58 7 Med Genet 1998;35:58-60 Familial persistent pulmonary hypertension of the newborn resulting from misalignment of the

pulmonary vessels (congenital alveolar capillary J Med Genet: first published as 10.1136/jmg.35.1.58 on 1 January 1998. Downloaded from dysplasia)

Humberto B Vassal, Marion Malone, Andy J Petros, Robin M Winter

Abstract score was 4 at one minute and 9 at three min- Misalignment ofthe pulmonary veins with utes. He had a poor perfusion and a heart rate congenital alveolar capillary dysplasia, of less than 100 at birth. At the age of 2 hours although rare, has been reported as a he was cyanosed and tachypnoeic. Echocardio- cause of persistent pulmonary hyperten- graphy showed an enlarged right ventricle and sion of the newborn. Reported cases have pulmonary hypertension; cardiac anatomy was been mainly sporadic. Familial occur- normal. rence has been reported in only three His respiratory condition deteriorated with instances. We present affected sibs with recurrent pneumothoraces and increased ven- this condition. In addition to pulmonary tilatory requirement. He had extracorporeal abnormalities, urogenital abnormalities, membrane oxygenation (ECMO) for 12 days. including ureteric and urethral obstruc- The subsequent course was characterised by tion, seem to be common. Autosomal respiratory and renal deterioration and he died recessive inheritance is suggested. on the 20th day of life. (T Med Genet 1998;35:58-60) Necropsy showed a heart with moderate hypertrophy of the right ventricle and a patent Keywords: congenital alveolar capillary dysplasia; mis- ductus arteriosus. The lungs were of appropri- alignment of the pulmonary vessels; persistent pulmo- nary hypertension of the newborn; autosomal recessive ate volume and weight for gestational age (the right lung weighed 65.8 g and the left lung 45.6 g). There was severe bilateral hydroneph- Persistent pulmonary hypertension of the new- rosis with both megaureters measuring about 8 born (PPHN) can be secondary to chronic cm in diameter. The bladder was hypertro- fetal hypoxia, pulmonary hypoplasia, perinatal phied and its wall was 1 cm thick. Posterior asphyxia, meconium aspiration syndrome, con- urethral valves were present. genital heart disease, pneumonia (particularly On microscopy, the lungs showed muscular arteries and veins lying in juxtaposition to the group B streptococal pneumonia), septicaemia, http://jmg.bmj.com/ and hyaline membrane disease.l Maternal bronchi and bronchioles. There was medial ingestion of prostaglandin synthetase inhibitors hypertrophy of the pulmonary arteries, many can also be associated with PPHN.' However, of which shared their adventitia with thin Mothercare Unit of walled and widened veins (fig 1). Alveolar septa Clinical Genetics and in some infants PPHN seems to be idiopathic and no predisposing factors can be found.3 were thickened with a paucity of capillaries. Fetal Medicine, was There Institute of Child A condition known as misalignment of There secondary lymphangiectasia. Health, 30 Guilford pulmonary vessels (MPV) or alveolar capillary was no pulmonary hypoplasia. The appear- Street, London WCIN dysplasia (ACD) has been reported as a cause ances were of misalignment of pulmonary ves- on October 4, 2021 by guest. Protected copyright. 1EH, UK of "idiopathic" PPHN. To date, about 19 spo- sels (congenital alveolar capillary dysplasia). H B Vassal Sections of the kidneys confirmed the R M Winter radic cases have been reported.'-" Familial occurrence was reported in only three presence of bilateral hydronephrosis and showed tubular and glomerular cysts in the Department of instances.'` 13 14 This is the fourth familial Histopathology, Great report, giving support to the suggestion of an superficial cortex; in the medulla there was an Ormond Street autosomal recessive gene in some families with Hospital for Children this condition. NHS Trust, London WC1N 3JH, UK M Malone Case reports to Neonatal Intensive The affected brother and sister were born Care Unit, Great healthy, unrelated, white parents. Two previous Ormond Street sibs, a girl and a boy, are normal. There was no Hospital for Children history of other unexpected fetal or neonatal NHS Trust, London deaths in the family. WC1N 3JH, UK A J Petros CASE 1 Correspondence to: This was the third child, a male infant. The Professor Winter. pregnancy was complicated by bilateral hy- dronephrosis with oligohydramnios diagnosed Figure 1 Photomicrograph of a bronchovascular bundle Received 5 May 1997 showing close apposition of the pulmonary artery and vein Revised version accepted for on antenatal scan at 35 weeks of gestation. which share an adventitial wall. (Elastic van Gieson publication 24 July 1997 Delivery was induced at 39 weeks. The Apgar stain.) Familial persistent pulmonary hypertension of the newborn 59

occasional dilated tubule. Patchy mild chronic The first familial report ofthis condition was inflammation was found in the medulla and by Shohet et a!l in 1984. They described two pelvis. Apart from some liver and spleen affected brothers and a sister of healthy, first congestion no other abnormalities were de- cousin, Tunisian, Jewish parents. McDonald- tected on histopathology. McGinn et af and Boggs et a!3 described affected male and female sibs of apparently J Med Genet: first published as 10.1136/jmg.35.1.58 on 1 January 1998. Downloaded from CASE 2 unrelated, healthy parents, both of Ukrainian This was a term female infant, weighing 3600 g Jewish descent. The male infant also had bilat- after normal vaginal delivery. She was the eral ureteropelvic junction obstruction with fourth child. The pregnancy was uneventful. hydronephrosis and bilateral cryptorchidism. It She was discharged home after six hours, but should be emphasised that there was no by 12 hours she had increasing respiratory dis- pulmonary hypoplasia. Simonton et all4 re- tress and had a respiratory and cardiac arrest at ported two affected sibs. The brother had bra- home. A right sided pneumothorax was chial amelia and distal phocomelia of the lower drained. Echocardiography showed evidence of limbs. The sister had phocomelia of the lower persistent pulmonary hypertension with a extremities. In the latter there was also structurally normal heart. duplication of the uterus. The striking clinical similarity with her sib Abdallah et all" reported a male newborn was apparent, and after discussion it was with PPHN and a sister who presented with decided not to offer ECMO. She died at 21 pulmonary hypertension just after 5 weeks of hours of age, following a further sudden age. Both had misalignment of the pulmonary deterioration with a gross pneumoperitoneum vessels. Manouvrier-Hanu et al'6 reported a and pneumothorax. similar sibship. One of the sibs presented with Necropsy showed a patent foramen ovale, pulmonary hypertension from birth (PPHN) measuring up to 1 cm in diameter. Lung weight and the other one after 15 days of life. They was normal for gestational age (the right lung had misalignment of the pulmonary vessels. In weighed 40.2 g and the left lung 38.6 g). both there was associated pelviureteric junc- Microscopy showed similar features to those tion obstruction. seen in case 1, without secondary lym- This is the fourth example of concordant phangiectasia. There were no urogenital or sibs with PPHN with MPV/ACD to be other abnormalities. reported. As described in other published cases, both sibs developed respiratory distress Discussion echocardiography, "Congenital alveolar dysplasia", "congenital soon after birth. Clinical, dysplasia", "misalignment of and necropsy data showed pulmonary hyper- alveolar capillary tension. There was no history of predisposing vessels", or "misalignment of the pulmo- lung factors. Morphological pulmonary findings nary veins with congenital alveolar capillary dysplasia" is characterised histologically by (1) were identical to those of the patients reported failure of formation and ingrowth of alveolar previously. In the families reported by do not make contact with Manouvrier-Hanu et a"l' and Abdallah et al,.5 capillaries that http://jmg.bmj.com/ alveolar epithelium, (2) medial muscular thick- one sib presented with pulmonary hyperten- ening of small pulmonary arterioles with (3) sion outside the neonatal period. This suggests extension of muscularisation to the smallest, that mutations in the same putative autosomal intra-acinar arterioles, (4) thickened alveolar recessive gene could be responsible for some walls, (5) anomalously situated pulmonary cases of pulmonary hypertension in infancy. veins running alongside pulmonary arterioles It should be emphasised that in case 1, the and often sharing a common adventitial sheath, histological findings of alveolar capillary dys- (6) reduced number of alveoli, and (7) dilated plasia cannot be put down to his associated on October 4, 2021 by guest. Protected copyright. lymphatics in some cases.'-" 7 9 posterior urethral valves with oligohydramnios. The infants reported by McMahon in 1948 Pulmonary hypoplasia, with small and poorly were probably the first description of this developed lungs in relation to the rest of the entity.5 About 19 sporadic cases have been body, with only subtle histological abnormali- reported.'5 12 The histological features have ties, is a distinct entity and is not compatible been noted to be sometimes variable.3 5 10 with the histological findings in this case.57 All infants have been born at or near term. There are three other reports of renal There is no sex predilection. Other congenital anomalies. Wagenvoort et at reported a female abnormalities have been described in six cases: infant and Boggs et ar' reported a male infant, these included retro-oesophageal left subcla- both with bilateral ureteropelvic junction ob- vian artery and bicornuate uterus; absent right struction with hydronephrosis. The two male umbilical artery and stenosis of distal ureters sibs reported by Manouvrier-Hanu et al" also with bilateral hydronephrosis; volvulus of the had ureteropelvic junction obstruction. It seems small bowel, duodenal stenosis, and aganglio- possible that the urogenital anomalies are a nosis of the colon; intestinal malrotation and a pleiotropic manifestation of the same gene. decreased number ofganglion cells in the distal This family reinforces the suggestion that colon; phocomelia; and Meckel diverti- persistent pulmonary hypertension of the new- culum.'"- All cases have presented with born with misalignment of the pulmonary respiratory distress resulting from pulmonary vessels/alveolar capillary dysplasia can be hypertension in the early postnatal period (at 1 caused by an autosomal recessive gene in some hour to 2 days of life) and all have died within families and can be associated with urinary the newborn period.'-" tract anomalies. 60 Vassal, Malone, Petros, Winter

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