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Home , Alagille syndrome, Blepharochalasis, COACH Syndrome, Corneal dystrophy, Horseshoe kidney, Hydronephrosis

DISEASE OF THE MONTH J Am Soc Nephrol 14: 516–529, 2003 EBERHARD RITZ, FEATURE EDITOR

Eye and : From Clinical Findings to Genetic Explanations

HASSANE IZZEDINE,* BAHRAM BODAGHI,† VINCENT LAUNAY-VACHER,* and GILBERT DERAY* * and † Departments, Pitie-Salpetriere Hospital, Paris, France.

Although the study of embryonic eye and kidney development The expression pattern of Wilms’ tumor suppressor 1 (WT1) was first studied in the middle of the 19th century, three during embryogenesis is highly complex. WT1 has at least two decades passed until scientists identified the molecular controls functions during the first stage of kidney development. First, it of both renal and eye organogenesis. Most of these advances may be required for the inductive signal that induces the have come from mouse and rodent gene manipulation. Trans- outgrowth of the from the mesonephros. Second, it lation of the mouse data to human congenital oculorenal dis- seems to be involved in either survival or reception of the ease has just begun. Examples of these genes include Pax2 and survival signal from the ureteric bud (3). In addition to its role morphogenic protein 7 (BMP-7). Others factors that in genitourinary formation, WT1 is required for the differenti- participate in mouse ocular and renal organogenesis, such as ation of ganglion cells in the developing (4). epithelial growth factor or integrins, may later be proven Wilms’ tumor gene was originally identified on the basis of important in human eye and kidney development. A variety of its mutational inactivation in 10 to 15% of all Wilms’ tumors. human congenital syndromes affecting both organs have been A preliminary report on the expression of WT1 in the devel- described. An interesting pathophysiological classification oping eye is remarkable because it points toward a possible scheme on kidney diseases has been very recently reported by role for WT1 in ocular development (5). Severe abnormalities Pohl et al (1). We propose a clinical diagnostic approach of were also found in the WT1Ϫ/Ϫ at later stages of oculorenal syndromes with their genetic’s links. development. Consistent with the expression of WT1 in the inner portion of the WT1ϩ/ϩ retina, a significant fraction of Renal Dysgenesis and Eye Abnormalities cells was lost apoptosis in the developing retinal ganglion cells Pax and WT1 Gene Families of mutant E18 embryos. Defects in the remaining ganglion Pax genes are a family of developmental control genes that cells in the WT1Ϫ/Ϫ retinas are indicated by failure of these encode nuclear transcription factors. They are characterized by cells to give rise to normally growing fiber bundles. the presence of the paired domain, a conserved This phenotype of the WT1Ϫ/Ϫ retinas is reminiscent of the motif with DNA-binding activity. Originally, paired-box-con- abnormalities seen in mice, which lack the POU-domain tran- taining genes were detected in Drosophila melanogaster, where scription factor Pou4f2 (also known as Brn-3b) (6). they exert multiple functions during embryogenesis. In verte- . Typical isolated ocular coloboma is a congen- brates, Pax genes are also involved in embryogenesis. Muta- ital abnormality caused by defective closure of the embryonic tions in four out nine characterized Pax genes have been fissure of the optic cup (Figure 1). The defect is typically associated with either congenital human diseases such as located in the lower part of the . The association of a Waardenburg syndrome (Pax3), (Pax6), Peter’s coloboma to urinary anomalies may evoke a papillorenal syn- anomaly (Pax6), renal coloboma syndrome (Pax2), or sponta- drome. However, among some patients with a ‘renal-colobo- neous mouse mutants, which all show defects in development. ma‘ syndrome, Pax2 mutation was not found. A clinical anal- Recently, analysis of spontaneous and transgenic mouse mu- ysis can nevertheless help the diagnostic orientation as shown tants has revealed that vertebrate pax genes are key regulators in Figure 2. during organogenesis of kidney, eye, ear, nose, limb muscles, Renal-Coloboma Syndrome (OMIM 120330). The predom- vertebral column, and brain (2). inant abnormalities associated with renal-coloboma syndrome are bilateral optic nerve and renal hypoplasia, with or without renal failure. A significant degree of clinical vari- Correspondence to Dr. Hassane Izzedine, Department of Nephrology, 47–83 Boulevard de l’Hoˆpital, 75013 Paris France. Phone: ϩ33-0-1-42-17-72-26; ation is observed between family members who share the same Fax: ϩ33-0-1-42-17-72-32; E-mail: [email protected] mutation (7). Moreover, patients with renal-coloboma syn- 1046-6673/1402-0516 drome and Pax2 mutations may have additional congenital Journal of the American Society of Nephrology anomalies that occur with variable penetrance. These anoma- Copyright © 2003 by the American Society of Nephrology lies include vesico-ureteral reflux (VUR), auditory anomalies, DOI: 10.1097/01.ASN.0000051705.97966.AD CNS anomalies, and and joint anomalies (8). J Am Soc Nephrol 14: 516–529, 2003 Eye and Kidney 517

Figure 1. Fundus photograph showing a large coloboma involving the and the adjacent retina.

Figure 2. Coloboma with renal anomalies.

Patients with mutations in Pax2 have colobomatous eye (8). Iris colobomas have not been observed in patients with defects. Developmental abnormalities of the optic fissure dur- mutations in Pax2. Sometimes the optic nerve colobomas in ing optic cup and stalk development result in a group of patients with renal-coloboma syndrome are described as morn- defects, including orbital cysts, , optic disc ing glory syndrome (10). dysplasia, and colobomas of the optic nerve and (9) All pa- Patients with Pax2 mutations often exhibit small kidneys tients identified to have mutations in Pax2 have been observed with reduction in size of both the and renal cortex. to have colobomatous defects at the posterior pole of the The renal disease in patients with Pax2 mutations is usually 518 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 516–529, 2003 progressive and frequently necessitates renal transplantation can also be associated with conditions af- after chronic renal failure (7,8), although patients with very fecting extrarenal organs, such as pigmentosa (SLS) minimal renal involvement have also been identified (3). Renal and ocular motor apraxia (Cogan syndrome). Except for the cortical biopsies have demonstrated mesangial fibrosis and ocular involvement, the pathologic and clinical features of SLS , involuting glomeruli, hyalinization of glo- are virtually identical to those of isolated nephronophthisis, meruli, atrophic tubules, and hyperplastic gomeruli with an including course of renal disease. Affected individuals invari- overall decreased number of glomeruli (7,8,11). Pathologic ably progress to end-stage renal failure, usually before the age examination of kidneys revealed cortical thinning, hypoplastic of 20 yr (18,19). They present a long-standing history of papillae with low numbers of gomeruli, and collecting ducts in polyuria-polydipsia, nocturia, mild proteinuria, unremarkable the cortex and the papilla, respectively, consistent with renal urine sediment, and symmetrically reduced-size kidneys con- hypoplasia (8). taining multiple small cysts. VUR is an important factor when considering determinants For nephronophthisis (NPHP), the primary genetic cause of of renal function loss in patients with renal-coloboma syn- chronic renal failure in young adults, three loci have been drome (12). It arises during development of the ureter in mapped, with forms on 2q13 (NPHP1, juvenile embryogenesis, and there is evidence that VUR can begin in form), 9q22 (NPHP2, infantile form), and 3q21-q22 (NPHP3, utero. VUR can cause both renal failure and scarring. It has adolescent form). Localization of a SLS locus to the region of been observed in 5 of 19 patients with Pax2 mutations, al- NPHP3 opens the possibilities of both diseases arising by though the frequency may be higher because VUR has a mutations within the same pleiotropic gene or two adjacent tendency to resolve with age (8,13). However, the more com- genes (20). Recently, a second locus associated with the juve- mon, nonsyndromic form of VUR maps to 1p13 and is not nile form of the disease, NPHP4, was mapped to linked to the PAX2 locus (14). The renal histology description 1p36 and constitutes a new locus for SLS associated with associated with renal-coloboma syndrome includes interstitial (21–23). fibrosis, glomerulosclerosis, and tubular atrophy and is similar CHARGE Syndrome (OMIM 302905). CHARGE syndrome to those observed in patients with VUR (12). In addition, later is named from its six major clinical features: Coloboma of the stages of in patients with VUR are associ- eye, defects, choanal Atresia, Retarded growth and de- ated with proteinuria and end-stage renal failure, which also velopment including CNS anomalies, Genital hypoplasia occur in patients with renal-coloboma syndrome. and/or urinary tract anomalies, and Ear anomalies and/or hear- The exact incidence of renal-coloboma syndrome (or of ing loss (24). Pax2 mutations) in the population is unknown. During embry- Ocular abnormalities were found in 44 of 50 patients diag- onic development, Pax2 expression (which gene localizes to nosed with CHARGE syndrome. The majority had retinocho- human chromosome band 10q24.3-q25.1 [15]) occurs in the roidal colobomata with optic nerve involvement, but only 13 developping urogenital system (kidney, ureter, and genital patients had an iris defect. Two patients had atypical iris tract), as well as the developing eye, ear, and central nervous colobomata with normal fundi. Additional features were mi- system (CNS) (16). In the kidney, Pax2 expression occurs in crophthalmos in 21 patients, in 4, nys- the early stages of mesenchymal to epithelial differentiation, tagmus in 12, and a vertical disorder of eye movement in 4 of preceding formation of the glomerulus. Pax2 expression is also the 22 cases with facial palsy (25). Of the 24 patients who found in the ureteric bud and at low levels in epithelia such as underwent renal ultrasound, 10 (42%) were diagnosed with collecting duct, renal pelvis, and ureter (16). In the developing urinary tract anomalies, including a solitary kidney, hydrone- eye, Pax2 expression starts in the optic placode and then phrosis, renal hypoplasia and duplex kidneys. Further evalua- continues in the optic vesicle. As the optic vesicle folds and tion revealed , neurogenic bladder second- becomes a bilayer optic cup, Pax2 expression is restricted to ary to spinal dysraphism, nephrolithiasis, ureteropelvic the optic fissure and along the length of the optic stalk (17). junction obstruction, and a nonfunctioning upper pole in both Renal-Coloboma Like Syndrome. Pax2 mutation was not duplex kidneys (26). found in some patients with renal-coloboma syndrome or a COACH Syndrome (OMIM 216360). COACH syndrome is renal-coloboma-like syndrome (13). Other syndromes that in- characterized by hypoplasia of , oligophrenia, volve renal and ocular anomalies and have similarities to congenital ataxia, coloboma, and hepatic fibrosis. The occur- renal-coloboma syndrome include Senior-Loken syndrome rence of multiple cases in single sibships suggests an autoso- (SLS), CHARGE syndrome (colobomas, heart anomalies, cho- mal recessive inheritance. Progressive renal insufficiency with anal atresia, retardation, genitourinary anomalies, and ear fibrocystic changes on is found as a common anomalies), COACH syndrome (cerebellar vermis hypo/apla- manifestation of COACH syndrome (27). Nephronophtisis, sia, oligophrenia, congenital ataxia, coloboma, hepatic fibro- fibrocystic renal disease, oligophrenia, and small medullar sis), , acrorenoocular syndrome, and bilateral cysts have also been described. macular coloboma with hypercalciuria syndrome. Aniridia. Aniridia is a severe characterized by Senior-Loken Syndrome (OMIM 266900). SLS is an auto- iris hypoplasia. Both sporadic and familial cases with autoso- somal recessive disorder defined by the association of - mal dominant inheritance have been reported. Mutations in the ophthisis and tapetoretinal degeneration. It occurs in approxi- Pax6 gene have been shown to be the genetic cause of the mately 18% of all cases of nephronophthisis (18). disease (OMIM 106210). Other ocular findings include de- J Am Soc Nephrol 14: 516–529, 2003 Eye and Kidney 519 creased vision, , glaucom, Peter’s anomaly (congenital abnormalities in the three ossicles of the middle ear derived anomaly of the anterior segment), and corneal clouding. Some from the first and second branchial arches, whereas the of the sporadic cases are caused by large chromosomal dele- branchial fistulae relates to abnormalities of the second, third, tions, some of which also include the Wilms tumor gene and fourth arches. In the embryonic human kidney, the EYA1 (WAGR syndrome), resulting in an increased risk of develop- gene is expressed strongly; in the BOR syndrome, there is an ing Wilms tumor (28). A variety of WT1 mutations induces inductive fault between the ureteric bud and the metanephric renal development defects such as the dominant Wilms tumor/ mesenchymal mass as the ureteric bud branches into the renal aniridia/genital anomaly/mental retardation syndrome (WAGR parenchyma (33). Mutations in human EYA1 gene are mapping syndrome; OMIM 194072), Denys-Drash syndrome (DDS; on chromosome 8q13.3. OMIM 194080), and Frasier syndrome (FS; OMIM 136680). The BOR syndrome is an autosomal dominant disease char- Wilms tumor (nephroblastoma) is a childhood tumor of the acterized by hearing loss of early onset, preauricular pits, kidney (1/10,000 live births) originating from the metanephric branchial clefts, and early progressive chronic renal failure in blastema. Patients with Wilms tumor are at an increased risk up to 40% of family affected members (33). Azuma et al. (34) for developing ocular disorders, including aniridia and, less identified three novel missense mutations in patients who had frequently, optic nerve hypoplasia resulting from inactivation congenital and ocular anterior segment anomalies. of the aniridia gene Pax6, which lies telomeric of WT1 on One of the patients had clinical features of BOR syndrome as chromosome 11p13 (29). Unlike the genetic mechanism lead- well. The most important renal abnormalities that lead to ing to the development of retinoblastoma, an embryonal tumor end-stage renal disease include unilateral with of childhood affecting the retina, which only requires the controlateral hypodysplasia characterized by decreased renal inactivation of one single gene, the biological pathways lead- volume and size, loss of ultrasound normal corticomedullary ing to the development of Wilms tumor are complex and likely differenciation, and hyperechogenicity of the renal cortex. His- involve several genetic loci (30). tologically there is glomerular hyalinization, mesangial prolif- Denys-Drash Syndrome. On 100 reports of intragenic WT1 eration, and basement membrane splitting. Bilateral renal agen- mutations, the accompanying clinical phenotypes revealed 5% esis is the extreme, leading to miscarriage or immediate of sporadic Wilms tumours and Ͼ90% of patients with the neonatal death. Other renal abnormalities include bifid kidneys DDS (renal nephropathy, severe , a steroid-resis- with double , cystic dysplasia, vesico-ureteric reflux, tant that rapidly progresses to end-stage and pelviureteric stenoses (33). The BOR syndrome should be renal disease before the age of 5 yr, male pseudohermaphro- included in the differential diagnosis of deafness and chronic dism, predisposition to Wilms tumor [31]). Renal biopsy renal failure in childhood and adolescence. showed diffuse mesangial sclerosis and focal segmental scle- rosis. Podocytes exhibit decreased or absent WT1 expression but persistent Pax2 expression. It is proposed that patients with BMP7 Mutation (OMIM 600779) early onset, rapidly progressive nephrotic syndrome and dif- The bone morphogenetic proteins are members of the fuse mesangial or focal segmental sclerosis should be tested for TGF-␤ superfamily purified by Ozkaynak et al. (35). Hahn et WT1 mutations to identify those at risk for developing Wilms al. (36) mapped the BMP7 gene to human by tumor (32). study of human-rodent somatic cell hybrid lines with cDNA Frasier Syndrome. FS includes a slowly progressing ne- probes. Marker et al. (37) suggested that the human BMP7 phrotic syndrome attributable to minimal glomerular changes gene may be on 20q13.1–q13.3, extrapolating from the fact or focal segmental glomerulosclerosis and complete male or that the BMP7 gene in the mouse is between Ada (localized to female gender reversal in 46 XY patients but no signs of Wilms 20q12–q13.11) and Pck1 (localized to 20q13.2–q13.31). tumor. In contrast to DDS, end-stage renal disease develops BMP-7 and Kidney Development. During vertebrate de- more slowly and at a later stage in life (3). velopment, the metanephric mesenchyme undergoes an epithe- lial transformation to form the glomerulus and the tubules of Eya1 Gene the . This nephrogenic process begins at 11.5 days The Drosophila eyes absent gene (eya) is involved in the post conception (dpc) with mesenchymal condensation and is formation of compound eyes. Flies with loss-of-function mu- initiated by signals coming from the ureteric bud such as tations of this gene develop no eyes and form the ectopic eye growth factors. Observations reported suggest that BMP-7 is an in the antennae and the ventral zone of the head on target early inducer of nephrogenesis. Moreover, deletion of BMP-7 expression. A highly conserved homologous gene in various in mice results in failure of the metanephric mesenchyme and invertebrates and vertebrates has been shown to function in the leads to loss of mesenchymal cell condensation around the formation of the eye. In contrast, a human homologue, EYA1, ureteric bud and eventually to glomerular and tubular agenesis has been identified by positional cloning as a candidate gene and severely hypoplastic kidneys. In addition to its role as a for branchio-oto-renal (BOR) syndrome (OMIM 113650), in renal morphogen, BMP-7 probably is a critical renal tubular which phenotypic manifestations are restricted to the areas of differentiation factor determining epithelial cell phenotype. In branchial arch, ear, and kidney, with usually no anomalies in the absence of BMP-7, only incomplete mesenchymal conden- the eye. The EYA1 gene is expressed very early, between the sations are identified in the kidney at 12.5 dpc and the meta- 4th and 6th weeks of human development. Deafness relates to nephric mesenchymal cells died before 14.5 dpc, a phenome- 520 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 516–529, 2003

Table 1. Oculorenal syndromesa Genes, Genes Lesions Products, and Clinical Syndrome Chromosomes Eye Kidney Before nephrogenesis Pax2 10q24.3– Orbital cysts, Renal agenesis, Renal-coloboma q25.1 microphthalmia duplication, vesico- syndrome coloboma (optic nerve, ureteral reflux, retina) hydronephrosis Pax6, WT1 11p13 Aniridia, decreased Nephroblastoma, renal WAGR contiguous vision, cataract, failure deletion syndrome , Peter’s anomaly, corneal clouding JAGϪ1 (NOTCH 1) Protenia embryotoxon, Renal dysplasia, Alagille syndrome 20q121 , mesangiolipidosis, , , tubulointerstitial retinitis pigmentosa , tubuloacidosis, renal failure, medullary cystic disease During nephrogenesis ureteric duct induction Pax2 10q24.3– Orbital cysts, Renal agenesis, Renal-coloboma q25.1 microphthalmia duplication, vesico- syndrome, morning coloboma (optic nerve, ureteral reflux, glory syndrome retina) hydronephrosis EYA1 8q13.3 Renal dysplasia/ BOR syndrome aplasia, renal collecting system anomalies, polycystic kidneys WT1 Aniridia Nephroblastoma, renal WAGR syndrome failure collecting system EGF, EYA1, Pax2 Renal hypo/dysplasia, Oligomeganephronia, development reduction in nephron BOR syndrome, number Renal-coloboma syndrome mesenchymal- BMP7 chr20 Absence of Renal hypo/dysplasia, ? epithelial transition Intergrin ␣8 formation (in mice) tubular agenesis glomerulogenesis filtration barrier LMX1b Strabismus cataract, Normal renal Nail-patella syndrome 9q34.1 micro-, architecture, microphthalmia, proteinuria, , glaucoma, microscopic keratoconus, , heterochromia glomerulonephritis, nephrotic syndrome, renal failure mesangial PDGF-␤ and Glomerulosclerosis Denys-Drash syndrome PDGF-␤ receptors WT1 After nephrogenesis collecting system, PKD1/PKD2 Cyst formation ADPKD mesenchyme-derived (16p/4q) tubules vHL Retinal hemangioma, Cyst formation, renal von Hippel Lindeau 3p26–p25 hemangioblastoma, disease renal cell carcinoma, renal cysts J Am Soc Nephrol 14: 516–529, 2003 Eye and Kidney 521

Table 1. Oculorenal syndromesa (cont’d) Genes, Genes Lesions Products, and Clinical Syndrome Chromosomes Eye Kidney

collecting system TSC1 (9q34) Retinal astrocystic Cyst formation, TSC TSC2 (Tuberin) hamartoma, angiomyolipoma, renal (16p13.3) microphthalmia, cell carcinoma , optic nerve atrophy

X-linked Cornea verticilata, Renal failure, isosthenuria, Fabry disease Xq22 cataract, conjunctival tubular dysfunction, irefrin- varicosity, retinal vessel gent lipid globules in tortuosity, retinal artery urine, foum vacuole cells occlusion Nephrocystin 2q13 Retinitis pigmentosa, retinal Medullary cystic disease, Nephronophthisis aplasia/hypoplasia, retinal renal failure, isosthenuria, Senior-Loken dystrophy hypokalemia, excess syndrome urinary sodium and potassium loss, interstitial fibrosis, tubular atrophy, relatively spared glomeruli PEX 7p11.23 , Cyst formation, proteinuria, Zellweger syndrome microphthalmia, retinal aminoaciduria, cortical degeneration, cataract dysplasia Hydronephrosis, absence renal peroxisomes Elastin 7q11.2 Stellate pattern of iris Small, or solitary kidney Williams-Beuren , nephrocal- syndrome cinosis, renal insufficiency, , vesicoureteral reflux P-type ATPase Kayser-Fleiscer corneal Proximal renal tubular Wilson disease 13q14.3 ring, cataract dysfunction, renal calculi glomerulus Col4A3A4 Progressive anterior Microscopic hematuria, (2q35–q37) lenticonus, pigment nephritis, renal failure, Col4A5 (xq11–q22) epitheliopathy, cataract nephrotic syndrome fundus punctatus, optic nerve drusen Fibrillin 1 (FBN1) Lens ectopia retinal Focal segmental and/or Marfan syndrome 15q21.1 detachment, corneal mesangial flatness, hydromygia, glomerulonephritis, renal iris hypoplasia, early artery stenosis glaucoma JAGϪ1 (NOTCH 1) Protenia embryotoxon, Renal dysplasia, mesangio- Alagille syndrome 20q12 keratoconus, strabismus, lipidosis, tubulointerstitial myopia, retinitis nephritis, tubuloacidosis, pigmentosa renal failure, medullary cystic disease LCAT 16q22.1 Corneal dystrophy, corneal Renal failure before 50 yr, LCAT deficiency lipid deposits, corneal Glomerular lacunes with (Norum syndrome) opacities, vascular dense bodies , arcus juvenitis, angoid streaks, , aniridia, megalocornea

a EGF, epithelial growth factor; BMP7, bone morphogenetic protein7; PDGF, platelet degradation growth factor; ADPKD, autosomal dominant polycystic disease; vHL, von Hippel Lindau; TSC, tuberous sclerosis complex; PEX, peroxysome; LCAT, Lecithin: acyltransferase. 522 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 516–529, 2003 non that is also observed when the metanephric mesenchyme is chemical signs of cholestasis. Thus the authors concluded cultured in the absence of proper inductive tissues (38). that AGS should be included in the differential diagnosis of BMP-7 and Eye Development. Lens formation is the cystic kidney disorders associated with cholestatic result of reciprocal inductive interaction between the optic disease. A mesangiopathic glomerulopathy with fibrillary vesicle and the surface ectoderm. Genetic evidence has dem- deposits and foam cells and medullar cysts have been de- onstrated that the optic vesicle is required for lens formation in scribed (46). Other renal lesions include membranous ne- mice (39). This reciprocal interaction leads to the formation of phropathy and lamellated glomerular basement membrane the lens vesicle from the surface ectoderm at ~10.5 dpc (40). In (47). Cystic renal disease with or without renal dysplasia, about 35 % of BMP-7m1/BMP-7m1 embryos, interaction be- tubulointerstitial nephritis, , renal ar- tween the optic vesicle and the surface ectoderm did not occur tery stenosis, renovascular hypertension, , properly, resulting in the unilateral or bilateral absence of lens and vesicoureteric reflux have also been reported in associ- formation in these animals. The expression of BMP-7 during ation with AGS. eye development suggests that it is involved directly in lens • Woolfenden et al. (48) described two children with sporadic formation. The importance of BMP-7 during eye development AGS associated with moya-moya. They interpreted this has also been suggested by in vitro culture experiments show- finding as indicating that AGS is a vasculopathy. Li et al. ing that anti-BMP-7 antibodies can block lens formation in (49) demonstrated that AGS is caused by mutations in the m1 cultured rat embryos. However, 86% of the BMP-7 embryos human homolog of Jagged-1 (Jag1), which encodes a ligand did develop lens (or lenses), indicating that genes segregating for Notch1. They concluded that AGS is caused by haplo- in the F2 animals can suppress this aspect of the BMP-7– insufficiency of Jag1. They mapped the human Jag1 gene deficient phenotype. (OMIM 601920) to the AGS critical region within 20p12. Giannakudis et al. (50) detected parental mosaicism for a and Ocular Abnormalities Jag1 mutation in 4 of 51 families in which mutations had Alagille Syndrome (AGS; OMIM 118450). In addition been identified in the AGS patients and where parental to neonatal , features of this syndrome include poste- DNA was available. The co-localization and genetic inter- rior embryotoxon and retinal pigmentary changes and: action of Jag1 and Notch2 (OMIM 600275) imply that this ligand and this receptor physically interact, forming part of • In the heart: pulmonic valvular stenosis as well as peripheral the signal transduction pathway required for glomerular arterial stenosis differentiation and patterning. Notch2(del1)/Notch2(del1) • In the : abnormal vertebrae (butterfly vertebrae) and homozygotes also display myocardial hypoplasia, , decrease in interpediculate distance in the lumbar spine and hyperplasia of cells associated with the hyaloid vascu- • In the nervous system: absent deep tendon reflexes and poor lature of the eye. These data identify novel developmental school performance roles for Notch2 in kidney, heart, and eye development (51). • In the facies: broad forehead, pointed mandible, and bulbous tip of the nose Zellweger Syndrome (OMIM 214100). Zellweger syn- • In the fingers: varying degrees of foreshortening (41,42) drome is a fatal recessively inherited disease with disturbed • The syndrome has an autosomal dominant inheritance, and function of many organs. The disease is caused by a defect of the gene is located at 20p12 (43). Most often, AGS leads to peroxisomes, subcellular organelles, which are absent in these chronic in childhood with severe morbidity and patients. Several genes are necessary for the formation and a mortality of 10 to 20%. LaBrecque et al. (44) described 15 function of the peroxisomes. The clinical picture of Zellweger affected persons in four generations. They all presented with syndrome can be caused by defects in a number of genes. renal dyslasia and associated in some Ophthalmic manifestations include corneal opacification, cat- cases with hypertension. Simple ophthalmic examination of aract, glaucoma, pigmentary retinopathy, tapetoretinal degen- children with neonatal cholestatic jaundice and their parents eration, and optic atrophy (52). Polycystic kidneys with ade- should allow early diagnosis of AGS, eliminating the need quate functional renal parenchyma and cortical renal cysts for extensive and invasive investigations. The most common were described. The Zellweger gene is on chromosome ocular abnormalities in patients were posterior embryotoxon 7q11.13. (95%), iris abnormalities (45%), diffuse fundus hypopig- Autosomal Dominant Polycystic (OMIM mentation (57%), speckling of the retinal pigment epithe- 601313, 173910). Autosomal dominant polycystic kidney lium (33%), and optic disc anomalies (76%). Microcornea disease (ADPKD) is a frequent affecting 1 out was not associated with large refractive errors, and visual of 1000 individuals. The predicted protein has been named acuity was not significantly affected by these ocular polycystin. Cell-matrix interactions have been suggested to be changes. Martin et al. (45) described three children with important for kidney development (53), and there is some Alagille syndrome, in two of whom a unilateral multicystic evidence that laminin-1 and its receptors could be involved dysplastic kidney was detected by prenatal ultrasound. In (54). the third child, a solitary cortical cyst was detected later in It has been determined that the embryogenetic stages of eye childhood. All had normal renal function, growth, and liver and kidney development occur rather simultaneously (55). synthetic function but continued to have clinical and bio- From the 7th to the 10th week, the development of the ocular J Am Soc Nephrol 14: 516–529, 2003 Eye and Kidney 523 architecture progresses in parallel with the differenciation of cysts and angiomas develop in approximately two thirds of the kidney tubules (56). It is conceivable that the unknown cases (70) and include benign cysts and renal cell carcinoma. factor leading to the development of renal tubular cysts in utero In addition, renal adenomas, hemangiomas, and adrenal cell might simultaneously affect the eye and the kidney. Meyrier et carcinoma occur but are rare. Simple cysts are most frequent al. (57) reported a strongly association between ADPKD and and are observed in about 75% of patients. Renal cell carci- blepharochalasis. Other ocular abnormalities including severe noma tends to occur in younger patients, has an equal gender myopia, cataracts, papilledema, and peripheral retinal pigmen- distribution, and is usually bilateral and multicentric. The clear tation have also been described in association with ADPKD cell type of renal cell carcinoma is the most common type of (58). cancer in vHL. Carcinomas occur in about one fourth of cases, Mutant mice that develop severe kidney phenotypes as metastasize in about half of those, and cause death in about one adults include the Bcl-2 mutant mice with polycystic kidneys third (71). It is estimated that renal carcinoma will develop in (59), the s-liminin/laminin ␤2 mutant mice, which develop approximately 70% of patients who survive to age 60 yr (70). massive proteinuria (60), the epidermal growth factor receptor Computer tomography scanning, which is more sensitive, mutant mice with cystic dilations of the collectiong ducts (61), should be performed every 3 yr or more frequently in patients the tensin mutant mice, which develop progressive kidney with multiple cysts (70). The renal lesions, depending or the degeneration (62), and the cyclooxygenase 2 mutant mice, sign and the number of the angiomata, could generate enlarge- which die from chronic renal failure most likely as a result of ment of the kidney and may cause renal failure. Pheochromo- reduced nephron mass (63). cytoma, which is often asymptomatic, may occur with equal Digenic inherantance have been reported for polycystic kid- frequency. Pheochromocytoma occurs in 10 to 19% of vHL ney disease, where it was hypothesized that cyst formation patients. There is usually bilateral involvement. The median results from the inheritance of one germinal mutation in one of age is 28 yr. Polycythemia, due to the ectopic production of two PKD1 or PKD2 genes, and the occurrence of a second-hit, erythropoietin by the hemangioblastoma or carcinoma, is oc- somatic mutation in the other interacting gene, thereby gener- casionnally present and may disappear after the excision of the ating a trans-heterozygous situation in the affected cystic cell tumor (72). (64). Sturge-Weber-Krabble Syndrome (Phacomatosis Pig- von Hippel Lindau Disease (OMIM 193300). The von mentovascularis; OMIM 185300). Sturge-Weber syndrome Hippel-Lindau (vHL) syndrome is transmitted as an autosomal (SWS) or encephalotrigeminal syndrome is a dermato-oculo- dominant trait with variable penetrance. Its clinical manifesta- neural syndrome involving cutaneous facial nevus flammeus in tions include cerebellar and retinal hemangioblastomas, pan- the area of the first and/or second division of the trigeminal creatic cysts, carcinoma, renal cell carcinoma, and pheochro- nerve, ipsilateral glaucoma, ipsilateral diffuse cavernous hem- mocytoma (65). The vHL gene is on chromosome 3 (3p25-26) angioma of the , and ipsilateral leptomeningeal hem- (66) and functions normally as a tumor suppressor by inhibit- angioma (73). The classical cutaneous feature of SWS is facial ing transcription elongation (67). nevus flammeus, which is usually unilateral and may be asso- The classic ophthalmologic finding is heamanglioblastoma, ciated with hypertrophy of the involved skin of the face. a round, red tumor of the retina with a pair of feeding vessels One of the ocular manifestations of SWS is diffuse choroidal showing an increase in diameter and tortuosity. Angiomatosis hemangioma (74), usually on the same side as facial nevus retinae may cause severe impairment of vision as a result of flammeus. The ocular component manifests as glaucoma and retinal detachment. Blindness or near-blindness typically hap- vascular malformations of the , episclera, choroid, pens without preceding symptoms and without pain. Capillary and retina. Glaucoma is present in approximately half of the hemangioma of the retina may occur as either an isolated cases on hemangioma’s facialis side. Patients in whom the retinal vascular abnormality or as one of the many systemic lesion affects the upper are at increased risk of glaucoma abnormalities of vHL disease. Progressive intraretinal and sub- (70). The Nevus of Ota is a melanocytic pigmentary disorder, retinal exudation occurs as the angioma develops. If it remains most commonly involving the area innervated by the trigemi- untreated, either exudative or tractional retinal detachment or nal nerve. Elevated intraocular pressure, with or without glau- may result (68). Retinal telangiectasis associated comatous damage, is observed in 10% of the cases (75). with facioscapulohumeral muscular dystrophy (69) and Alport Episcleral venous telangiectasia vessels were prominent fea- syndrome may also cause massive outpouring of exudate into tures. Other ocular manifestations (retinal vascular tortuosity, the outer retinal layers and may result in exudative retinal iris heterochromia, choroidal hemangioma, buphthalmos, reti- detachment. nal detachment, and strabismus) also occurred (70–76). Optic Kidney disorders have been found in up to 60% of vHL neuropathy has not been reported as a component of this subjects at autopsy. The mean age at detection of renal lesions syndrome (77). is approximately 35 yr (65). Loin pain or complaints of an The involvement of the kidneys or urinary tract occurs abdominal mass and, infrequently, gross hematuria have been usually by hemangiomas. Vascular manifestations occur within reported, mainly in patients with large tumors. Hypertension, the renal pelvis, papilla, and . They are gener- renal function deterioration, and proteinuria have rarely been ally solitary, causing varying degrees of hematuria. Occasion- observed in vHL patients with renal lesions. Cysts as numerous ally, the hemangioma may present as a mass with perirenal as in polycystic kidney disease are very seldom too (65). Renal hematoma associated with other abnormalities, such as dupli- 524 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 516–529, 2003 cation of the inferior vena cava or abnormalities of the renal rosis, glomerular microharmartomas (92), renal artery stenosis venous system (78). (93), ureteropelvic junction stenosis, and horseshoe kidney. Tuberous Sclerosis Complex (OMIM 191100). Tuber- Bardet-Biedl Syndrome (OMIM 209900). Bardet-Biedl ous sclerosis complex (TSC, synonym: Bourneville-Pringle syndrome (BBS) is a genetically heterogeneous disorder with disease) (79) an autosomal dominant disease with variable the primary features of obesity, pigmentary retinopathy, poly- penetrance, is a multisytem disorder characterized by the for- dactyly, renal malformations, mental retardation, and hypogen- mation of angiomyolipomas or tubers affecting predominantly italism. BBS is considered an autosomal recessive disorder, the brain, the skin (called adenoma sebaceum), the kidneys, the with increased risk for diabetes mellitus, hypertension, and eyes, and the heart (80). Two different genetic loci have been congenital heart disease. The incidence of BBS is approxi- identified: one on chromosome 9 (TSC1) and one on chromo- mately 1/100,000 with a predicted heterozygote frequency of some 16p (TSC2) that is immediately adjacent to the gene for 1/160, and it has been suggested that heterozygotes are at the most common form of autosomal dominant polycystic increased risk of obesity and hypertension. What was once kidney disease (PKD1) (81). thought to be a homogeneous autosomal recessive disorder is The most suggestive eye finding of TSC is the retinal astro- now known to map to at least six loci: 11q13 (BBS1), 16q21 cytic hamartoma found in 50 to 85% of patients (82). Other (BBS2), 3p13 p12 (BBS3), 15q22.3 q23 (BBS4), 2q31 (BBS5), internal eye findings may include atypical colobomas, mi- and 20p12 (BBS6). There has been considerable interest in crophthalmia, exophtalmos, hypomelanotic maculs, and optic identifying the genes that underlie BBS, because some com- nerve atrophy. ponents of the phenotype are common. Cases of BBS mapping The main renal manifestations of TSC are angiomyolipo- to BBS6 are caused by mutations in MKKS; mutations in this mas, cysts, and renal cell carcinomas. Hematuria is not a gene also cause McKusick-Kaufman syndrome (hydrometro- common feature, possibly because of the expansive rather than colpos, post-axial polydactyly and congenital heart defects). infiltrative growth. On rare occasions, patients may have a The BBS6 protein has similarity to a Thermoplasma acidophi- catastrophic presentation of sudden flank pain associated with lum chaperonin, whereas BBS2 and BBS4 have no significant a palpable abdominal mass and symptoms of anemia. This similarity to chaperonins. It has recently been suggested that complex syndrome is referred to as the Wunderlich triad and is three mutated alleles (two at one locus, and a third at a second caused by spontaneous rupture of the tumor into the retroper- locus) may be required for manifestation of BBS (triallelic itoneal space (83). Less than 40% of the patients with renal inheritance). The identification of the gene BBS1 is a frequent angiomyolipoma have significant proteinuria. Massive protein- cause of BBS and is not involved in triallelic inheritance (94). uria are rare. There is a high incidence of hypertension in TSC, Ocular abnormalities include rod-cone dystrophy, onset be even when the renal function is normal (84). Many patients end of second decade (major), retinitis pigmentosa, strabismus, with tuberous sclerosis have no symptoms referable to the and cataracts Renal abnormalities have been described in up to kidney. Renin-dependent hypertension, due to focal areas or 100% of BBS patients, and renal failure occuring in 30 to 60% around the cyst, and chronic renal failure also can of patients is the major cause of morbidity and early mortality occur. Rarely, hypertension may result from renal artery aneu- in BBS. Hypertension has been noted in 50 to 66% of cases. rysm (85). The development of end-stage renal disease is Dysplasia, chronic glomerulonephritis, cystic tubular disease, unusual and appears to result primarily from the replacement calyceal and lower urinary tract malformations, defects of and compression of the renal parenchyma by angiomyolipoma tubular concentrating ability, nephrogenic , and cysts. The angiomyolipoma is found in 50 to 80% of the and microaneurysms and occlusions in renal arterioles have all patientsand bilateral localisation has also been reported. The been reported (95). main manifestations of the renal angiomyolipomas relate to their potential for hemorrhage (hematuria, intratumoral, or Glomerulopathies and Eye Abnormalities retroperitoneal hemorrhage) and mass effects (abdominal or Alport Syndrome. The classic phenotype as described by flank mass and tenderness, hypertension, renal insufficiency) Alport (96) is nephritis, often progressing to renal failure, and (86). Angiomyolipomas can also cause fever of unknown ori- sensorineural hearing loss affecting both genders in successive gin (87). Cystic disease is the second most common renal generations. The renal disease becomes evident as recurrent manifestation of TSC (88). Renal cysts in TSC are predomi- microscopic or gross hematuria as early as childhood, earlier in nately bilateral, multiple and vary in size from microscopic males than in females. Progression to renal failure is gradual “hamartial germs” to that of a “grapefruit,” often similar to the and usually occurs in males by the fifth decade. Nephrotic adult type of polycystic kidney disease. The major clinical syndrome is unusual but has been reported. The renal histology problem associated with severe cystic changes in TSC is the is nonspecific; both glomerular and interstitial abnormalities, development of nephrolithiasis, hypertension, and renal failure. including foam cells, occur. Immunofluorescence studies have The majority of the patients with TSC that present with poly- provided little evidence for an immunologic basis for renal cystic-like kidneys at an early age have a contiguous gene damage. Hearing loss, which is sensorineural and primarily syndrome with deletions affecting both the TSC-2 and the affects high tones, occurs in 30 to 50% of relatives with renal PKD1 genes (89). Renal cell carcinoma in TSC has also been disease. In about 85% of AS pedigrees, the disease is X-linked reported (90). Other associations rarely recognized include (Xq22) (OMIM 301050), and mutations identified so far are in renal interstitial disease (91), focal segmental glomeruloscle- the ␣5 (IV) collagen chain gene (COL4A5) (97). In the vast J Am Soc Nephrol 14: 516–529, 2003 Eye and Kidney 525 majority of the remaining families, the transmission is autoso- immediately brings to mind the AS with which every nephrol- mal recessive with mutations detected in the genes coding ␣3 ogist is well acquainted; this is not always correct. Morever, (IV) and ␣4 (IV) collagen chains (chromosome 2) (98). The there are various inherited conditions in which sensorineural gene frequency of AS is about 1 in 5000, and the disease deafness is associated with renal disease, including Alport’s accounts for about 0.6% of all patients who start renal replace- variants, Muckle-Wells syndrome, Refsum disease, Cockayne ment therapy in Europe. Diffuse leiomyomatosis and megath- syndrome, renal tubular acidosis, ichtyosis and prolinuria, rombocytopenia have also been described in AS. Charcot-Marie-Thoot syndrome, Alstro¨m’s syndrome, ataxia, The ocular manifestations (15 to 30%) of AS mainly involve hyperuricemia, photomyoclonus, familial spastic paraplegia the lens. Bilateral anterior lenticonus is the most specific with intellectual retardation, mitochondrial disorders, and hypo abnormality (97–99). When present, the lenticonus is bilateral and hyperparathyroidism (104). in about 75% of patients. It is far more common in affected Nail Patella Syndrome (NPS, Onychoosteodysplasia) males but may occur in females. Lens opacities may be seen in (OMIM 161200). Hereditary osteo-onychodysplasia (HOOD) conjunction with lenticonus, occasionally resulting from rup- or nail-patella syndrome (NPS) is a rare, autosomal dominant ture of the anterior lens capsule. Anterior lenticonus has been disorder. Dysplasia of the nails and absent or hypoplastic patellae confused with anterior pyramidal opacities, which may be are the cardinal features but others are iliac horns, abnormality of associated with microcornea and anterior chamber cleavage the elbows interfering with pronation and supination, and in some anomalies. Macular flecks are a second characteristic feature of cases nephropathy. Renal involvement is an inconstant finding as AS. Govan (100) concluded that the diagnosis of AS may be the presence of fibrillar collagen within the GBM. The gene is made on the presence of characteristic features. Nontraumatic closely linked to those coding for ABO blood groups and for recurrent corneal erosion (101) and an association with a adenylate kinase. The three genes are located at the distal end of macular lesion similar to the cone dystrophy have only infre- the long arm of chromosome 9 (9q34) (105). quently been reported. Pigmentary changes in the perimacular Ocular manifestations include a dark pigmentation at inner region, consisting of whitish or yellowish granulations sur- margin of iris. Strabismus, lens opacities, Lester sign, micro- rounding the foveal area and corneal endothelial vesicles, have cornea, microphthalmia, kerotoconus, cataracts, heterochro- also been reported. Cataract, spherophakia, and cone dystrophy mia, , and nystagmus have also been reported (106). were also described in AS. Anterior segment anomalies can lead to impaired vision and Persistent microscopic hematuria is a constant feature in glaucoma (107). male patients with AS. Many also have episodic gross hema- Clinical renal involvement seems to occur in about 30 to 40 turia, precipitated by upper respiratory infections, during the % of cases (108). Proteinuria, sometimes associated with mi- first two decades of life. Proteinuria is usually absent during croscopic haematuria, is the most frequent presenting feature. the first few years of life but develops eventually in males with Nephrotic syndrome was observed in 3 of 122 patients re- X-linked AS and proteinuria increases progressively with age viewed by Meyrier et al. (109). Progression to end-stage renal and may culminate in the nephrotic syndrome. Hypertension failure occurs in about 30% of patients with renal symptoms. also increases in incidence and severity with age. The rate of Cases of rapid evolution to renal failure have been observed in progression to renal failure is fairly constant among affected the pediatric population. Various types of superimposed ne- males within a particular family, although significant intrakin- phritis, Goodpasture syndrome (110), membranous nephropa- dred variability in the rate of progression to renal failure has thy (111), necrotizing angiitis (112), and IgA nephropathy occasionally been reported. (109) have been observed in HOOD patients. As demonstrated Anti-GBM disease appears in 5 to 10% of Alport patients by electron microscopy by Morita et al. (113) among others, who received a kidney transplant after the development of many collagen fibrils are present in the thickened basement renal failure. These antisera do not bind to Alport glomerular membranes and in mesangial matrix of otherwise normal glo- basement membrane and were found to be reactive to the meruli. Abnormalities of collagen at this site have also been ␣3(IV) chain. Kalluri et al. (102) found that posttransplant demonstrated in AS. Both of these conditions may be special anti-GBM alloantibodies harvested from an X-linked Alport forms of heritable disorders of connective tissue. patient with complete COL4A5 gene deletion that were specif- The Goodpasture antigen, an autoantibody, is directed ically targeted to the ␣3(IV) chain. In further studies, Kalluri et against type IV collagen of basement membrane or some al. demonstrated posttransplant anti-␣3(IV) collagen alloanti- element closely associated with it. The occurrence of Good- bodies in a patient with autosomal recessive AS caused by pasture syndrome in a patient with NPS (110) may be more deletion of the last 198 amino acids of the ␣3(IV) chain. than a coincidence. Taguchi et al. (114) demonstrated that Milliner et al. (103) estimated that approximately 1 to 5% of characteristic ultrastructural changes in the glomerulus can be Alport patients who received renal transplants develop a spe- present, even in patients without apparent clinical renal in- cific anti-GBM nephritis, subsequently leading to loss of the volvement. From study of a large family with 30 patients with renal graft. These data suggested that Alport syndrome patients NPS (which the authors referred to as HOOD), Looij et al. with a type IV collagen mutation resulting in absence of the (115) concluded that a person with NPS has a risk of about 1 NC domain have an increased risk of developing anti-GBM in 4 of having a child with NPS nephropathy and a risk of about nephritis after renal transplantation. 1 in 10 of having a child in whom renal failure will develop. In nephrology, the association of renal failure and deafness The nail-patella locus and the ABO blood group locus are 526 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 516–529, 2003 linked. The recombination fraction is about 10%, but it is the regulation of aqueous humor outflow. Mutations in the higher in females than in males (116). The LIM-homeodomain coding region of the human NBC1 gene in exons common to protein Lmx1b plays a central role in dorsal/ventral patterning both pNBC1 and kNBC1 result in a syndrome with a severe of the vertebrate limb. Targeted disruption of Lmx1b results in ocular and renal phenotype (blindness, , glau- skeletal defects, including hypoplastic nails, absent patellae, coma, cataracts, and proximal renal tubular acidosis) (122). and a unique form of renal dysplasia (117). Dreyer et al. (118) showed that the Lmx1B gene maps to 9q in the same region References than the NPS locus by fluorescence in situ hybridization. Most 1. Pohl M, Bhatnagar V, Mendoza SA, Nigam SK: Toward an NPS families only inquire about prenatal diagnosis in the hope etiological classification of developmental disorders of the kid- that severity can be predicted. It is in this regard that ultrasound ney and upper urinary tract. Kidney Int 61: 10–19, 2002 may be of use in detecting early signs of severe renal damage, 2. Dahl E, Koseki H, Balling R: Pax genes and organogenesis. because there is no correlation between the Lmx1b mutation Bioessays 19: 755–765, 1997 and the presence of kidney disease or overall NPS severity. 3. Mrowka C, Schedl A: Wilms’ tumor suppressor gene WT1: LCAT Deficiency (OMIM 245900). Familial lecithin: From structure to renal pathophysiologic features. JAmSoc cholesterol acyltransferase (LCAT) deficiency syndrome is Nephrol 11: S106-S115, 2000 inherited as an autosomal recessive disorder and is character- 4. Wagner N, Wagner KD, Schley G, Coupland SE, Heimann H, ized by disturbances in . The gene for LCAT is Grantyn R, Scholz H: The wilms’ tumor suppressor is found on the long arm of chromosome 16 in the region 16q22 associated with the differentiation of retinoblastoma cells. Cell Growth Differ 13: 297–305, 2002 (119) and appears to be linked to the serum ␣-haptoglobin 5. Armstrong JF, Pritchard-Jones K, Bickmore WA, Hastie ND, locus (120). Clinically this enzymatic defect is characterized Bard JB: The expression of the Wilms’ tumour gene, WT1, in the by diffuse corneal opacities: “arcus lipoides juvenits”, target developing mammalian embryo. Mech Dev 40: 85–97, 1993 cell hemolytic anemia, lipid accumulation, and “sea-blue” his- 6. Wang SW, Gan L, Martin SE, Klein WH: Abnormal polarization tiocytes on bone marrow, spleen, and arterial walls, and de- and axon outgrowth in retinal ganglion cells lacking the POU- creased cone plasma esterified cholesterol and kidney defects. domain transcription factor Brn-3b. Mol Cell Neurosci 16: 141– Corneal opacities are found in all patients. They consist of 156, 2000 numerous minute, grayish dots in the entire corneal stroma 7. Schimmenti LA, Cunliffe HE, McNoe LA, Ward TA, French giving the cornea a cloudy to misty appearance. 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