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Unilateral lobar pulmonary agenesis in sibs
  1. SIV FOKSTUEN,
  2. ALBERT SCHINZEL
  1. Institut für Medizinische Genetik, Universität Zürich, Rämistrasse 74, 8001 Zürich, Switzerland
  1. Professor Schinzel,schinzel{at}medgen.unizh.ch

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Editor—Pulmonary agenesis is an extremely rare congenital malformation which has been classified morphologically by the extent to which bronchopulmonary tissue is absent. Spencer1 divided pulmonary agenesis into (1) bilateral complete agenesis, (2) unilateral agenesis with (a) complete absence of bronchi, (b) rudimentary bronchus present but no pulmonary tissue, or (c) poorly developed main bronchus with poorly organised parenchyma, and (3) lobar agenesis. The incidence of this rare condition is not known. According to the calculations of Mardini and Nyhan2it may range between 0.0034 and 0.0097%. Familial pulmonary agenesis is even more uncommon. We found only two published reports of affected sibs.3 4 One pair of sibs had agenesis of the right upper and middle lobes3 and the other pair suffered from bilateral agenesis.4

The paucity of such observations prompts us to report another instance of pulmonary agenesis in a brother and a sister of healthy and non-consanguineous parents. The family history was unremarkable and both pregnancies were uneventful. The mother had no infections and denied any abuse of teratogenic substances. Chromosomes were not studied in either case.

The first child, a female, was delivered spontaneously at term with a birth weight of 3500 g. Birth length and head circumference were not recorded. The mother was 27 years old and the father 36 years old. At the age of 11 months she was admitted to hospital because of stridor and dyspnoea. The interpretation of the chestx ray was spontaneous pneumothorax on the left side with dextrocardia and compression atelectasis of the right upper lobe. Over the following years, she suffered from asthmatic bronchitis secondary to recurrent infections. Psychomotor development was within the normal range. Pulmonary re-evaluation at the age of 12 years, including bronchoscopy, showed a suspicion of partial agenesis of the right lung. At the age of 24 years her bronchial asthma deteriorated. Ten years later she was admitted to hospital because of decompensated cor pulmonale. Since then she has had repeated episodes of acute cardiopulmonary decompensation. She died at the age of 42 years following a further episode of decompensated cor pulmonale. Necropsy disclosed dextrocardia, agenesis of the middle lobe, aplasia of the upper lobe, and hypoplasia of the lower lobe of the right lung with hypoplasia of the right pulmonary artery.

The younger brother was born at term six years after his sister. Birth weight was 2980 g and length 48 cm. From early on, tachypnoea, dyspnoea, and feeding difficulties were noticed. Physical examination showed diminished breath sounds on the right upper side with the cardiac impulse shifted to the right side and a systolic heart murmur. Chest x ray (fig 1) showed no heart on the left side but a hypervoluminous left lung with prominent vasculature. The carina projected at the level of T6 and the right main stem bronchus seemed sharply cut off at its lower end. The right side was reduced in volume and seemed almost completely opacified except for a median lucency from herniated left lung. No skeletal abnormalities were visible. At the age of 7 months, he was treated for right sided pneumonia. Two months later he was admitted to hospital because of severe asthmatic bronchitis. There was a rapid deterioration leading to respiratory arrest. Necropsy disclosed agenesis of the right upper lobe, partial atelectasis of the remaining right lung, severe hypoplasia of the right pulmonary artery, dextrocardia, hypertrophy of the right atrium and ventricle, a patent foramen ovale, and a defect in the upper part of the ventricular septum. Furthermore, there was bilateral meatal ureteral stenosis with hydroureters and hydronephrosis, a small accessory spleen, and mild hydrocephalus internus.

Figure 1

Chest x ray of patient 2 showing an almost completely opacified right chest.

In the review on agenesis of the lung by Gilbert and Opitz,5 approximately 200 patients with unilateral involvement were found. In 70% of cases the left side was involved and males predominated over females. Associated malformations were present in 50% of the cases. Major anomalies included congenital heart defects, spinal anomalies, anal atresia, tracheo-oesophageal atresia, spleen anomalies, diaphragmatic hernia, renal anomalies, cleft palate, and limb and facial defects.6 Cunningham and Mann7 found that ipsilateral anomalies of the first and second branchial arch or radial ray defects or both are the most common overt malformations. In contrast to bilateral agenesis of the lung, unilateral absence is compatible with life, but has a high mortality, most likely because of the presence of associated malformations/infections of the remaining lung tissue. Infants with right sided lung agenesis have a higher mortality and die significantly earlier. This is probably related to a more severe mediastinal and cardiac displacement into the right chest.8 Survival to adult age is possible as shown in our patient 1 or in a case with agenesis of the left lung detected at necropsy in a 72 year old woman.9

Most cases present in the neonatal period with non-specific respiratory symptoms such as cyanosis, tachypnoea, dyspnoea, stridor, or feeding difficulties. Physical examination may be normal, but can show diminished breath sounds on the affected side with the heart and mediastinum shifted to the ipsilateral side. Chestx rays which show a homogeneous density in one hemithorax suggest the diagnosis, but endoscopic, bronchographic, and echocardiographic studies, as well as computerised tomography are necessary for confirmation.

The aetiology of lung agenesis remains unknown. According to the possible associated anomalies, this rare malformation has been discussed as part of the VACTERL association10 and Goldenhar syndrome.11 Warkany et al 12 induced pulmonary agenesis of one lung, but also other major malformations of the eyes and cardiovascular and urogenital systems by maternal gestational vitamin A deficiency in rats. Chromosomes were not studied in the older reports. However, Sayet al 13 described a patient with agenesis of the left lung who had a duplication of the region 2p21→p24 resulting in a partial trisomy 2p and Schoberet al 14 reported a case with left pulmonary agenesis and associated malformations in partial trisomy 2p (p21→pter) and 21q (pter→q21) owing to an unbalanced segregation of a maternal reciprocal translocation t(2;21). The minimal overlapping region of duplication includes the segment 2p21→p24. Therefore, Say and Carpenter15 suggested studying patients with pulmonary agenesis for the presence of such a duplication. Unilateral agenesis has also been documented in trisomy 1816 and in trisomy of a C group chromosome.17

Pulmonary agenesis in twins was reviewed by Lehmann.18 In female monozygotic twins, one sister had agenesis of the left and the other agenesis of the right lung.19 Yount20documented agenesis of the right lung in concordantly affected monozygotic twins, while others found pulmonary agenesis in only one of monozygotic twins.21 22 Concordant occurrence of congenital malformations in monozygotic twins does not necessarily imply a genetic cause and vice versa.23

The only clear indication of possible autosomal recessive inheritance of unilateral pulmonary agenesis so far was the family reported by Brimblecombe.3 The healthy parents were first cousins and had two normal children and two affected girls with agenesis of the right upper and middle lobes. Our report is the second case of unilateral lobar pulmonary agenesis in sibs and supports the hypothesis of an autosomal recessively inherited disease. Alternatively, our observation could be explained by an extrinsic origin (infection during pregnancy, drugs, environmental substances, etc), for which, however, we do not have the slightest proof. Further support for the presence of a rare autosomal recessive gene for unilateral pulmonary agenesis comes from the observation of Mardini and Nyhan,2 who documented parental consanguinity in four patients; two patients had right upper and middle lobe agenesis and two presented with left sided pulmonary agenesis. All had associated congenital heart defects and three infants presented with abnormalities of the thumb. Podlechet al,4 who observed a family with one healthy and two affected children with bilateral agenesis of the lung, concluded that an autosomal recessive mode of inheritance could also be valid for bilateral pulmonary agenesis. Embryogenesis of human lung development is poorly understood, but in mice Fgf10 (fibroblast growth factor 10) is an important regulator of limb and lung formation.24 Homozygous Fgf10 deficient mice die at birth owing to lack of lung development.

In conclusion, our report suggests an autosomal recessive gene or genes which cause pulmonary agenesis with optional heart, kidney, and other defects. In such cases, a 25% recurrence risk should be considered in genetic counselling.

Acknowledgments

We are grateful to Dr U Willi for interpretation of the chestx ray.

References

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