Hypoplastic left heart syndrome is one of the most severe types of cardiovascular malformations. Clinical management and palliation of these patients carries its own difficulties and challenges, which can be significantly exacerbated by associated genetic disorders and extracardiac anomalies. There are associated anomalies in about one-quarter of afflicted patients.1 Physicians who care for children with these lesions, therefore, must always remain aware of the potential for associated anomalies, which can complicate the care of these children. In this report, we describe an infant with both hypoplastic left heart syndrome and Type I spinal muscular atrophy.
Case report
The infant, born at full term, was a male weighing 3.7 kilograms. Initially vigorous, he became tachypnoeic in the delivery room, with a peripheral saturation of oxygen of 90 to 93%. After seven hours of life, the infant had become more tachypnoeic, with intermittent oximetric measurement of 70% despite supplemental oxygen.
Examination revealed an active praecordium, a normal first heart sound, a single second heart sound, and a Grade 2 systolic ejection murmur heard best at the lower left sternal border. The lungs were clear, with shallow respirations and no retractions. There was no hepatomegaly. Pulses were weak in all limbs. A chest radiograph revealed bilateral, interstitial fluid. Serial measurements of arterial blood gases included partial pressures of oxygen of approximately 150 torr, with 100% oxygen administered, and mild metabolic acidosis.
Echocardiography demonstrated critical mitral valvar stenosis, aortic valvar atresia, a hypoplastic aortic arch with a discrete coarctation, patency of the arterial duct, and a small but patent oval foramen. The infant was intubated and inspired oxygen was reduced to 21%. Prostaglandins and inotropic support were initiated prior to transfer to a tertiary medical facility.
At six days of age, the patient underwent the first stage of functionally single ventricular palliation, consisting of a Damus–Kaye–Stansel procedure with a conduit placed from the right ventricle to the pulmonary arteries and reconstruction of the aortic arch. The infant was extubated, and several days later experienced an aspiration event which necessitated reintubation. The conduit from the right ventricle needed to be replaced by a modified Blalock–Taussig shunt to the right pulmonary artery approximately one month later due to mechanical compression of the conduit.
Following the second stage of palliative surgery, the infant was changed from mechanical ventilation to mechanical assistance with positive airway pressure, but he could not be weaned from the latter support. Global hypotonia was noted on examination. A biopsy demonstrated marked atrophy of skeletal muscular fibres without evidence of a mitochondrial or storage disorder. Cytogenetic analysis revealed a normal, male karyotype. At this time, a specific etiology for the hypotonia was not identified.
The infant remained hospitalized for two more months until a cardiac catheterization was performed in preparation for construction of a bidirectional cavopulmonary anastomosis. This demonstrated acceptable hemodynamic measurements, including a transpulmonary gradient of 8 millimetres of mercury, and a calculated pulmonary vascular resistance of 1.2 Wood units per metre squared. Angiography demonstrated even distribution of contrast from the aorto-pulmonary shunt into the right and left pulmonary arteries. There were no obvious stenoses of the pulmonary vasculature, or significant aorto-pulmonary collateral arteries, and no residual aortic coarctation. We proceeded, therefore, to construct the cavopulmonary anastomosis. Following this, the patient failed several attempts at extubation and weaning from mechanical ventilation. Eventually, a tracheostomy was required.
Approximately one month later, the results of molecular genetic testing became available, and revealed homozygous deletions in exons 7 and 8 of the survival motor neuron gene on chromosome 5q, consistent with the diagnosis of spinal muscular atrophy. The infant was eventually discharged from the hospital to home in hemodynamically stable condition, with a mechanical ventilator. He died at 8 months of life.
Discussion
Spinal muscular atrophy is a disorder of the motor neurons characterized by degeneration of the anterior horn cells of the spinal cord, leading to progressive weakness and atrophy of muscles in a symmetrical pattern. Occasionally, the brainstem is involved. Affected individuals typically have a normal mental state, and normal cognitive development.
Spinal muscular atrophy is classified into four major types by the International Spinal Muscular Atrophy Consortium.2 So-called Type I, also known as Werdnig–Hoffman disease, is the most common, most homogeneous, and the most severe form, usually presenting within the first 6 months of life. It follows an autosomal recessive inheritance pattern. Affected children are unable to sit without support, and have significant respiratory compromise secondary to involvement of the diaphragm and intercostal muscles. Death, secondary to respiratory distress, is typical within the first eighteen months of life.
Type II, or Dubowitz disease, is characterized by onset within the first 2 years of life. Affected individuals are able to sit without support, but are never able to walk. This is a more heterogeneous form of spinal muscular atrophy. Prognosis is variable and depends upon the degree of respiratory involvement. The third type, also known as Kugelberg–Welander disease, is a milder and more chronic form, with symptoms beginning after 2 years of age. Affected children can stand and walk without assistance, at least initially, and do not develop respiratory distress. This type is also more heterogeneous and usually follows an autosomal recessive pattern. Autosomal dominant patterns have been described. The fourth type is the mildest, with onset typically in young adulthood.
Spinal muscular atrophy is the second most frequent autosomal recessive disease in Caucasians, with an incidence of 1 per 6000 to 10,000 live births, and a carrier frequency of from 1 in 34 to 1 in 50.3–5 In over nine-tenths of afflicted individuals, all types of the disease are linked to the same region of chromosome 5q.6, 7 This region contains the survival motor neuron gene, which may have areas of inversion, duplication, or deletion.8
Hypoplastic left heart syndrome is known to be associated with certain genetic conditions, including Turner's syndrome, or 45 XO, Jacobsen syndrome characterized by terminal deletion of chromosome 11q, Trisomy 13 and 18, Holt–Oram syndrome, and duplication of chromosome 12. Furthermore, there is an increased incidence of left-sided obstructive lesions in first-degree relatives of infants with hypoplastic left heart syndrome, including a twelve-fold increased risk of bi-commissural aortic valve, and a five-fold increased risk of any left-side lesion in siblings of these patients.9, 10 Another possible genetic linkage has been suggested by recent investigation into migration from the cardiac neural crest and development of the ventricular outflow tracts.10 There have been reports of 2 and 3 siblings with hypoplastic left heart syndrome that are suggestive of an autosomal recessive pattern. Multiple investigations, nonetheless, support a multi-factorial mode of inheritance.6, 7, 10 Although it is well recognized that hypoplastic left heart syndrome is frequently associated with significant extracardiac abnormalities, in our review of the literature we were unable to find other reported patients with both hypoplastic left heart syndrome and spinal muscular atrophy. Clinicians must remain aware of such genetic disorders, which may considerably alter the clinical management of patients with congenital heart disease.
Acknowledgment
We express our thanks to Sydney P. Primis, Division of Pediatric Critical Care, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.
