Eur J Pediatr (1994) 153:460-463 �9 Springer-Verlag 1994

B. Frey A. F le ischhauer M. Gersbach

Familial isolated pulmonary hypoplasia: a case report, suggesting autosomal recessive inheritance

Received: 27 July 1993 Accepted: 21 September 1993

B. Frey (Y:~) Intensive Care Unit, University Children's Hospital, Inselspital, CH-3010 Berne, Switzerland A. Fleischhauer Department of Pathology, University Hospital, Inselspital, CH-3010 Berne, Switzerland

M. Gersbach Department of Medical Genetics, University Children's Hospital, Inselspital, CH-3010 Berne, Switzerland

A b s t r a c t The except ional observa- t ion o f a heal thy couple with two girls and a boy suffering f rom pul- monary hypoplas ia and two normal chi ldren is reported. The affected in- fants d ied 1, 2 and 20 h after birth respectively. No other mal format ions were found. His to logica l f indings suggest that the underdeve lopment of the lungs has its or igin at a more p rox imal level than the terminal bronchioles . Au tosoma l recess ive inheri tance is suggested.

K e y w o r d s Pu lmonary hypoplas ia Fami l ia l �9 Newborn

Introduction

Pulmonary hypoplas ia occurs commonly in associa t ion with congeni ta l d iaphragmat ic hernia, o l igohydranmios (most ly related to renal dysfunct ion) , skeletal dysplas ias , fetal hydrops, mal format ions of the CNS and neuromus- cular diseases [2, 5, 8]. Pr imary isola ted bi la teral pul- monary hypoplas ia is rare [5, 6, 8], and famil ia l occur- rence except ional [1, 3, 5]. We report a fami ly with two proven and one suspected isola ted pu lmonary hy- poplasias.

Case reports

Case 1

The first child was a girl, born in 1983 to a 21-year-old mother and a 25-year-old father. Pregnancy was uneventful. Two ultrasono- graphic examinations in the 14th and 32nd week of gestation re- spectively, revealed normal amounts of amniotic fluid. Delivery was at term and normal, except for fetal bradycardia. Birth weight (2450 g) was below the 10th percentile, whereas length (48 cm) and head circumference (34 cm) were within normal limits. The Apgar score was 1/1/1 after 1, 5 and 10 min respectively. The baby was pale and needed immediate intubation because of absent spon-

taneous respiration. The capillary blood pH taken 40 min after de- livery was 6.9. After a short period of spontaneous breathing the child became asystolic at 60 min. Resuscitation was successful, but a second cardiac arrest occurring at 2 h of life was fatal. The X-ray of the whole baby showed normal osseous structures, a right-sided pneumothorax, bilateral elevation of the diaphragm and short hor- izontal diameters of the apex of the lungs in relation to the ab- domen (Fig. 1 a).

Case 2

The second child, a boy, was born in 1984 at term. Pregnancy had been normal without ultrasonographic signs of oligohydramnios. Already 1 h before birth, the cardiotocogram showed late deceler- ations. The infant's weight (2950 g), length (49 cm) and head cir- cumference (34 cm) were normal. The boy was pale and cyanotic. Despite of normal tone, his respiration was slow and superficial. After intubation there was high resistance to inflation, and no tho- racic expansions could be obtained. Transiently the boy's skin- colour became rosy, but 1 h postpartum he died from irreversible cardiac arrest. His karyotype was normal.

Cases 3 and 4

The third and fourth pregnancies (1986 and 1988) ended in normal deliveries of healthy boys with standard birth weights and no pul- monary problems.

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F i g . l a Babygram of case 1; small lungs, pneumothorax on the right, diaphragmatic eleva- tion. b Chest X-ray of case 5 after drainage of a pneumo- thorax on the left; small lungs, pleural effusion on the right

a b

Table 1 Summary of autopsy Case findings Gestational

age (weeks)

1 40 2 39 " Related to gestational age

b means + 1 S.D 5 38

Combined lung weight (g) Lung/heart ratio

Patient Expected". b [7] Patient Expected a [7]

Not available 53.9 + 20.4 Not available > 2.5 16 50 _+ 13.7 0.62 >2.5 12 46.1 + 13.2 0.75 >2.5

Case 5

The fifth pregnancy was characterized by retardation of fetal growth beginning in the 30th week of gestation. In the 38th week (1992) a girl with birth weight (1980 g) and length (43 cm) below the 10th percentile and a normal head circumference (32 cm) was delivered by Caesarean section because of fetal malposition. The cardiotocogram had been normal. Colour and amount of amniotic fluid were inconspicuous. However, the girl adapted very badly to extra-uterine life. Her Apgar score was 1/1/1. She made only ir- regular gasps. The rest of the clinical examination was normal. She was ventilated with a mask and then endotracheal intubation was performed. High resistance to inflation was observed. As a result of severe postnatal asphyxia, the lactate level was highly elevated (22.9 mmol/1, 3 h after birth). During the first 12 h the child could be adequately oxygenated by conventional mechanical ventilation. But she developed pneumothoraces necessitating bilateral drain- age. In addition, the chest X-rays showed small lungs, a progres- sive pleural effusion on the right and normal skeletal structures (Fig. 1 b). The ultrasonography of the head was normal, as were subsequently the baby's karyotype and blood culture. The infant developed severe hypoxaemia resistant to oscillatory ventilation and died 20 h postpartum.

Autopsy findings

Combined lung weights and lung/hear t rat ios are shown and compared with normal values [7] in Table 1. Unfortu- nately, weights of lung and heart f rom case 1 were not

recorded. The lungs were we ighed pr ior to formal in fixa- tion. The r ight lung f rom case 1 showed only two lobes. No other abnormal i t ies have been noted in this case and none in the other two infants. Except for the lungs, all or- gan weights (avai lable in case 2 and 5) were within nor- mal l imits compared to body length.

Addi t iona l h is to logica l examinat ions were done ac- cording to Emery and Mitha l as descr ibed by Swischuk et al. [8]. The examinat ion consis ted in drawing a perpen- dicular l ine f rom the pleural surface to the nearest termi- nal b ronchio le and counting a lveolar septa be tween pleura and bronchio le (radial a lveolar count). Severa l stains (Sil- ver, Haemalaun-Eos in , E las t ica -van-Gieson) were used for count ing atelectat ic alveoles. Be tween 16 and 20 mea- surements f rom three to four h is to logica l sections were taken f rom the three affected infants and six weight- matched cont ro l -newborns without pu lmonary hypopla- sia. The h is to logica l texture in all its aspects ( including vessels) and a lveolar counts appeared normal in all 3 neonates compared with the six controls. There was in fact no difference in ca lcula ted radial a lveolar counts be- tween the patients with hypop las ia and the controls (Table 2). Tentat ive assessment of bronchia l structures per unit area or unit length o f in terbronchia l a lveolar septa did not y ie ld conclus ive data, different to control values, par t ly because the lung pa renchyma sampled f rom the first two

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Table 2 Radial alveolar counts

Case/controP Body weight Radial alveolar count b at autopsy (g) [8]

Case 1 2430 4.8 Control A/B 2420/2560 4.35/4.35

Case 2 2950 4.9 Control C/D 2 880/2900 4.0/5.05

Case 5 2 020 5.5 Control E/F 2060/2 080 5.5/4.65

a Controls A-F: matched for body weight without pulmonary hypoplasia b 16--20 counts between pleura and terminal bronchiole were aver- aged

siblings was insufficient. The number of bronchial branchings between the main bronchus and terminal bron- chioles had not been determined at the time of autopsy.

Family history

The parents are healthy and apparently nonconsan- guineous. However, the four grandparents stem from the same rural region in the central part of Switzerland, the largest distance between their villages being 15 km. In previous generations, there had been one stillbirth, but no known pulmonary malformations. Pulmonary function tests and chest X-rays of the parents were normal as were the clinical examinations and chest X-rays of their two healthy sons. Except for the second pregnancy, the mother was smoking one pack of cigarettes per day during all pregnancies.

Discussion

Whereas pulmonary hypoplasia is anatomically proven in cases 2 and 5, this diagnosis cannot be ascertained in case 1 because of unrecorded lung weight. However, there are at least two elements suggesting pulmonary hypoplasia in this infant too: the clinical course, which was identical to that of the other two siblings and the fulfilment of the ra- diological criteria proposed by Swischuk et al. [8].

Pulmonary hypoplasia occurs commonly in conditions associated with reduction of intrathoracic space (congeni- tal diaphragmatic hernia, oligohydramnios secondary to

renal malformations or premature rupture of fetal mem- branes, skeletal dysplasias of the thoracic cage, fetal hy- drops) and in conditions associated with impaired fetal breathing (malformations of the CNS, neuromuscular dis- eases). Other causes include obstructing lesions of the tra- cheo-bronchial tree and the pulmonary vasculature [2, 5, 8]. Primary pulmonary hypoplasia is rare and the majority of cases are sporadic [5, 6, 8]. However, there are in addi- tion to our cases at least three reports of this anomaly oc- curring in siblings: Fraser observed pulmonary hypoplasia in 2 siblings [3]; Langer and Kaufmann [5] found in their series of nine cases with isolated pulmonary hypoplasia two pairs of affected identical twins; Boylan et al. [1] de- scribed a male and a female, both of them born prema- turely at 33 weeks of gestation, with polyhydramnios and associated malformations (prominent epicanthic folds,

�9 mild micrognathia, low set ears, one of them with an ad- ditional complete cleft palate). An older sibling had a par- tial defect of the right diaphragm and a rudimentary right lung. In contrast to the cases of Boylan et al., our patients had no other malformations (isolated pulmonary hypopla- sia) and normal amounts of amniotic fluid.

In our family the two healthy siblings and the parents have so signs of pulmonary defect and in the previous generations there are no similar cases. As in the observa- tions of Boylan et al. [1] and Fraser [3], the pattern of our family suggests that some rare cases of isolated pul- monary hypoplasia may have a genetic basis: male and fe- male patients born to healthy parents leads us to evoke au- tosomal recessive inheritance. On the other hand, a multi- factorial aetiology or genetic heterogeneity of the disorder cannot be excluded on the basis of the small number of cases published so far.

From the pathogenetic point of view, we found normal numbers of peripheral alveoles in all three patients. This is in contrast to the findings of Swischuk et al. [8], who described reduced mean radial alveolar counts (two to three) in four neonates with primary pulmonary hypopla- sia. In our cases the number of alveoles in relation to ter- minal bronchioles is normal. Therefore we suggest that in this family a pathological correlation should be sought at a more proximal level than the terminal bronchiole, al- though the crucial evidence cannot be produced. A re- duction in the number of bronchial generations, suggest- ing interference with lung development before 16 weeks of gestation, has been described in pulmonary hypo- plasias associated with diaphragmatic hernia, Rhesus isoimmunization, renal dysplasias and phrenic nerve agenesis [41.

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