American Journal of Medical Genetics 44:269-273 (1992)
Cystic Kidney Dysplasia and Polydactyly in 3 Sibs With Bardet-Biedl Syndrome Ruth Gershoni-Baruch, Tal Nachlieli, Rina Leibo, Shimon Degani, and Irith Weissman Division of Genetics, Department of Pediatrics, Rambam Medical Center, (R.G-B., T.N., I.W.); Department of OBIGYN, Bnei-Zion Medical Center (S.D.); The Rappoport Family Institute of Medical Research, Technwn-Israel Institute of Technology (R.L.),Haifa, Israel
Two infants with cystic kidney dysplasia and polydactyly were born to consanguineous parents. One infant died at age 2 months, and the other is currently 3.5 years old. A third pregnancy was terminated following ultrasonographic visualization of large echodense fetal kidneys and polydactyly. Although none had apparent brain anomalies, they were considered to represent the Meckel syndrome. Extinguished responses on electroretinography in our 3.5-year-old patient h a s led to the diagnosis of Bardet-Biedl syndrome. This observation offers an opportunity to revisit the Bardet-Biedl syndrome and provides further evidence that structural renal abnormalities are characteristic of the syndrome. We wish to alert the clinician to the diagnosis of BardetBiedl syndrome in patients with infantile cystic kidney dysplasia. o 1992 Wiley-Liss, Inc.
KEY WORDS Polydactyly, infantile polycystic kidney, autosomal recessive inheritance, Meckel syndrome, cystic kidney dysplasia, Bardet-Biedl syndrome INTRODUCTION Cystic kidney dysplasia (CKD) and polydactyly occur together in the Meckel syndrome (MS), Bardet Biedl syndrome (BBS), and short rib-polydactyly syndromes (SRPS).These syndromes are normally easy to differentiate. MS is characterized by CKD, craniofacial defects, central nervous system malformations, and polydactyly [Opitz and Howe, 19691. CKD is considered a constant
Received for publication January 23, 1991; revision received January 30,1992. Address reprint requests to Dr. Ruth Gershoni-Baruch,Department of Pediatrics, Division of Genetics,Rambam Medical Center, POB 9649, 31096 Haifa, Israel. 0 1992 Wiley-Liss,
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manifestation of the disorder [Fraser and Lytwyn, 1981; Salonen and Norio, 19841. BBS refers to the pleiotropic combination of polydactyly, obesity, mental retardation, retinal dystrophy, and hypogonadism [Amman, 19701. Renal abnormalities were not considered, until lately, characteristic of the syndrome [Amman, 1970; Churchill et al., 19811. SRPS is an early lethal form of short limb dwarfism associated with polysyndactyly.Infants with SRPS have a narrow thorax and short horizontal ribs and die of respiratory insufficiency soon after birth. CKD is another possible manifestation [Jones, 19881. We report on 3 sibs with cystic renal disease and postaxial polydactyly. One infant died at 2 months, and one pregnancy was terminated following ultrasonographic visualization of large echodense fetal kidneys and polydactyly. Another child, currently 3.5 years old, has abnormal retinal responses on electroretinogram, allowing for the diagnosis of BBS. These cases, originally considered to represent the MS, offer an opportunity to further delineate the spectrum of renal abnormalities in BBS. CLINICAL REPORTS Patient 1 N.B. was the first-born infant, delivered by cesarean section because of breech presentation, following a normal 42-week gestation, to a 21-year-old mother and a 23year-old father. The parents are first cousins of Christian Arab descent. Birth weight (BW) was 3,860 g and head circumference (OFC) 36 cm; Apgar score was 9 at both 1and 5 minutes. Clinical signs noted at birth were large, apparently low-set ears, deep-set eyes, short, webbed neck, right torticollis, pigeon chest, right cryptorchidism, cubitus valgus, and bilateral postaxial polydactyly of feet. Both kidneys were palpable. The infant was transferred to the neonatal intensive care unit. Laboratory investigations documented the following ranges of values: blood urea nitrogen (BUN),61-90 mgl dl; creatinine, 3.6-5.0 mg/dl; sodium, 136-142 meqll; potassium, 5.0-6.7 meq/l; calcium, 10.4-10.7 mg/dl;pH, 7.11-7.17; bicarbonate, 11-17 meq/l. Results of liver and thyroid function tests and urinalysis were normal. Roentgenograms showed 11 normal ribs with normal configuration and normal spine. Excretory urogram
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showed slow excretion by the kidneys. Ultrasonography genetic clinic for reassessment. She had brachycephaly, (US)showed large, cystic kidneys. Computerized tomog- a small anterior fossa, upslanting palpebral fissures, raphy of the brain was normal. Chromosome constitu- epicanthal folds, a prominent nasal bridge, a broad nose, tion (lymphocytes) was normal (46,XY) with a long Y a thin upper lip, and downturned angles of mouth. She also had low posterior hairline, flaring eyebrows, hirsuchromosome, considered a normal variant. The infant died of renal failure a t age 2 months. The tism, and a bifid right 5th toe. Her weight was 17,000 g diagnosis of MS was considered and the parents were (90th centile), length 96 cm (75th centile), and OFC 47.5 cm (25th centile). She was hyperactive, and her speech counselled a 25% recurrence risk. was delayed. Gross and fine motor development seemed Patient 2 normal. At 36 months an electroretinogram showed extinA.B was delivered by cesarean section because of breech presentation. This 2nd pregnancy was monitored guished responses, in keeping with the diagnosis of retiby US from the 17th week. Two large (4.7 x 2.6 cm) nitis pigmentosa. echogenic kidneys were visualized and the diagnosis of Case 3 CKD was made. BW was 3,900 g, and Apgar score was 10at 1and 5 minutes. The infant girl was unremarkable Following the birth of a normal girl, a 4th pregnancy except for palpable kidneys and a bifid right 5th toe. was again monitored by US. Large echogenic kidneys Ultrasound showed the kidneys to be echogenic and still (Fig. 2) and polydactyly were shown. At week 20 the enlarged. Kidney failure as evidenced by laboratory fetus was delivered by hysterotomy. The fetus weighed tests (BUN, 60 mg/dl; creatinine, 1.5 mg/dl; phosphorus, 360 g, was 15 cm long, and had a generally normal 7.6 mg/dl), and mild hypertension warranted treatment appearance except for bilateral postaxial polydactyly of from age 3 weeks with chlorosal, propranolol, and cal- the upper and lower limbs. There were 3 vessels in the cium carbonate. Repeated US at 6 weeks showed 2 large umbilical cord. The fetal membranes appeared normal. echogenic kidneys with no differentiation between cor- The placenta measured 8.5 x 9.5 x 1.5 cm and weighed tex and medulla. Brain US was normal. The diagnosis of 105 g. Postmortem examination showed oversized MS was made. spongy kidneys, 3.5 x 2.2 x 2.0 cm on the right and 4.5 The child was then followed at our nephrology clinic. x 2.5 x 2.3 cm on the left. The presence of multiple Repeated laboratory investigations documented the fol- cysts in the corticomedullary and medullar zone was lowing ranges of values: BUN, 11-21 mg/dl; sodium, confirmed.The brain and the other internal organs were 142-149 meq/l; potassium, 4.8-5.1 meq/l; creatinine, normal. Microscopic examination of the kidneys (Fig. 3) 0.5-0.7 mg/dl; phosphorus, 5.1-6.8 mg/dl; calcium, showed cystic dysplasia. Cortex and medulla were filled 8.6-10.2 mg/dl; Total bilirubin, 0.4 mg/dl; uric acid, with round or elongated cysts of varying size (0.1-2 3.4-4.5 mg/dl; transaminase, 20-21 UA; alkaline phos- mm), lined with flat to cuboidal epithelium. The thin phatase, 312-316 U/1; bicarbonate, 17-20.5 mmol/l; and cortex contained numerous glomeruli of appropriate pH, 7.3-7.38. Results of urinalysis were normal. Kidney histologic appearance, the corticomedullary junction scan at 28 months showed normal size kidneys with seemed indistinct, and the stroma slightly edematous. reasonably good concentration and delayed excretion. US showed normal size echogenic kidneys with no differentiation between cortex and medulla. Liver US and scan were normal. Physical growth was normal. Psychomotor development seemed appropriate. At 32 months (Fig. 1) the child was referred to the
Fig. 1. Patient 2: (a) face, (b)feet. Note bifid right 5th toe.
Fig. 2. Ultrasonogram of fetus, showing polycystic kidneys.
Cystic Renal Disease and Polydactyly
Fig. 3. (a)Low magnificationview of the kidney, showing extensive replacement of parenchyma by round cysts, sparing a narrow rim of outer cortex (arrow). (b)Cysts lined by flat to cuboidal epithelium. Glomeruli are shown (arrow).
DISCUSSION Three abnormal offsprings from a consanguineous relationship showed a similar pattern of cystic renal changes with polydactyly. They were initially diagnosed to have MS, which refers to the variable combination of occipital encephalocele, polydactyly, CKD, cleft lip and palate, and various other anomalies. CKD associated with at least 2 other “relevant” anomalies” were considered as the minimal diagnostic criteria of MS [F’raser and Lytwyn, 19811. Salonen and Norio 119841have later shown that CKD with fibrotic changes in the liver, and occipital encephalocele or some other anomalies of the central nervous system are universal findings in MS. Polydadyly when present involves mainly the hands [F’raser and Lytwyn, 19811. MS is fatal, and survival rarely exceeds 24 hours [Salonen and Norio, 19841. Variability in the clinical expression of the syndrome was reported [Seller, 1981; Anderson, 19821 and survival to 1, 2, and 3 years has been described [Malpuech et al., 1979; Schurig et al., 1980;Anderson, 1982;Lowry et al., 19831.
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Taking into account all of the above, the occurrence of CKD and polydactyly with absence of brain anomalies in all of our affected cases and the unusual longevity of case 2 do not justify the diagnosis of MS. SRPS was not considered a diagnostic possibility. The finding of extinguished responses on electroretinography, in patient 2, is in keeping with the diagnosis of BBS. Laurence-Moon-Biedl syndrome (LMBS) was traditionally described as characterized by retinal dystrophy, obesity, mental retardation, polydactyly, hypogonadism, and spastic paraparesis [Ammann, 19701. It is likely that this syndrome comprises 2 disorders; Laurence-Moon syndrome and the BBS [Schachat and Maumenee, 19821. In the former, polydactyly is rare and spastic paraparesis predominates, whereas neurological complications are very unusual in the latter. Although renal involvement is well documented in BBS, it has not been considered, until lately, characteristic of the syndrome [Churchill et al., 19811, and a clear definition of its spectrum and severity is lacking. Autopsy data have demonstrated almost universal renal involvement [Bauman and Hogan, 19733, whereas some clinical series have reported infrequent renal involvement [Ammann, 19701. Variability of expression of the cardinal features of BBS (retinal dysplasia, mental retardation, obesity, hypogonadism, and polydactyly) has been reported [Ammann, 1970; Bergsma et al., 19751. This variation is both inter- and intrafamilial, especially in the case of mental retardation, polydactyly, degree of obesity, reproductive dysfunction, and abnormalities of renal function. Variability, however, is less evident with respect to the type of retinal dystrophy, the presence of obesity, and the presence of abnormal renal calyces [Bergsma et al., 19751. Green et al. [19891 have studied 32 patients with BBS to show that polydactyly, mental retardation, and hypogonadism should not be considered as cardinal manifestations of the disorder, that retinal dystrophy and obesity are very common, and that the renal abnormalities are universal. Recent studies have shown that almost all patients with LMBS have renal structural and minor functional abnormalities [Harnett et al., 19881. Whereas the reported incidence of severe renal impairment varies from 15%to 55% [Alton and McDonald, 1973; Hurley et al. 1975; Linne et al., 1986; Harnett et al., 19891excretory urograms of patients with LMBS have almost always shown parenchymal changes with irregular reduction, blunting and clubbing of calyces, abnormalities of pericalyceal system, and the presence of cysts communicating with dilated calyces [Alton and McDonald, 1973; Labrune et al., 1974; Hurley et al. 1975; Bluett et al., 1977; Lee and Turetz, 1978; Churchill et al., 1981;Price et al., 1981; Tieder et al., 1982; Okuyama et al., 1983; Gourd01 et al., 1984; Linne et al., 1986; Cramer et al., 1988; Harnett et al., 19891.Persistent fetal lobulation is another feature of the LMBS [McLoughlin et al., 1967; Bluett et al., 1977; Price et al., 1981; Okuyama et al., 1983; Cramer et al., 1988;Harnett et al., 19891, suggesting a defect in maturation of the kidneys. Excretory changes were also documented in children, 2.5 years and
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older [Alton and McDonald, 1973; Okuyama et al., 19831. Harnett et al. [1988] studied 20 adult patients with BBS. Three patients had end-stage renal disease, 17 had normal serum creatinine values and estimated creatinine clearances, half had hypertension, 14 of 17 could not concentrate urine, and only one had complete renal tubular acidosis. Intravenous pyelography, however, detected renal abnormalities in all of the 20 patients studied. These included calyceal clubbing or blunting, calyceal cysts or diverticula. Seventeen of 19 patients had lobulated renal outlines of the fetal type and 4 patients had diffuse renal cortical loss. The data indicate that urographic changes are universal in the LMBS and that impairment in urine concentration is common. A defect in urine concentration was reported by others [Bluett et al., 1977; Linne et al., 19861. It is consistent with tubular dysfunction and may indicate decreased responsiveness of the kidney to vasopressin [Harnett et al., 19881. The lack of correlation between structural and functional abnormalities suggests that microscopic changes define functional disturbances. A wide variety of histologic changes have been described. These include periglomerular and interstitial fibrosis, cystic dilatation of tubules, glomerular changes, mesengial proliferation, and cortical and medullary cysts [Hurley et al., 1975; Falkner et al., 1977;Price et al., 1981;Tieder et al., 1982; Roussel et al., 1985; Sat0 et al., 1988; Barakat et al., 19901. These changes may correlate with functional abnormalities, but no data to substantiate this is available. Rather, the results of renal histology are conflicting and the ultrastructural changes described range from changes in the glomerular membrane to tubuloinstertitial lesions [Falkner et al., 1977; Price et al., 1981; Gourdol et al., 1984; Sat0 et al., 19881. Tubuloinstertitial lesions seem to predominate [Gourdol et al., 19841, and both the chronic glomerulopathy and the cystic tubulo-intertistial disease may progress to chronic renal failure [Churchill et al., 1981;Linne et al., 19861. Roussel et al. [1985]described a 6-year-old LMBS girl with chronic glomerulonephritis and glomerulosclerosis requiring chronic dialysis. Recently, another 6-year-old child with LMBS and focal sclerosing glomerulonephritis [Barakat et al., 19901 and a patient with glomerulonephropathy and proteinuria [Cheng et al., 19881 were reported. Only few cases of LMBS have been reported in children less than 3 years of age [Mcloughlin et al., 1967; McLoughlin and Shanklin, 1967; Hurley et al., 1975; Alton and McDonald, 1973; Bauman and Hogan, 1973; Ehrenfeld et al., 1970; Moini et al., 1975; Falkner et al., 1977; Prosperi et al., 1977; Ritchie et al., 19881. The diagnosis was determined in the young infant usually when an elder sib with LMBS was present in the family. The 3 sibs reported by us presented, either at birth or prenatally, with large echogenic kidneys mimicking infantile polycystic kidneys (IPCK).When re-evaluated at 28 months, patient 2 had normal size kidneys and at 3.5 years, she still has a renal tubular defect in urine concentration and acidification and her treatment regimen includes chlorosal and propranolol for hypertension. Mcloughlin et al. (1967) reported on a 3-month-old
infant with LMBS and glomerular dysplasia of the fetal type. Magro and Peres [19701reported 3 LMBS children with renal dysplasia who had no clinical evidence of renal disease. Labrune et al. [1973] described radiological appearance similar to those found in children with renal dysplasia in 5 of 9 symptomless subjects. Fralick et al. [1990] documented the presence of calyceal blunting and multiple renal cortical cysts in a 3-year-old boy with obesity, developmental delay, decreased renal function, and hypertension. Here again, a retinal disorder shown by electroretinography has led to the diagnosis of BBS Ritchie et al. [19881 have reported on the prenatal diagnosis of IPCK in an infant subsequently found to have the LMBS. The kidneys were enlarged and echogenic by the end of the second trimester but did not continue to enlarge thereafter. The infant had an elder brother known to be affected with LMBS, but the prenatal diagnosis remained IPCK. The authors argue that despite “painstaking attention, one may not always be able to differentiate IPKD from more rare but clinically significant imitators.” Our 3 BBS patients had US findings similar to those described in IPKD. The evolution from large kidneys to normal size kidneys in patient 3 is perhaps a differentiating feature. We conclude, then, that the diagnosis of BBS should be considered in any neonate with CKD mimicking IPKD.
REFERENCES Alton DJ, McDonald P (1973):Urographic findings in the Bardet-Biedl syndrome,formerly the Laurence-Moon-Biedlsyndrome. Radiology 109:659-663. Ammann F (1970): Investigations cliniques et genetiques sur le syndrome de Bardet-Biedl en Suisse. J Genet Hum 18:Suppl:1-310. Anderson VM (1982): Meckel syndrome: Morphologic considerations. In Nyhan WL, Jones KL (eds):“Dysmorphology.”New York Alan R. Liss, Inc., for the National Foundation-March of Dimes, BD:OAS XVIII(3B),pp 145-160. Barakat AJ,Arianas P, Glick AD, Butler MG (1990):Focal sclerosing glomerulonephritisin a child with Laurence-Moon-Biedlsyndrome. Child Nephrol Urol 10(2):109-111. Bauman ML, Hogan GR (1973): Laurence-Moon-Biedl syndrome: Report of two unrelated children less than three years of age. Am J Dis Child 126:119-126. Bergsma DR, Brown KS (1975). Assessment of opthalmologic, endocrinologic and genetic findings in the Bardet-Biedlsyndrome.Birth Defects: 11:132-136. Bluett NH, Chantler C, Singer JD, Saxton HM (1977). Congenital renal abnormalities in the Laurence-Moon-Biedl syndrome. Arch Dis Child 52:968-970. Cheng IK, Chan KW, Chan MK, Kung A, Ma J, Wang C (1988): Glomerulonephropathy of Laurence-Moon-Biedl syndrome. Postgrad Med J 64:621-625. Cramer BC, Green JS, Harnett JD, Johnson GJ, McManamonP, Farid N, Pryse-Phillips W, Parfrey PS (1988): Sonographic and urographic correlation in Bardet-Biedl syndrome, formerly Laurence-Moon-Biedlsyndrome. Urol Radio1 10:176-180. Churchill DN, McManamon P, Hurley RM (1981): Renal disease-a sixth cardinal feature of the Laurence-Moon-Biedl syndrome.Clin Nephrol 16:151-154. Erhenfeld EN, Rowe H, Auerbach E (1970): Laurence-Moon-BardetBiedl syndrome in Israel. Am J Ophthalmol 70:524-532. Falkner B, Langman C, Katz S (1977):Renal histopathologicalchanges in a child with Laurence-Moon-Biedl syndrome. J Clin Pathol 30:1077-1081. Fralick RA, Leichter HE, Sheth KJ (1990): Early diagnosis of BardetBiedl syndrome. Pediatr Nephrol 4(3):264-265.
Cystic Renal Disease and Polydactyly Fraser FC, Lytwyn A (1981): Spectrum of anomalies in the Meckel syndrome, or: “Maybe there is a malformation syndrome with a t least one constant anomaly.” Am J Med Genet 967-73. Gourd01 0, David L, Colon S, Bouvier R, Ayral A, Aguercif M, Francois R (1984): Renal involvement in the Laurence-Moon-Biedl syndrome. A propos of 3 cases. Pediatrie 39:175-178. Green JS, M e y PS, Harnett JD, Farid N, Cramer BC, Johnson G, Heath 0,McManamon P, O’Leary E, Pryse-Phillips W (1989): The cardinal manifestations of Bardet-Biedl syndrome, a form of Laurence-Moon-Biedl syndrome. N Engl J Med 321(15):1002-1009. Harnett JD, Green JS, Cramer BC, Johnson G, Chafe L, McManamon P, Farid N,Pryse-Phillips W, Parfrey PS (1988): The spectrum of renal disease in Laurence-Moon-Biedl syndrome. N Engl J Med 319515-618. Hurley RM, Dery P, Nogrady MB, Drummon KN (1975): The renal lesion of the Laurence-Moon-Biedl syndrome. J Pediatr 87206-209. Jones KL (1988): “Smith’s Recognizable Patterns of Human Malformation,” 4th Ed. Philadelphia: Saunders, pp 286-289. Labrune M, Graux JC, Brault B (1974): Le syndrome de LaurenceMoon-Biedl signes urographiques. Annals Radiologie 17:385-389. Lee JW, ‘hretz F (1978): Laurence-Moon-Biedl syndrome-Urographic observations. N Y State J Med 78:959-960. Linne T, Wikstad L, Zetterstrom R (1986). Renal involvement in Laurence-Moon-Biedl syndrome: functional and radiological studies. A d a Pediatr Scand 75:240-244. Lowry RB, Hill RH, Tischler B (1983):Survival and spectrumofanomalies in the Meckel syndrome. Am J Med Genet 14:417-421. Magro FC, Peres E (1970):Nefropathia do sindrome do Laurence-MoonBardet-Biedl. Nota preliminar. Revista Iberica de Endocrinologia 17:243-253. Malpuech G, Palcoux JB, Desbordes AM, Dalens B (1979): Syndrome de Meckel: Genealogie inhabituelle. J Genet Hum 27:167-174. McLoughlin TG, Krovetz LJ, Schiebler GL (1964): Heart disease in the Laurence-Moon-Bardet-Biedlsyndrome. A review and a report of three brothers. J Pediatr 65:388-399. McLoughlin TG, Shanklin DR (1967): Pathology of Laurence-MoonBiedl syndrome. J Pathol Bacteriol 93:65-79.
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Moini AR, Emamy H, Asadian A (1975): The Laurence-Moon-Biedl syndrome. Clinical Pediatrics 14:812-815. Okuyama A, Itatani H. Sonoda T (1983). Angiographic findings in the kidney in the Laurence-Moon-Biedl syndrome. Br J Urol 55:243-244. Opitz JM, Howe JJ (1969):The Meckel syndrome (Dysencephalia splac‘The Clinical hnocystica, the Gruber syndrome). In Bergsma D (ed): Delineation of Birth Defects. Part 2. Malformation Syndromes.” New York: The National Foundation-March of Dimes, BD:OAS V, pp 167-179. Price D, Gartner JG, Kaplan BS (1981): Ultrastructural changes in the glomerular basement membrane of patients with Laurence-MoonBiedl syndrome. Clin Nephrol 16:283-288. Prosperi L, Cordella M, Bernasconi S (1982): Electroretinography and diagnosis of the Laurence-Moon-Bardet-Biedl syndrome in childhood. J Pediatr Ophtalmol 14305-308. Roussel B, Leroux B, Gaillard D, Fandre M (1985): Laurence-MoonBiedl syndrome, chronic diffuse tubulo-interstitial nephritis and liver involvements. Helv Pediatr Acta 40(5): 405-413. Salonen R, Norio R (1984): The Meckel syndrome in Finland: Epidemiologic and genetic aspects. Am J Med Genet 18591-698. Sat0 H, Saito T, Yamakage K, Kyogoku Y, h r u y a m a T, Yoshinaga K (1988): Renal histopathology of Laurence-Moon-Biedl syndrome: tubulointerstitial nephritis without specific glomerular changes. Nephron 49(4):337-338. Schachat AP, Maumence IH (1982): Bardet-Biedl syndrome and related disorders. Arch Opthalmol 100:285-288. Schurig V, Bowen P, Harley F, Schiff D (1980):The Meckel syndrome in the Hutterites. Am J Med Genet 5:373-381. Seller MJ (1981):Phenotypicvariation in Meckel syndrome. Clin Genet 20:74-77. Tieder M, Levy M, Gubler MC, Gagnadoux MF, Broyer M (1982):Renal abn in the B-B Syndrome. Int J Pediatr Nephrol 3:199-203. Ritchie G, Jequier S, Lussier-Lazaroff J (1988): Prenatal renal ultrasound of Laurence-Moon-Biedl syndrome. Pediatr Radio1 19(1): 65-66.
Cystic Kidney Dysplasia and Polydactyly in 3 Sibs With Bardet-Biedl Syndrome Ruth Gershoni-Baruch, Tal Nachlieli, Rina Leibo, Shimon Degani, and Irith Weissman Division of Genetics, Department of Pediatrics, Rambam Medical Center, (R.G-B., T.N., I.W.); Department of OBIGYN, Bnei-Zion Medical Center (S.D.); The Rappoport Family Institute of Medical Research, Technwn-Israel Institute of Technology (R.L.),Haifa, Israel
Two infants with cystic kidney dysplasia and polydactyly were born to consanguineous parents. One infant died at age 2 months, and the other is currently 3.5 years old. A third pregnancy was terminated following ultrasonographic visualization of large echodense fetal kidneys and polydactyly. Although none had apparent brain anomalies, they were considered to represent the Meckel syndrome. Extinguished responses on electroretinography in our 3.5-year-old patient h a s led to the diagnosis of Bardet-Biedl syndrome. This observation offers an opportunity to revisit the Bardet-Biedl syndrome and provides further evidence that structural renal abnormalities are characteristic of the syndrome. We wish to alert the clinician to the diagnosis of BardetBiedl syndrome in patients with infantile cystic kidney dysplasia. o 1992 Wiley-Liss, Inc.
KEY WORDS Polydactyly, infantile polycystic kidney, autosomal recessive inheritance, Meckel syndrome, cystic kidney dysplasia, Bardet-Biedl syndrome INTRODUCTION Cystic kidney dysplasia (CKD) and polydactyly occur together in the Meckel syndrome (MS), Bardet Biedl syndrome (BBS), and short rib-polydactyly syndromes (SRPS).These syndromes are normally easy to differentiate. MS is characterized by CKD, craniofacial defects, central nervous system malformations, and polydactyly [Opitz and Howe, 19691. CKD is considered a constant
Received for publication January 23, 1991; revision received January 30,1992. Address reprint requests to Dr. Ruth Gershoni-Baruch,Department of Pediatrics, Division of Genetics,Rambam Medical Center, POB 9649, 31096 Haifa, Israel. 0 1992 Wiley-Liss,
Inc.
manifestation of the disorder [Fraser and Lytwyn, 1981; Salonen and Norio, 19841. BBS refers to the pleiotropic combination of polydactyly, obesity, mental retardation, retinal dystrophy, and hypogonadism [Amman, 19701. Renal abnormalities were not considered, until lately, characteristic of the syndrome [Amman, 1970; Churchill et al., 19811. SRPS is an early lethal form of short limb dwarfism associated with polysyndactyly.Infants with SRPS have a narrow thorax and short horizontal ribs and die of respiratory insufficiency soon after birth. CKD is another possible manifestation [Jones, 19881. We report on 3 sibs with cystic renal disease and postaxial polydactyly. One infant died at 2 months, and one pregnancy was terminated following ultrasonographic visualization of large echodense fetal kidneys and polydactyly. Another child, currently 3.5 years old, has abnormal retinal responses on electroretinogram, allowing for the diagnosis of BBS. These cases, originally considered to represent the MS, offer an opportunity to further delineate the spectrum of renal abnormalities in BBS. CLINICAL REPORTS Patient 1 N.B. was the first-born infant, delivered by cesarean section because of breech presentation, following a normal 42-week gestation, to a 21-year-old mother and a 23year-old father. The parents are first cousins of Christian Arab descent. Birth weight (BW) was 3,860 g and head circumference (OFC) 36 cm; Apgar score was 9 at both 1and 5 minutes. Clinical signs noted at birth were large, apparently low-set ears, deep-set eyes, short, webbed neck, right torticollis, pigeon chest, right cryptorchidism, cubitus valgus, and bilateral postaxial polydactyly of feet. Both kidneys were palpable. The infant was transferred to the neonatal intensive care unit. Laboratory investigations documented the following ranges of values: blood urea nitrogen (BUN),61-90 mgl dl; creatinine, 3.6-5.0 mg/dl; sodium, 136-142 meqll; potassium, 5.0-6.7 meq/l; calcium, 10.4-10.7 mg/dl;pH, 7.11-7.17; bicarbonate, 11-17 meq/l. Results of liver and thyroid function tests and urinalysis were normal. Roentgenograms showed 11 normal ribs with normal configuration and normal spine. Excretory urogram
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showed slow excretion by the kidneys. Ultrasonography genetic clinic for reassessment. She had brachycephaly, (US)showed large, cystic kidneys. Computerized tomog- a small anterior fossa, upslanting palpebral fissures, raphy of the brain was normal. Chromosome constitu- epicanthal folds, a prominent nasal bridge, a broad nose, tion (lymphocytes) was normal (46,XY) with a long Y a thin upper lip, and downturned angles of mouth. She also had low posterior hairline, flaring eyebrows, hirsuchromosome, considered a normal variant. The infant died of renal failure a t age 2 months. The tism, and a bifid right 5th toe. Her weight was 17,000 g diagnosis of MS was considered and the parents were (90th centile), length 96 cm (75th centile), and OFC 47.5 cm (25th centile). She was hyperactive, and her speech counselled a 25% recurrence risk. was delayed. Gross and fine motor development seemed Patient 2 normal. At 36 months an electroretinogram showed extinA.B was delivered by cesarean section because of breech presentation. This 2nd pregnancy was monitored guished responses, in keeping with the diagnosis of retiby US from the 17th week. Two large (4.7 x 2.6 cm) nitis pigmentosa. echogenic kidneys were visualized and the diagnosis of Case 3 CKD was made. BW was 3,900 g, and Apgar score was 10at 1and 5 minutes. The infant girl was unremarkable Following the birth of a normal girl, a 4th pregnancy except for palpable kidneys and a bifid right 5th toe. was again monitored by US. Large echogenic kidneys Ultrasound showed the kidneys to be echogenic and still (Fig. 2) and polydactyly were shown. At week 20 the enlarged. Kidney failure as evidenced by laboratory fetus was delivered by hysterotomy. The fetus weighed tests (BUN, 60 mg/dl; creatinine, 1.5 mg/dl; phosphorus, 360 g, was 15 cm long, and had a generally normal 7.6 mg/dl), and mild hypertension warranted treatment appearance except for bilateral postaxial polydactyly of from age 3 weeks with chlorosal, propranolol, and cal- the upper and lower limbs. There were 3 vessels in the cium carbonate. Repeated US at 6 weeks showed 2 large umbilical cord. The fetal membranes appeared normal. echogenic kidneys with no differentiation between cor- The placenta measured 8.5 x 9.5 x 1.5 cm and weighed tex and medulla. Brain US was normal. The diagnosis of 105 g. Postmortem examination showed oversized MS was made. spongy kidneys, 3.5 x 2.2 x 2.0 cm on the right and 4.5 The child was then followed at our nephrology clinic. x 2.5 x 2.3 cm on the left. The presence of multiple Repeated laboratory investigations documented the fol- cysts in the corticomedullary and medullar zone was lowing ranges of values: BUN, 11-21 mg/dl; sodium, confirmed.The brain and the other internal organs were 142-149 meq/l; potassium, 4.8-5.1 meq/l; creatinine, normal. Microscopic examination of the kidneys (Fig. 3) 0.5-0.7 mg/dl; phosphorus, 5.1-6.8 mg/dl; calcium, showed cystic dysplasia. Cortex and medulla were filled 8.6-10.2 mg/dl; Total bilirubin, 0.4 mg/dl; uric acid, with round or elongated cysts of varying size (0.1-2 3.4-4.5 mg/dl; transaminase, 20-21 UA; alkaline phos- mm), lined with flat to cuboidal epithelium. The thin phatase, 312-316 U/1; bicarbonate, 17-20.5 mmol/l; and cortex contained numerous glomeruli of appropriate pH, 7.3-7.38. Results of urinalysis were normal. Kidney histologic appearance, the corticomedullary junction scan at 28 months showed normal size kidneys with seemed indistinct, and the stroma slightly edematous. reasonably good concentration and delayed excretion. US showed normal size echogenic kidneys with no differentiation between cortex and medulla. Liver US and scan were normal. Physical growth was normal. Psychomotor development seemed appropriate. At 32 months (Fig. 1) the child was referred to the
Fig. 1. Patient 2: (a) face, (b)feet. Note bifid right 5th toe.
Fig. 2. Ultrasonogram of fetus, showing polycystic kidneys.
Cystic Renal Disease and Polydactyly
Fig. 3. (a)Low magnificationview of the kidney, showing extensive replacement of parenchyma by round cysts, sparing a narrow rim of outer cortex (arrow). (b)Cysts lined by flat to cuboidal epithelium. Glomeruli are shown (arrow).
DISCUSSION Three abnormal offsprings from a consanguineous relationship showed a similar pattern of cystic renal changes with polydactyly. They were initially diagnosed to have MS, which refers to the variable combination of occipital encephalocele, polydactyly, CKD, cleft lip and palate, and various other anomalies. CKD associated with at least 2 other “relevant” anomalies” were considered as the minimal diagnostic criteria of MS [F’raser and Lytwyn, 19811. Salonen and Norio 119841have later shown that CKD with fibrotic changes in the liver, and occipital encephalocele or some other anomalies of the central nervous system are universal findings in MS. Polydadyly when present involves mainly the hands [F’raser and Lytwyn, 19811. MS is fatal, and survival rarely exceeds 24 hours [Salonen and Norio, 19841. Variability in the clinical expression of the syndrome was reported [Seller, 1981; Anderson, 19821 and survival to 1, 2, and 3 years has been described [Malpuech et al., 1979; Schurig et al., 1980;Anderson, 1982;Lowry et al., 19831.
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Taking into account all of the above, the occurrence of CKD and polydactyly with absence of brain anomalies in all of our affected cases and the unusual longevity of case 2 do not justify the diagnosis of MS. SRPS was not considered a diagnostic possibility. The finding of extinguished responses on electroretinography, in patient 2, is in keeping with the diagnosis of BBS. Laurence-Moon-Biedl syndrome (LMBS) was traditionally described as characterized by retinal dystrophy, obesity, mental retardation, polydactyly, hypogonadism, and spastic paraparesis [Ammann, 19701. It is likely that this syndrome comprises 2 disorders; Laurence-Moon syndrome and the BBS [Schachat and Maumenee, 19821. In the former, polydactyly is rare and spastic paraparesis predominates, whereas neurological complications are very unusual in the latter. Although renal involvement is well documented in BBS, it has not been considered, until lately, characteristic of the syndrome [Churchill et al., 19811, and a clear definition of its spectrum and severity is lacking. Autopsy data have demonstrated almost universal renal involvement [Bauman and Hogan, 19733, whereas some clinical series have reported infrequent renal involvement [Ammann, 19701. Variability of expression of the cardinal features of BBS (retinal dysplasia, mental retardation, obesity, hypogonadism, and polydactyly) has been reported [Ammann, 1970; Bergsma et al., 19751. This variation is both inter- and intrafamilial, especially in the case of mental retardation, polydactyly, degree of obesity, reproductive dysfunction, and abnormalities of renal function. Variability, however, is less evident with respect to the type of retinal dystrophy, the presence of obesity, and the presence of abnormal renal calyces [Bergsma et al., 19751. Green et al. [19891 have studied 32 patients with BBS to show that polydactyly, mental retardation, and hypogonadism should not be considered as cardinal manifestations of the disorder, that retinal dystrophy and obesity are very common, and that the renal abnormalities are universal. Recent studies have shown that almost all patients with LMBS have renal structural and minor functional abnormalities [Harnett et al., 19881. Whereas the reported incidence of severe renal impairment varies from 15%to 55% [Alton and McDonald, 1973; Hurley et al. 1975; Linne et al., 1986; Harnett et al., 19891excretory urograms of patients with LMBS have almost always shown parenchymal changes with irregular reduction, blunting and clubbing of calyces, abnormalities of pericalyceal system, and the presence of cysts communicating with dilated calyces [Alton and McDonald, 1973; Labrune et al., 1974; Hurley et al. 1975; Bluett et al., 1977; Lee and Turetz, 1978; Churchill et al., 1981;Price et al., 1981; Tieder et al., 1982; Okuyama et al., 1983; Gourd01 et al., 1984; Linne et al., 1986; Cramer et al., 1988; Harnett et al., 19891.Persistent fetal lobulation is another feature of the LMBS [McLoughlin et al., 1967; Bluett et al., 1977; Price et al., 1981; Okuyama et al., 1983; Cramer et al., 1988;Harnett et al., 19891, suggesting a defect in maturation of the kidneys. Excretory changes were also documented in children, 2.5 years and
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older [Alton and McDonald, 1973; Okuyama et al., 19831. Harnett et al. [1988] studied 20 adult patients with BBS. Three patients had end-stage renal disease, 17 had normal serum creatinine values and estimated creatinine clearances, half had hypertension, 14 of 17 could not concentrate urine, and only one had complete renal tubular acidosis. Intravenous pyelography, however, detected renal abnormalities in all of the 20 patients studied. These included calyceal clubbing or blunting, calyceal cysts or diverticula. Seventeen of 19 patients had lobulated renal outlines of the fetal type and 4 patients had diffuse renal cortical loss. The data indicate that urographic changes are universal in the LMBS and that impairment in urine concentration is common. A defect in urine concentration was reported by others [Bluett et al., 1977; Linne et al., 19861. It is consistent with tubular dysfunction and may indicate decreased responsiveness of the kidney to vasopressin [Harnett et al., 19881. The lack of correlation between structural and functional abnormalities suggests that microscopic changes define functional disturbances. A wide variety of histologic changes have been described. These include periglomerular and interstitial fibrosis, cystic dilatation of tubules, glomerular changes, mesengial proliferation, and cortical and medullary cysts [Hurley et al., 1975; Falkner et al., 1977;Price et al., 1981;Tieder et al., 1982; Roussel et al., 1985; Sat0 et al., 1988; Barakat et al., 19901. These changes may correlate with functional abnormalities, but no data to substantiate this is available. Rather, the results of renal histology are conflicting and the ultrastructural changes described range from changes in the glomerular membrane to tubuloinstertitial lesions [Falkner et al., 1977; Price et al., 1981; Gourdol et al., 1984; Sat0 et al., 19881. Tubuloinstertitial lesions seem to predominate [Gourdol et al., 19841, and both the chronic glomerulopathy and the cystic tubulo-intertistial disease may progress to chronic renal failure [Churchill et al., 1981;Linne et al., 19861. Roussel et al. [1985]described a 6-year-old LMBS girl with chronic glomerulonephritis and glomerulosclerosis requiring chronic dialysis. Recently, another 6-year-old child with LMBS and focal sclerosing glomerulonephritis [Barakat et al., 19901 and a patient with glomerulonephropathy and proteinuria [Cheng et al., 19881 were reported. Only few cases of LMBS have been reported in children less than 3 years of age [Mcloughlin et al., 1967; McLoughlin and Shanklin, 1967; Hurley et al., 1975; Alton and McDonald, 1973; Bauman and Hogan, 1973; Ehrenfeld et al., 1970; Moini et al., 1975; Falkner et al., 1977; Prosperi et al., 1977; Ritchie et al., 19881. The diagnosis was determined in the young infant usually when an elder sib with LMBS was present in the family. The 3 sibs reported by us presented, either at birth or prenatally, with large echogenic kidneys mimicking infantile polycystic kidneys (IPCK).When re-evaluated at 28 months, patient 2 had normal size kidneys and at 3.5 years, she still has a renal tubular defect in urine concentration and acidification and her treatment regimen includes chlorosal and propranolol for hypertension. Mcloughlin et al. (1967) reported on a 3-month-old
infant with LMBS and glomerular dysplasia of the fetal type. Magro and Peres [19701reported 3 LMBS children with renal dysplasia who had no clinical evidence of renal disease. Labrune et al. [1973] described radiological appearance similar to those found in children with renal dysplasia in 5 of 9 symptomless subjects. Fralick et al. [1990] documented the presence of calyceal blunting and multiple renal cortical cysts in a 3-year-old boy with obesity, developmental delay, decreased renal function, and hypertension. Here again, a retinal disorder shown by electroretinography has led to the diagnosis of BBS Ritchie et al. [19881 have reported on the prenatal diagnosis of IPCK in an infant subsequently found to have the LMBS. The kidneys were enlarged and echogenic by the end of the second trimester but did not continue to enlarge thereafter. The infant had an elder brother known to be affected with LMBS, but the prenatal diagnosis remained IPCK. The authors argue that despite “painstaking attention, one may not always be able to differentiate IPKD from more rare but clinically significant imitators.” Our 3 BBS patients had US findings similar to those described in IPKD. The evolution from large kidneys to normal size kidneys in patient 3 is perhaps a differentiating feature. We conclude, then, that the diagnosis of BBS should be considered in any neonate with CKD mimicking IPKD.
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