preexcitation. Five of these had a history of supraventricular tachycardia, and 4 of the 5 had undergone invasive electrophysiologic studies: 2 had enhanced atrioventricular-nodal conduction and 1 had normal atrioventricular-nodal conduction; only 1 had an accessory pathway. Our results indicate that, although many patients with tricuspid atresia meet the surface electrocardiographic criteria for preexcitation, many of these patients may not have an atrioventricular bypass tract; this state might be termed "pseudo-preexcitation." In these instances, invasive studies probably would not be necessary; regrettably, it may be difficult to distinguish between the presence and the absence of preexcitation in such patients without invasive electrophysiologic studies.

We studied 12 children with pectus excavatum (mean age, 13.8 years) using pulmonary function and exercise testing. Eight patients had surgical repair and were studied before and after repair. Four patients did not have repair and were tested twice. The degree of chest wall deformity in the two groups was similar. All patients reached 86% or more of their maximal predicted heart rate with exercise. Total lung capacity decreased 8% (p less than 0.01) after operation. In the nonoperated control group, total lung capacity was similar during both studies. The ratio of ventilation at maximal exercise to maximal voluntary ventilation was 68% +/- 12% before and 66% +/- 9% after operation in the operated group and 69% +/- 18% and 79% +/- 30% at two studies in the nonoperated group (nonsignificant changes). Maximal oxygen uptake was 36.1 +/- 4.4 ml/kg/min preoperatively and 38.1 +/- 8.1 postoperatively and 41.2 +/- 7.3 ml/kg/min and 43.0 +/- 6.9 on two studies in the nonoperated group (nonsignificant changes). Cardiac output and stroke volume increased appropriately with exercise both before and after operation. Operation had no physiologically significant effect on the cardiorespiratory response to exercise. Slight changes in cardiorespiratory function occurred in both operated and nonoperated subjects. These results emphasize the importance of studying patients before and after operation and of using a control group.

Developmental changes in cardiac muscle function were assessed in isolated dog ventricular muscle strips obtained from dogs of three age groups: 2 day, 4 wk, and adult. Active tension (AT) and maximum rate of contraction and relaxation (+dT/dt, -dT/dt) increased significantly with age. Total contraction time increased with age. Time to peak tension increased between 4 wk and adulthood, and relaxation time increased between 2 day and 4 wk (P less than 0.05). The degree of post-"extra stimulus" potentiation in response to a single premature extra stimulus (SPES) or to sustained paired stimulation (SPS) was similar in all age groups. However, a longer period of SPS was necessary to reach peak AT in young animals than in adults. AT, +dT/dt, -dT/dt, and (-dT/dt)/T increased significantly in all age groups in response to increasing concentrations of isoproterenol. However, while (+dT/dt)/T increased significantly in the 4-wk and adult groups, it remained unchanged from control in the 2-day group with increasing concentration of isoproterenol. The ED50 of isoproterenol was significantly greater in the 2-day and 4-wk groups than in the adult group. AT increased significantly in young muscles but not in adult muscles when additional calcium was added to the bath containing the highest concentration of isoproterenol. In adult muscles SPS produced the greatest AT but not in the 2-day group, which required increased calcium concentration as well as isoproterenol. Maturation of several membrane systems is implicated.

Using a matrix isolation technique an attempt was made to detect gas phase methyl radicals which had been formed at 500°C on a polycrystalline Pt catalyst dispersed with SiO2, and at 900°C on a Pt single-crystal catalyst. Reaction products were condensed onto a sapphire rod which was then lowered into an EPR microwave cavity for analysis. No increase in the amount of radicals over the background was detected. Thus, the role of the Pt catalyst in the catalytic combustion of methane is to provide a catalytic surface for the reaction of CH4 and O2, and not to facilitate the gas phase reaction by generating free radicals.

From 1957 through September, 1983, 35 patients with tetralogy of Fallot and absent pulmonary valve underwent operation. Two subgroups of patients were recognized: minimally symptomatic (Group A, n = 21) and markedly symptomatic (Group B, n = 14). Group B patients were symptomatic at an earlier age and were younger at operation. Ages ranged from 1 day to 42 years (mean = 7.8 +/- 7.4 SD). Repair consisted of closure of the ventricular septal defect and relief of the right ventricle-pulmonary artery pressure gradient (nine patients received a tissue valve). In five patients, partial resection and/or plication of the aneurysmal pulmonary arteries also was performed. Operative mortality was 4.8% in Group A and 35.7% in Group B. In up to 25 years of follow-up, there was one late death in Group A (an early case with complete heart block); the remaining 19 patients are asymptomatic. In Group B, there were four late deaths, three related to cardiopulmonary insufficiency. These results indicate pulmonary valve insufficiency is tolerated well in minimally symptomatic patients. For markedly symptomatic patients, results may be improved if repair includes establishment of pulmonary valvular competence and reduction of size and length of aneurysmal pulmonary arteries.

Although isoproterenol is the sympathomimetic amine used most often to augment cardiovascular function in infants and children, little is known about the hemodynamic effects of this drug on the immature cardiovascular system. To compare the hemodynamic effect of isoproterenol in the young animal with that in the mature animal, we infused the drug into 11 puppies of 12-38 days of age, 12 puppies of 56-89 days of age and 10 adult beagle dogs. The animals were chronically instrumented and nonsedated during the study. Isoproterenol was infused in doses of 0.05, 0.125, 0.25 and 0.5 microgram/kg/min. Isoproterenol decreased systemic arterial mean blood pressure, increased heart rate and had no effect on renal blood flow in all three groups of animals. While cardiac output was increased and systemic vascular resistance decreased in the adult dogs, neither changed in puppies. Stroke volume increased slightly in adult dogs, but decreased in puppies. This refractoriness to change of cardiac output in immature dogs may be a function of elevated resting cardiac output, developmental changes of contractility or ventricular compliance or developmental changes of vascular smooth muscle responsiveness.