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Angiotensin Converting Enzyme (ACE) Inhibitors J Med Genet 1997;34:541-545 541 Congenital renal tubular dysplasia and skull ossification defects similar to teratogenic effects of J Med Genet: first published as 10.1136/jmg.34.7.541 on 1 July 1997. Downloaded from angiotensin converting enzyme (ACE) inhibitors Dhavendra Kumar, Gail Moss, Rob Primhak, Robert Coombs Abstract An apparently autosomal recessive syn- drome of congenital renal tubular dyspla- sia and skull ossification defects is described in five infants from two sepa- rate, consanguineous, Pakistani Muslim kindreds. The clinical, pathological, and Centre for Human Genetics, 117 radiological features are similar to the Manchester Road, phenotype associated with fetal exposure Sheffield S1O 5DN, UK to angiotensin converting enzyme (ACE) D Kumar inhibitors: intrauterine growth retarda- Department of tion, skull ossification defects, and fetal/ Paediatrics, Sheffield neonatal anuric renal failure associated Children's Hospital, with renal tubular dysplasia. There was no Sheffield, UK fetal exposure to ACE inhibitors in the G Moss affected infants. similarities R Primhak Phenotypic between these familial cases and those Neonatal Unit, Jessop associated with ACE inhibition suggest an Hospital for Women, abnormality of the "renin-angiotensin- Sheffield, UK aldosterone" system (RAS). It is postu- R Coombs lated that the molecular pathology in this Correspondence to: uncommon autosomal recessive proximal Dr Kumar. renal tubular dysgenesis could be related http://jmg.bmj.com/ to mutations of the Received 4 March 1996 gene systems govern- Revised version accepted for ing the RAS. publication 6 March 1997 (JMed Genet 1997;34:541-545) Figure 2 Skull radiograph ofIV.5,family 1: note poor ossification and wide skull sutures. Family 1 Keywords: proximal renal tubular dysplasia; renin- on September 30, 2021 by guest. Protected copyright. angiotensin system (RAS); angiotensin converting enzyme (ACE) inhibitors; fetal ACE inhibitors syn- drome Several reports of primary renal tubular dysplasia (RTD)' have been published since the original description.2 Recurrence in sibs3 and parental consanguinity5 favour autosomal recessive inheritance (MIM 267430).1 The 11 precise molecular mechanism leading to the phenotype of RTD is not clear. The putative gene(s) is yet to be mapped and cloned. This report describes five infants from two unrelated consanguineous Muslim families presenting with multiple congenital anomalies III (MCA) including RTD. The purposes of this report are to delineate further the phenotype of autosomal recessive RTD and to draw atten- tion to striking similarities with the teratogenic effects of maternal administration of angio- 3 4 tensin converting enzyme (ACE) inhibitors IV (for example, captopril, enalapril), which include skull ossification defects and anuric neonatal renal failure.6 7 The phenotype of Figure 1 Pedigree offamily 1. "fetal ACE inhibitors syndrome" is now 542 Kumar, Moss, Primhak, Coombs Family 2 Case reports FAMILY 1 2 A Pakistani Muslim woman (III.4, fig 1) presented in her second pregnancy (IV.2) com- J Med Genet: first published as 10.1136/jmg.34.7.541 on 1 July 1997. Downloaded from plicated with oligohydramnios. Parental con- sanguinity was noted at the time of antenatal 11 booking. The first pregnancy (IV. 1) had miscarried spontaneously at around 12 weeks' gestation. A female infant was delivered at term who looked dysmorphic (abnormally shaped, III small head and joint contractures). A clinical diagnosis of Potter syndrome was made, but renal ultrasound scan showed that both kidneys were of normal size, structure, and IV echogenicity. She died within 24 hours ofbirth; consent for necropsy was not given. The next conception produced a healthy male infant Figure 3 Pedigree offamily 2. (IV.3). The fourth pregnancy resulted in a live born male infant (IV.4). Dysmorphic features no- ticed at birth included Potter facies, abnor- ix mally shaped, small head, and large joint contractures. Skull x ray showed poor ossifica- tion of the skull vault. The baby was anuric from birth and renal failure associated with . El severe hypotension persisted until death at 7 4i I1 weeks. Renal ultrasound examination indicated ga,,.fe - i i apparently normal kidneys. Permission for necropsy was again refused. The last pregnancy produced a female infant (IV.5). Oligohydram- nios was suspected in the later part of pregnancy; a fetal ultrasound examination showed normal kidneys. At birth the baby had an abnormally shaped skull with widely separated sutures (fig 2) and large joint contractures. The baby was anuric from birth with severe hypotension. An ultrasound examination showed normal sized kidneys with http://jmg.bmj.com/ normal echogenicity. Biochemical investiga- tions indicated high plasma renin activity (PRA). This baby died from respiratory failure within a few hours of birth and consent for necropsy was again refused. on September 30, 2021 by guest. Protected copyright. FAMILY 2 A consanguineous Pakistani Muslim couple (III.3, III.4, fig 3) presented in their second pregnancy. The first pregnancy terminated prematurely in a male stillbirth with Potter it% syndrome at 29 weeks' gestation (IV.1). The ~ A kidneys could not be visualised on antenatal ultrasound scan. Consent for necropsy was not a~~~~~Op given. The product of the second pregnancy, a live born male infant delivered at term (IV.2), had dysmorphic features consistent with the Potter phenotype. In addition, the head looked abnormal with widely separated sutures and a large anterior fontanelle. Intensive care was required in view of severe respiratory distress probably related to pulmonary hypoplasia, profound hypotension, and anuric renal fail- accepted.8 We believe that this is the first report ure. Both kidneys appeared normal in shape illustrating similarities between the phenotypes and size with normal echogenicity on renal associated with fetal ACE exposure and geneti- ultrasound examinations. Despite intensive cally determined RTD. We believe that the management including peritoneal dialysis, the molecular pathology of the RAS might be asso- baby died at 17 days of age. ciated with the distinct and recognisable Biochemical investigations showed high syndrome of primary renal tubular dysplasia PRA and low angiotensin I levels. Molecular with skull ossification defects. genetic investigations showed the child to be a Autosomal recessive proximal renal tubular dysplasia 543 homozygote for the insertion polymorphism Z Z Z X z Z (II) in the ACE gene. Blood was not available for determination of ACE or 0 parental genotype 'o~~ J Med Genet: first published as 10.1136/jmg.34.7.541 on 1 July 1997. Downloaded from zzzzzz zz zzz molecular analysis of the angiotensinogen gene "~zm->-ZZZ> 9 ,ZZZZZZ ZZ ZZZ in either the parents or infant. Necropsy showed macroscopic pulmonary -ZZZZZZ ZZ ZZZ" hypoplasia, microscopic evidence of pulmo- 11 nary immaturity, and a cuboidal alveolar zZZZ 00 000ZZ epithelium. Interstitial emphysema and lobular Izzzzzz zz zzz~ 9) overdistension were <<ZZZz ZZZZZ also present, consistent with changes secondary to mechanical ventila- 9) tion. Histopathological examination of the kid- siZZE>9 H Z Z P. >. '. Z 0 9) neys showed variably sized glomerular cysts, >9>>>9-~ Z>-ZdZ>9Z ~I very poor maturation of cortical tubules, and Q, 9 cq Z Z L1 C- >- H- ZZ99) nodular collections of tubules suggestive of -o early tubular dysplasia (fig 4A, B). There was o -_o'I no evidence of acute tubular necrosis. These iX findings prompted the diagnosis of "proximal renal tubular z E9 dysgenesis". 0 o0 6 The third pregnancy resulted in a ~->9>9 Z " 9) healthy z >9 01 male infant who had a normal skull x 9) (IV.3) ray cq ~~~~~.0 9 . 'I and renal ultrasound scan. Z Z v.n > Z It >. s Z P.> Z > 0z >9> z~9zz9 z Discussion -ZZ° There are two to >9<Z09>-Z0 t C aspects this report: firstly, fur- - Z:;.Cn>9Z.> ,zZ'~> .ZZcZ ther delineation of the syndrome of autosomal -v0 -o recessive proximal RTD and, secondly, o0 0 examination of the evidence provided by the 0 o0 0 9) clinical resemblance between this and the >9Z090 > >9 zzz z11 "fetal ACE inhibitor z >~z P-0 >9>9Z>9o0 syndrome". 0 0 o C la 909, These families are Pakistani 1 Mus- z S 'M >z>. Z ,> ZZ>Zc 'I reported 91) 909,-P lim with parental consanguinity. The affected 9) 0 resulted in or ) 0 z Z 0 0 3 pregnancies early loss, stillbirth, e' Z ~' m>- - Z ZZ >9 z z 9>-> >9 z >1 z infants presenting after second trimester oligo- C' ;..) o o Z _I hydramnios with intrauterine growth retarda- z z >9 -,91) z z >9 C'ZZZZ ZZ Z >- Z tion, skull ossification and onset 0r defects, early -z . 0 renal failure. All affected liveborn died http://jmg.bmj.com/ 04 o C4Z o. infants x z z z >9 CzzzZ zz z >1 z 9) in the neonatal period. It is postulated that the 9)19) 11 same aetiology could account for all these 0Z) presentations. zII The clinical picture is compatible with Potter or the Q. zs syndrome oligohydramnios sequence.9 Z X This is usually associated with chronic 0zZ0 Z ._0 leakage o x0 of amniotic fluid from midgestation, severe -Z z.> Z>9ZX- >99zxzz -1 on September 30, 2021 by guest. Protected copyright. X z > z 'O I' bilateral renal malformation including agen- CC 49. 0 esis, dysgenesis, polycystic kidney disease, and >>9>9zz C494 4 7 0 multicystic kidney disease, or critical urinary ISzc 90 C 0 tract obstruction. However, apart from infant oZzENssZ X >99>99 -o IV. 1 (family 2) where bilateral agenesis was csszEc>ZzCC4 p 0 0 on antenatal 49)0W >99>>Z 9) suspected ultrasound scan alone, >zzZX Z En no evidence of these underlying problems was found in the affected >~ CaZ>9ZZ pregnancies. > Z >Z Z Profound hypotension resistant to treatment o ix was a major feature in infants IV.4 (family 1) z > Z Z >Z Z P42 and IV.2 (family 2) which could account for the o 9: associated renal failure.
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