Jacobs syndrome

Sharon Calaman MD, A Jacobs MD, G Crooke MD, A Racine MD, PhD, J Glickstein MD, J Weingarten-Arams MD FCCP--Department of Pediatrics, Divisions of Pediatric Critical Care & Pulmonary Medicine and Cardiology, Department of Cardiothoracic Surgery, Albert Einstein College of Medicine, Children's Hospital at Montefiore, Bronx, NY

Introduction: Marfan syndrome is a disorder of connective tissue characterized by variable phenotypes and autosomal dominant inheritance with frequent spontaneous mutation. Marfan syndrome involves multiple organs; commonly the skeletal, ocular and cardiovascular systems. However, the pulmonary, skin and integument, and central nervous systems are also involved. Though infrequently diagnosed in the perinatal period, the syndrome carries a very high morbidity and mortality, with infants primarily dying of cardiovascular manifestations.

Case Presentation: A 5 week old infant presented with acute respiratory distress, hepatomegaly, and failure to thrive. She was born at 38 weeks gestation and had physical characteristics consistent with Marfan Syndrome: arachnodactyly, flexion contractures, skin and joint hypermobility, distinctive facies, high arched palate and large floppy ears. Echocardiogram demonstrated dilation of all cardiac chambers; tricuspid and mitral valve prolapse and aortic root effacement. Ophthalmologic exam, chromosomes and urine homocysteine were normal. CXR showed the liver bulging into the right hemithorax. She was discharged but required admission at 5 weeks of age with symptoms of congestive heart failure. On anticongestive therapy, repeat echocardiography demonstrated progression of the tricuspid, mitral, and aortic insufficiency. In addition, an echodense area in the right ventricular outflow tract was seen. Abdominal sonogram showed the superior aspect of the liver bulging into the right hemithorax with appropriate movement with respirations suggestive of eventuation of the diaphragm. The liver appeared to be compressing the right lung and shifting the heart to the left. Her respiratory distress persisted despite control of her cardiac disease and was ascribed to decreased lung volume. MRI was performed to better elucidate the diaphragmatic and cardiac abnormalities. The liver was herniating through the right diaphragm causing compression of the right lung. The cardiac images confirmed previous findings with the mass lesion consistent with a lipoma. At 9 weeks of age she had respiratory failure with RSV and shifting lobar atelectasis requiring intubation and mechanical ventilation. Upon recovery from bronchiolitis she underwent surgical repair of the right diaphragmatic hernia which resulted in normal lung expansion and heart position. She however failed several extubation attempts due to recurrent left lung collapse. She was diagnosed with left main stem bronchomalacia by flexible bronchoscopy and remained on mechanical ventilation. However, she developed recurrent hyperinflation of the right lung with emphysematous changes and mediastinal shift. The tricuspid regurgitation worsened and the frequency of respiratory decompensation increased. At 3 1/2 months of age, with her family at her side, support was withdrawn.

Discussion: Marfan syndrome (MS) is well described in older children and adults, however, it is infrequently diagnosed early in infancy. In the absence of a family history, the requirements for diagnosis include skeletal abnormalities-arachnodactyly, high arched palate and abnormal joint mobility--and manifestations in two or more other organ systems (usually ocular and cardiovascular). Pulmonary findings including spontaneous pneumothorax and apical blebs are uncommon and usually present late in life. Diaphragmatic hernias have also been described. The pathology associated with MS is a defect in fibrillin metabolism. The fibrillin 1 (FBN1) gene on chromosome 15q21.1 has been associated with this pattern of abnormalities. Our patient had many of the cardiac manifestations of MS including aortic root dilatation and aortic insufficiency, mitral regurgitation and severe tricuspid valve prolapse and regurgitation. Congestive heart failure was well controlled, but her respiratory symptoms persisted despite repair of the right diaphragmatic hernia. Different from other infants with severe cardiovascular symptoms of MS, our patients's life threatening manifestations were bronchomalacia and emphysema. The finding of bronchomalacia has only been reported in one other patient.[1] This patient also died at 3 months of age. The mean age of survival in all patients with Marfan syndrome is 40 years of age. It seems there is a cohort of patients in whom the disease is diagnosed early in life who have severe cardiorespiratory manifestations, limited life expectancy and no family history. It is likely that different mutations in the FBN1 gene account for the severe infantile phenotypes.

Conclusion: Marfan syndrome has heterogeneous clinical expression with a broad spectrum of organ system involvement and age at diagnosis. Although the cardiovascular manifestations are the usual cause of mortality and morbidity, this case highlights that pulmonary manifestations are also significant.

Reference

[1] Gross DM, et al. Severe Perinatal Marfan Syndrome. Pediatrics 1989:84 (1): 83-9

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