Renal Tubular Dysgenesis with Calvarial Hypoplasia

8464 JMed Genet 1997;34:846-848 Renal tubular dysgenesis with calvarial hypoplasia:

report of two additional cases and review J Med Genet: first published as 10.1136/jmg.34.10.846 on 1 October 1997. Downloaded from

Deborah E McFadden, J Tapio Pantzar, Margot I Van Allen, Sylvie Langlois

Abstract gestational age (GA) was normal. At 32 weeks' We report two cases of renal tubular GA, the woman presented with vaginal bleed- dysgenesis (RTD) with calvarial hypopla- ing and mild abdominal pain. Ultrasound sia and review the originally reported examination showed severe oligohydramnios cases of RTD that came from our institu- with large, echogenic fetal kidneys. Spontane- tion and published reports regarding the ous breech delivery occurred shortly thereafter. association of RTD and skull abnormali- The infant had severe respiratory failure and ties. Although previously reported in profound hypotonia. The fontanelles were association with RTD, calvarial hypopla- noted to be abnormally large. The diagnosis of sia is probably under-recognised. The Zellweger syndrome was considered. cases reported here support the idea that The child died five hours after birth and the skull abnormalities observed in the necropsy was performed. Examination showed inherited form ofrenal tubular dysgenesis an infant with growth parameters at the 75th to are a common component of the disorder, 90th centile for 32 weeks' gestation and head as they are in the acquired form of RTD circumference at the 25th to 50th centile. associated with maternal use of ACE Although measurements were not recorded, inhibitors. Renewed attention to this clini- the fontanelles were noted to be abnormally cal manifestation of RTD may be impor- large with the anterior fontanelle extending tant in suggesting the diagnosis before into the middle of the forehead and the poste- death, providing more complete infor- rior fontanelle extending to just above the mation to parents and physicians facing occipital bone; the sagittal suture was ex- inportant management decisions and en- tremely wide. Grossly, the kidneys were large suring appropriate pathological examin- with a combined weight of 28.6 g versus an ation postmortem. expected combined weight of 14.5 + 4.8 g and (JMed Genet 1997;34:846-848) were somewhat spongy in appearance. Histo- logically, the kidneys showed diffuse glomeru- Keywords: renal tubular dysgenesis; calvarial hypopla- locystic change and renal tubular dysgenesis sia; enlarged fontanelles characterised by absence of the proximal http://jmg.bmj.com/ tubules as seen on routine microscopy and Renal tubular dysgenesis (RTD), first de- staining with PAS (present in the brush borders scribed in a pair ofsibs in 1983, is an autosomal of proximal tubules) and epithelial membrane recessive condition characterised by hypoplasia antigen (present within distal tubules). There of the proximal tubules of the kidney, which was pulmonary hypoplasia as determined by volume measurement. may present with late onset oligohydramnios. l 2 Sedimentable catalase Similar renal pathology is seen in some assay was normal and electron microscopic on September 30, 2021 by guest. Protected copyright. non-genetic conditions, characterised by renal examination showed normal peroxisomes, ex- hypoperfusion3-' and in infants born to women cluding a diagnosis of Zellweger syndrome. who took angiotensin converting enzyme Cytogenetic analysis showed a normal female inhibitors during pregnancy.6 karyotype. Neuropathological examination In a review of reported cases of RTD,7 showed only rare small foci ofheterotopic neu- underdeveloped cranial bones or wide sutures rones; there were no morphological abnormali- and fontanelles were noted in 6/24 cases. This ties to account for the hypotonia which was thus attributed to the failure. Departments of finding was also present in other more recently respiratory Pathology and Medical reported cases.810 We have examined two cases Genetics, University of in which the presence of abnormally large fon- CASE 2 British Columbia and taneNles was particularly striking and was noted This was delivered at 32 BC Children's infant weeks' gestation before death. This led us to review the Hospital, 4480 Oak to a gravida 2, para 1 woman who was said to Street, Vancouver, BC originally reported cases.' have congenital deafness. Gestational diabetes V6H 3V4, Canada had been diagnosed one week before delivery. D E McFadden Case reports There was no history of maternal drug use J T Pantzar CASE 1 during pregnancy. M I Van Allen A female infant was delivered at 32 weeks' At birth, the infant had failure S Langlois respiratory gestational age to a gravida 2, 26 year old and was hypotonic. The skull was abnormal Correspondence to: woman, who had had one therapeutic abortion; with large fontanelles. There were contractures Dr McFadden. she was not on any medication during at the knees and elbows with hyperflexibility at pregnancy. The first and second trimesters of the ankles and wrists. A diagnosis of Zellweger Received 29 January 1997 Revised version accepted for pregnancy were uncomplicated. An ultrasound syndrome was considered. The child died a few publication 8 April 1997 examination performed at 13-14 weeks' hours after birth. Renal tubular dysgenesis with calvarial hypoplasia 847

Necropsy showed a male infant with length large fontanelles or undermineralisation of the at the 75th to 90th centile, weight at the 90th skull bones in RTD, as in ACE inhibitor

centile, and head circumference at the 25th to fetopathy, are more common than reported J Med Genet: first published as 10.1136/jmg.34.10.846 on 1 October 1997. Downloaded from 50th centile for a gestational age of 32 weeks. and are often unrecognised or overlooked.6 The fontanelles were very large, with the ante- These skull abnormalities appear to occur rior confluent with the posterior, measuring 15 commonly enough in RTD that their presence cm x 6 cm. There were prominent infraorbital could serve to raise the diagnosis clinically, fol- creases, the thumbs were proximally im- lowed by pathological confirmation. There are planted, and there were contractures, without a number of conditions associated with en- pterygia, at the knees and elbows. The kidneys larged fontanelles; for many, exclusion from the were large with a combined weight of 33.8 g differential diagnosis is readily accomplished versus an expected combined weight of 14.5 ± on the basis of the other clinical features. In 4.8 g. The renal parenchyma was grossly both of our cases, a diagnosis of Zellweger syn- normal. Histologically, there was renal tubular drome was considered; the differential diagno- dysgenesis with absence of the proximal sis for infants presenting in this fashion should tubules. There was pulmonary immaturity with also include RTD. Hypotonia in infants with lung development appropriate for a gestational RTD may occur on the basis of hypoxia owing age of 28 weeks in contrast to the actual to respiratory failure (pulmonary hypoplasia) gestational age of 32 weeks. Analysis of very and thus may not be seen in all cases ofRTD as long chain fatty acids was normal as was the normal lung development has been reported.8 sedimentable catalase assay, excluding Zell- The basis for the skull abnormality in RTD weger disease. Cytogenetic analysis showed a is unknown. Similar renal and skull changes are normal male karyotype. Neuropathological seen in antenatal exposure to angiotensin con- examination showed extensive hypoxic- verting enzyme inhibitors (ACEI fetopathy). It ischaemic damage which was thought to has been postulated that the renal and calvarial account for the hypotonia. abnormalities reflect the effects of fetal hypo- With the finding ofmarkedly enlarged fonta- tension induced by maternal ACEI ingestion nelles in two infants found at necropsy to have with the resultant hypoxia affecting those renal tubular dysgenesis, we reviewed the organs requiring a high oxygen tension for nor- necropsy reports of cases of RTD examined in mal growth.5 6 An alternative explanation is our institution, including the two cases that based on the finding that angiotensin II is a were the subject of the initial report by renal growth factor'3 with the renal tubular Allanson et al.' In case 1 from that report (34 abnormalities in ACE inhibitor fetopathy being week GA stillborn), the necropsy report states attributed to lack of angiotensin II growth that "the sutures are very wide, the superior stimulation. The finding of calvarial hypoplasia sagittal suture measuring 3 cm in width, with in these cases has been interpreted as suggest- the large anterior and posterior fontanelle ing that calvarial bone growth may also be merging into each other". In the second case stimulated by angiotensin II.'" In RTD, high (36 week GA, stillborn), the report states "the levels of renal renin have been found and it has http://jmg.bmj.com/ skull bones are widely open, up to 2 cm, the been suggested that an impaired feedback anterior fontanelle measures 5 cm in all mechanism accounts for this.'4 The possibility dimensions". In a third case examined at our of this impaired feedback mechanism involving institution, the necropsy report noted that the angiotensin receptors has been raised (though anterior and posterior fontanelles were large, not formally examined) as the link between the each measuring 3 cm in coronal and sagittal high renin levels in the kidneys and the tubular

dimensions. dysgenesis; if there are abnormalities in angi- on September 30, 2021 by guest. Protected copyright. otensin receptors in RTD kidneys there may be similar receptor abnormalities in the calvar- Discussion ium, providing the link between the renal and The possibility of renal tubular dysgenesis may calvarial developmental abnormalities. be raised when there is late onset of In conclusion, abnormalities of the skull oligohydramnios,2 but the diagnosis is made occur fairly frequently in RTD and are often only after histopathological examination. Large not recognised clinically, as is the case in ACE fontanelles or hypoplastic calvaria have been inhibitor fetopathy. The finding of enlarged reported in a number of cases with renal tubu- fontanelles in an infant with oliguria, with or lar dysgenesis. In a review of reported cases of without respiratory failure or hypotonia, RTD, Allanson et af noted that six of 24 should serve to raise the possibility of RTD. reported cases had associated microcephaly, underdeveloped cranial bones, or widely patent fontanelles. By history, one of the patients 1 Allanson JE, Pantzar JT, MacLeod PM. Possible new auto- somal recessive syndrome with unusual renal histopatho- reported by Swinford et al had "extraordinar- logical changes. Am J Med Genet 1983;16:57-60. ily wide cranial sutures and fontanelles" and 2 Swinford AAE, Bernstein J, Toriello HV, Higgins JV. Renal tubular dysgenesis: delayed onset of oligohydramnios. AmJ7 the two cases initially reported by Allanson et Med Genet 1989;32:127-32. all also had extremely large fontanelles, raising 3 Genest DR, Lage JM. Absence of normal-appearing proximal tubules in the fetal and neonatal kidney: the proportion to nine of 24. Since then, addi- prevalence and significance. Hum Pathol 1991;22:147-53. tional cases have been reported of calvarial 4 Martin RA, Jones KL, Mendoza A, Barr M, Benirschke K. Effect of ACE inhibition on the fetal kidney: decreased hypoplasia in association with RTD8-'0; other renal blood flow. Teratology 1992;46:317-21. reports note a normal skull" while others fail to 5 Landing BH, Ang SM, Herta N, Larson, EF, Turner M. Labeled lectin studies of renal tubular dygenesis and renal mention the skull at all.'2 Our review of the atrophy of postnatal renal ischemia and end-stage kidney original two cases indicates that abnormally disease. Pediatr Pathol 1994;14:87-99. 848 McFadden, Pantzar, Van Allen, Langlois

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