Natural History of MYH7-Related Dilated Cardiomyopathy.

BACKGROUND: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers. RESULTS: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare.

Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature.

OBJECTIVE: Atrial septal defect (ASD) is the second most common congenital heart defect (CHD) and is observed in families as an autosomal dominant trait as well as in nonfamilial CHD. Mutations in the NKX2-5 gene, located on chromosome 5, are associated with ASD, often combined with conduction disturbances, cardiomyopathies, complex CHD, and sudden cardiac death as well. Here, we show that NKX2-5 mutations primarily occur in ASD patients with conduction disturbances and heritable ASD. Furthermore, these families are at increased risk of sudden cardiac death. RESULTS: We screened 39 probands with familial CHD for mutations in NKX2-5 and discovered a novel mutation in one family (2.5%) with ASD and atrioventricular block. A review of the literature revealed 59 different NKX2-5 mutations in 202 patients. Mutations were significantly more common in familial cases compared to nonfamilial cases (P = 7.1 × 10(-9) ). The majority of patients (74%) had ASD with conduction disturbance. Nineteen patients (15%) of 120 with familial ASD and conduction disturbance died from sudden cardiac death of which nine (8%) were confirmed mutation carriers, and 10 were possible carriers. CONCLUSIONS: NKX2-5 mutations mainly occur in familial CHD, the signature phenotype is ASD with conduction disturbances and mutation carriers are at increased risk of sudden cardiac death. We suggest that familial ASD patients should be screened for NKX2-5 mutations and, if they are mutation carriers, implantation of an implantable cardioverter-defibrillator should be considered in these patients.

N-Terminal Pro-B Type Natriuretic Peptide as a Marker of Bronchopulmonary Dysplasia or Death in Very Preterm Neonates: A Cohort Study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a serious complication of preterm birth. Plasma N-terminal pro-B type natriuretic peptide (NT-proBNP) has been suggested as a marker that may predict BPD within a few days after birth. OBJECTIVES: To investigate the association between NT-proBNP day three and bronchopulmonary dysplasia (BPD) or death and further to assess the impact of patent ductus arteriosus (PDA) on this association in neonates born before 32 gestational weeks. METHODS: A cohort study of 183 neonates born before 32 gestational weeks consecutively admitted to the Neonatal Intensive Care Unit, Aarhus University Hospital, Denmark. On day three plasma samples were collected and echocardiography carried out. NT-proBNP was measured by routine immunoassays. The combined outcome BPD or death was assessed at 36 weeks of postmenstrual age. Receiver operator characteristic (ROC) analysis was performed to determine the discrimination ability of NT-proBNP by the natural log continuous measure to recognize BPD or death. The association of BPD or death was assessed in relation to natural log NT-proBNP levels day three. RESULTS: The risk of BPD or death increased 1.7-fold with one unit increase of natural log NT-proBNP day three when adjusted for gestational age at birth (OR = 1.7, 95% CI 1.3; 2.3). The association was found both in neonates with and without a PDA. Adjusting for GA, PDA diameter, LA:Ao-ratio, or early onset sepsis did not change the estimate. CONCLUSION: We found NT-proBNP to be associated with BPD or death in very preterm neonates. This association was not only explained by the PDA. We speculate that NT-proBNP may help the identification of neonates at risk of BPD as early as postnatal day three.

[Molecular genetic diagnostics of the cause of ventricular arrhythmias in children]. / Molekylærgenetisk diagnostik af årsag til ventrikulær arytmi hos et barn.

Andersen-Tawil syndrome (ATS) is a rare hereditary multi--system disorder consisting of a triad of symptoms, ventricular arrhythmias, periodic paralysis and dysmorphic features. The syndrome is associated with a loss of function mutation in the gene KCNJ2, which encodes the Kir2.1 inward rectifier potassium channel. We represent a case story of a 15-year-old girl who had unexplained arrhythmias for six years. Molecular genetic screening with a 75-heart-panel revealed a pathogenic KCNJ2 missense mutation. The patient was diagnosed with ATS.

Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3.

OBJECTIVE: To assess the association between a patent ductus arteriosus (PDA) on day 3 of life and severe morbidity and mortality. DESIGN: Cohort study. SETTING: Neonatal Intensive Care Unit, Aarhus University Hospital, Denmark. PATIENTS: All neonates with a gestational age less than 32 weeks admitted from 2010 to 2012. INTERVENTIONS: All neonates (n=183) were routinely screened with echocardiography for PDA on day 3 of life. Information on baseline characteristics and outcome was collected by structured coding sheets and medical records. MAIN OUTCOME MEASURES: The association among PDA diameter and pulmonary haemorrhage, intraventricular haemorrhage (IVH), necrotising enterocolitis, bronchopulmonary dysplasia (BPD), death, and the composite outcome of death or severe morbidity was assessed. RESULTS: In neonates, born prior to 28 gestational weeks, a PDA on day 3 of life was associated with a threefold increase in odds of death or severe morbidity compared with neonates without PDA (OR=3.4; CI 1.1 to 11). The odds were highest in neonates with a large PDA (diameter ≥1.5 mm). Neonates with a large PDA were also found to have increased odds of IVH (OR 4.2; CI 1.3 to 14) and BPD (OR 3.7; CI 1.0 to 14) compared with neonates with no PDA. CONCLUSIONS: In neonates born with a gestational age below 28 weeks the presence of a PDA on day 3 of life was associated with adverse outcome; this association was even more pronounced with a large PDA. Thus, early echocardiography may facilitate the identification of neonates suitable for a targeted approach to intervention in future randomised controlled trials.

Reversibility of acute intermediate phase bilirubin encephalopathy.

AIM: To show the potential for reversing acute intermediate to advanced phase bilirubin encephalopathy. METHODS: Case studies. RESULTS: Six extremely jaundiced infants had symptoms of intermediate to advanced phase acute bilirubin encephalopathy. The infants were treated aggressively. Two patients had brain magnetic resonance imaging showing increased signals in the globus pallidus. On follow-up, all infants are neurologically normal. CONCLUSIONS: Intermediate-to-advanced stage acute bilirubin encephalopathy may occasionally be reversible. These cases provide a strong argument in favour of rapid and aggressive intervention in infants presenting with extreme jaundice and neurological symptoms.

Obstetric outcome in Danish children with a validated diagnosis of kernicterus.

OBJECTIVE: To validate the use of the kernicterus diagnosis in a clinical register in Denmark and to describe occurrence and obstetric outcome in children with a validated kernicterus diagnosis. DESIGN: Population-based cohort study. SETTING: Denmark. POPULATION: All children born from 1 January 1994 to 31 December 2003. METHODS: We established a national population-based cohort of children with a diagnosis of kernicterus based on data obtained from a mandatory national register and from a clinically established cohort. Information on obstetric outcome and child development was obtained from the registers and from the medical records. MAIN OUTCOME MEASURES: Validation of the kernicterus diagnosis and description of obstetric and long-term outcomes in children with kernicterus. RESULTS: We found 15 children with a diagnosis of kernicterus in the Danish National Hospital Register and eight children with a diagnosis of kernicterus in a clinically established cohort. A total of nine children had a validated diagnosis of kernicterus which leads to a cumulative incidence of kernicterus in Denmark of 1.3/100.000 newborns. Most of the nine children experienced suboptimal growth but otherwise normal pregnancy and delivery outcomes. All except one child developed severe neurological impairment in childhood. CONCLUSION: Kernicterus is still an existing disease in Denmark. The children with kernicterus experienced overall normal pregnancy and delivery outcomes but long-term outcomes were affected. Validation of the kernicterus diagnosis in the hospital register was necessary.

[Adrenal insufficiency during inhaled corticosteroid treatment in a child with asthma]. / Binyrebarkinsufficiens under steroidinhalationsbehandling hos et barn med astma.

We report a 12 year-old asthmatic girl with adrenal insufficiency during inhaled corticosteroid treatment. Symptoms, investigations and treatment are discussed.

Surveillance of extreme hyperbilirubinaemia in Denmark. A method to identify the newborn infants.

AIM: To describe the incidence of infants born at term or near-term with extreme hyperbilirubinaemia. METHODS: The study period was between 1 January 2002 and 31 December 2005, and included all infants born alive at term or near-term in Denmark. Medical reports on all newborn infants with a total serum bilirubin concentration (TSB) > or = 450 micromol/L were obtained by linking laboratory data to the unique Danish personal identification number. RESULTS: In total, 113 infants were included, that is, an incidence of 45/100,000 live births. Thirty-seven infants presented in hospital, 2 after home birth and the others after having been discharged. The maximum TSB was 485 (450-734) micromol/L (median [range]) and appeared latest amongst those infants admitted from home, but was not different from the maximum TSB of the nondischarged infants. Forty-three infants had symptoms of early-phase acute bilirubin encephalopathy; one infant had advanced-phase symptoms. Four infants received an exchange transfusion. ABO blood group incompatibility was present in 52 infants. Thirty-seven infants were of non-Caucasian descent. CONCLUSION: A method to obtain the national epidemiological data is presented. The observed incidence of extreme hyperbilirubinaemia is higher than previously reported in Denmark. This is mainly due to a very sensitive method of identifying the study group.

[Incidence of kernicterus in newborn infants in Denmark]. / Genoptraeden af kernikterus hos nyfødte børn i Danmark.

INTRODUCTION: Kernicterus is an infrequent but serious complication of neonatal hyperbilirubinaemia. The purpose of this investigation was to describe the incidence of the condition in Denmark, its causes and its prevention. A follow-up was done to illustrate the serious consequences of this disease. METHODS: The study included all infants in Denmark born term or near term, with symptoms of classical kernicterus, in the period from 1977 to 2003. RESULTS: From 1977 to 1993, no cases of kernicterus were reported. In the following period, from 1994 to 2002, eight patients were registered. The maximum plasma total bilirubin concentration was 531-745 mol/l. The aetiology was determined in two infants: spherocytosis and galactosaemia. Most likely, ABO blood type immunization was the reason in four cases. In two cases, the aetiology was unknown. Seven infants had symptoms of chronic bilirubin encephalopathy. One child had only minor signs of this condition. Seven were boys, and six infants were of Caucasian descent. Two of the infants died. CONCLUSION: The incidence of kernicterus in Denmark is increasing, as in the rest of the Western world; this after a period of at least 20 years in which no cases were reported. A change in the assessment of the risk and inadequate knowledge of the serious consequences of bilirubin encephalopathy may be explanations. Through information and education of health personnel, it is possible to provide sufficient information to parents, perform screening procedures and commence therapy at the appropriate time. This could possibly contribute to a reduction in the incidence of the disease and its serious consequences.

[Stress hyperglycemia in a child with severe acute gastroenteritis]. / Stresshyperglykaemi hos et barn med svaer akut gastroenteritis.

A case of a two years and ten months old girl with severe acute gastroenteritis, dehydration, and hyperglycaemia is described. Transient hyperglycaemia is a common clinical finding in children under stress. We discuss the distinction between hyperglycaemia as a prediabetic state and that as a physiological response to stress during acute illness.