Lung Agenesis, Congenital Heart Defects, And Thumb Anomalies Syndrome
Description
The Mardini-Nyhan association comprises uni- or bilateral lung agenesis, complex cardiac defects, particularly total anomalous pulmonary venous return (TAPVR), and thumb abnormalities (summary by Hastings et al., 2009).
Clinical FeaturesBoxer et al. (1978) reported a female infant with agenesis of the left lung and total anomalous pulmonary venous return. She was noted to have tachypnea on day 2 of life. Chest radiographs showed absence of the left lung with a large right lung and mediastinal shift to the left. At age 3.5 months, she was admitted with severe respiratory distress and heart murmur, and was found to have total anomalous pulmonary return to the right atrium, absent left pulmonary artery, and small patent ductus arteriosus, associated with pulmonary artery hypertension. Surgery was successful. Additional congenital malformations were not noted.
Mardini and Nyhan (1985) reported 4 unrelated Saudi Arabian infants, all born of consanguineous parents, with unilateral lung agenesis, ipsilateral absence of the pulmonary artery, and atrial septal defect (ASD). Three patients had different ipsilateral malformations of the thumb, including a triphalangeal and angulated thumb, preaxial polydactyly, and short first metacarpal. Two patients had ipsilateral hemivertebrae. All were symptomatic in infancy, with cyanosis and respiratory insufficiency. In 3, symptoms improved during 2 to 6 years of follow-up. One, who died at age 1 month, had a unique combination of agenesis of the right upper and middle lobes and a hypoplastic right lower lobe supplied by systemic arteries from below the diaphragm. This patient also had complex cardiac defects, including TAPVR, tricuspid regurgitation with severe right atrial dilatation, and patent ductus arteriosus. Two patients had dysmorphic facial features. The coexistence of these malformations suggested interference with embryologic development in the fourth week of fetal life.
Hastings et al. (2009) reported 3 unrelated patients with the Mardini-Nyhan association. The first patient was found to have left lung agenesis and abnormal heart positioning at 20 weeks' gestation. The apex of the heart was rotated and pointing back and up toward the left shoulder. At birth, she showed respiratory distress, which stabilized after a week. She had complex cardiac malformations, including aortic arch hypoplasia, atrial septal defect, absence of the left pulmonary artery, and total anomalous pulmonary venous return with the right pulmonary veins draining into the coronary sinus. The TAPVR and ASD were surgically corrected. She was also noted to have a proximally placed left thumb. Development was normal at age 9 months. An older sister, who had died unexpectedly at age 3.5 months from bowel perforation, had multiple congenital heart defects, including coarctation of the aorta, bicuspid aortic valve, persistent left superior vena cava draining into the right atrium via a dilated coronary sinus, perimembranous ventricular septal defect (VSD), and dysplastic tricuspid and pulmonary valves. She also had bilateral incomplete lobation of the lungs. The second proband was noted to have diaphragmatic hernia and atrioventricular septal defect (AVSD) at 21 weeks' gestation. At birth, she showed respiratory and cardiac insufficiency, and she died at age 4.5 months. Detailed imaging showed agenesis of the left lung with absence of left pulmonary veins, shifting of the heart into the left hemithorax with clockwise rotation, and a dilated right atrium and ventricle. There was partial anomalous pulmonary venous drainage; the right upper pulmonary veins drained into the right atrium, whereas the right lower pulmonary vein was attenuated between the right pulmonary artery and aorta and drained into the left atrium. She also had left preaxial polydactyly with an additional rudimentary thumb. A previous pregnancy had resulted in miscarriage at 15 weeks. The third proband had right lung agenesis and AVSD detected at 20 weeks' gestation. She was stable at birth, but showed hypoplastic thumbs, with only 1 phalanx each. Molecular studies excluded mutations in selected coding exons of the TBX5 (601620), SALL4 (607343), and SALL1 (602218) genes in this patient. None of the 4 patients had pathogenic microdeletions or duplications on analysis by array CGH. Hastings et al. (2009) concluded that the triad of pulmonary agenesis, congenital cardiac defects, and radial ray anomalies represents a distinct autosomal recessive entity.
Jaiman et al. (2016) reported a female fetus, conceived of unrelated parents of Indian descent, with LACHT syndrome. There was intrauterine fetal demise at 36 weeks' gestation. Examination showed overall growth restriction and agenesis of the right lung with absence of the ipsilateral pulmonary artery. Cardiac anomalies included hypoplastic left heart, patent foramen ovale, ventricular septal defect, and persistent left superior vena cava opening into the coronary sinus. There was also an abnormal right thumb with rudimentary first phalanx and an obliquely placed first metacarpal. The placenta showed 10% infarction, diffuse chorangiomatosis, massive perivillous fibrin deposition, and villous fibrinoid necrosis. Jaiman et al. (2016) concluded that the fibrin deposition in the placenta caused intrauterine death, and suggested that the placenta should be examined in similar cases.
InheritanceAll 4 cases reported by Mardini and Nyhan (1985) were born of consanguineous parents, suggesting autosomal recessive inheritance.