Eye and Kidney
Authors: Hassane Izzedine, Bahram Bodaghi, Vincent Launay-Vacher, Gilbert Deray
Journal: Journal of the American Society of Nephrology (2003)

Although the study of embryonic eye and kidney development was first studied in the middle of the 19th century, three decades passed until scientists identified the molecular controls of both renal and eye organogenesis. Most of these advances have come from mouse and rodent gene manipulation. Translation of the mouse data to human congenital oculorenal disease has just begun. Examples of these genes include Pax2 and bone morphogenic protein 7 (BMP-7). Others factors that participate in mouse ocular and renal organogenesis, such as epithelial growth factor or integrins, may later be proven important in human eye and kidney development. A variety of human congenital syndromes affecting both organs have been described. An interesting pathophysiological classification scheme on kidney diseases has been very recently reported by Pohl et al (1). We propose a clinical diagnostic approach of oculorenal syndromes with their genetic's links. Renal Dysgenesis and Eye Abnormalities Pax and WT1 Gene Families Pax genes are a family of developmental control genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA-binding activity. Originally, paired-box-containing genes were detected in Drosophila melanogaster, where they exert multiple functions during embryogenesis. In vertebrates, Pax genes are also involved in embryogenesis. Mutations in four out nine characterized Pax genes have been associated with either congenital human diseases such as Waardenburg syndrome (Pax3), Aniridia (Pax6), Peter's anomaly (Pax6), renal coloboma syndrome (Pax2), or spontaneous mouse mutants, which all show defects in development. Recently, analysis of spontaneous and transgenic mouse mutants has revealed that vertebrate pax genes are key regulators during organogenesis of kidney, eye, ear, nose, limb muscles, vertebral column, and brain (2). The expression pattern of Wilms' tumor suppressor 1 (WT1) during embryogenesis is highly complex. WT1 has at least two functions during the first stage of kidney development. First, it may be required for the inductive signal that induces the outgrowth of the ureter from the mesonephros. Second, it seems to be involved in either survival or reception of the survival signal from the ureteric bud (3). In addition to its role in genitourinary formation, WT1 is required for the differentiation of ganglion cells in the developing retina (4). Wilms' tumor gene was originally identified on the basis of its mutational inactivation in 10 to 15% of all Wilms' tumors. A preliminary report on the expression of WT1 in the developing eye is remarkable because it points toward a possible role for WT1 in ocular development (5). Severe abnormalities were also found in the WT1−/− retinas at later stages of development. Consistent with the expression of WT1 in the inner portion of the WT1+/+ retina, a significant fraction of cells was lost apoptosis in the developing retinal ganglion cells of mutant E18 embryos. Defects in the remaining ganglion cells in the WT1−/− retinas are indicated by failure of these cells to give rise to normally growing optic nerve fiber bundles. This phenotype of the WT1−/− retinas is reminiscent of the abnormalities seen in mice, which lack the POU-domain transcription factor Pou4f2 (also known as Brn-3b) (6). Coloboma. Typical isolated ocular coloboma is a congenital abnormality caused by defective closure of the embryonic fissure of the optic cup (Figure 1). The defect is typically located in the lower part of the iris. The association of a coloboma to urinary anomalies may evoke a papillorenal syndrome. However, among some patients with a 'renal-coloboma' syndrome, Pax2 mutation was not found. A clinical analysis can nevertheless help the diagnostic orientation as shown in Figure 2.Figure 1.: Fundus photograph showing a large coloboma involving the optic disc and the adjacent retina.Figure 2.: Coloboma with renal anomalies.Renal-Coloboma Syndrome (OMIM 120330). The predominant abnormalities associated with renal-coloboma syndrome are bilateral optic nerve colobomas and renal hypoplasia, with or without renal failure. A significant degree of clinical variation is observed between family members who share the same mutation (7). Moreover, patients with renal-coloboma syndrome and Pax2 mutations may have additional congenital anomalies that occur with variable penetrance. These anomalies include vesico-ureteral reflux (VUR), auditory anomalies, CNS anomalies, and skin and joint anomalies (8). Patients with mutations in Pax2 have colobomatous eye defects. Developmental abnormalities of the optic fissure during optic cup and stalk development result in a group of defects, including orbital cysts, microphthalmia, optic disc dysplasia, and colobomas of the optic nerve and (9) All patients identified to have mutations in Pax2 have been observed to have colobomatous defects at the posterior pole of the globe (8). Iris colobomas have not been observed in patients with mutations in Pax2. Sometimes the optic nerve colobomas in patients with renal-coloboma syndrome are described as morning glory syndrome (10). Patients with Pax2 mutations often exhibit small kidneys with reduction in size of both the renal pelvis and renal cortex. The renal disease in patients with Pax2 mutations is usually progressive and frequently necessitates renal transplantation after chronic renal failure (7,8), although patients with very minimal renal involvement have also been identified (3). Renal cortical biopsies have demonstrated mesangial fibrosis and glomerulosclerosis, involuting glomeruli, hyalinization of glomeruli, atrophic tubules, and hyperplastic gomeruli with an overall decreased number of glomeruli (7,8,11). Pathologic examination of kidneys revealed cortical thinning, hypoplastic papillae with low numbers of gomeruli, and collecting ducts in the cortex and the papilla, respectively, consistent with renal hypoplasia (8). VUR is an important factor when considering determinants of renal function loss in patients with renal-coloboma syndrome (12). It arises during development of the ureter in embryogenesis, and there is evidence that VUR can begin in utero. VUR can cause both renal failure and scarring. It has been observed in 5 of 19 patients with Pax2 mutations, although the frequency may be higher because VUR has a tendency to resolve with age (8,13). However, the more common, nonsyndromic form of VUR maps to 1p13 and is not linked to the PAX2 locus (14). The renal histology description associated with renal-coloboma syndrome includes interstitial fibrosis, glomerulosclerosis, and tubular atrophy and is similar to those observed in patients with VUR (12). In addition, later stages of reflux nephropathy in patients with VUR are associated with proteinuria and end-stage renal failure, which also occur in patients with renal-coloboma syndrome. The exact incidence of renal-coloboma syndrome (or of Pax2 mutations) in the population is unknown. During embryonic development, Pax2 expression (which gene localizes to human chromosome band 10q24.3-q25.1 [15]) occurs in the developping urogenital system (kidney, ureter, and genital tract), as well as the developing eye, ear, and central nervous system (CNS) (16). In the kidney, Pax2 expression occurs in the early stages of mesenchymal to epithelial differentiation, preceding formation of the glomerulus. Pax2 expression is also found in the ureteric bud and at low levels in epithelia such as collecting duct, renal pelvis, and ureter (16). In the developing eye, Pax2 expression starts in the optic placode and then continues in the optic vesicle. As the optic vesicle folds and becomes a bilayer optic cup, Pax2 expression is restricted to the optic fissure and along the length of the optic stalk (17). Renal-Coloboma Like Syndrome. Pax2 mutation was not found in some patients with renal-coloboma syndrome or a renal-coloboma-like syndrome (13). Other syndromes that involve renal and ocular anomalies and have similarities to renal-coloboma syndrome include Senior-Loken syndrome (SLS), CHARGE syndrome (colobomas, heart anomalies, choanal atresia, retardation, genitourinary anomalies, and ear anomalies), COACH syndrome (cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, hepatic fibrosis), Joubert syndrome, acrorenoocular syndrome, and bilateral macular coloboma with hypercalciuria syndrome. Senior-Loken Syndrome (OMIM 266900). SLS is an autosomal recessive disorder defined by the association of nephronophthisis and tapetoretinal degeneration. It occurs in approximately 18% of all cases of nephronophthisis (18). Nephronophthisis can also be associated with conditions affecting extrarenal organs, such as retinitis pigmentosa (SLS) and ocular motor apraxia (Cogan syndrome). Except for the ocular involvement, the pathologic and clinical features of SLS are virtually identical to those of isolated nephronophthisis, including course of renal disease. Affected individuals invariably progress to end-stage renal failure, usually before the age of 20 yr (18,19). They present a long-standing history of polyuria-polydipsia, nocturia, mild proteinuria, unremarkable urine sediment, and symmetrically reduced-size kidneys containing multiple small cysts. For nephronophthisis (NPHP), the primary genetic cause of chronic renal failure in young adults, three loci have been mapped, with forms on chromosomes 2q13 (NPHP1, juvenile form), 9q22 (NPHP2,infantile form), and 3q21-q22 (NPHP3,adolescent form). Localization of a SLS locus to the region of NPHP3 opens the possibilities of both diseases arising by mutations within the same pleiotropic gene or two adjacent genes (20). Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 and constitutes a new locus for SLS associated with retinitis pigmentosa (21–23). CHARGE Syndrome (OMIM 302905). CHARGE syndrome is named from its six major clinical features: Coloboma of the eye, Heart defects, choanal Atresia, Retarded growth and development including CNS anomalies, Genital hypoplasia and/or urinary tract anomalies, and Ear anomalies and/or hearing loss (24). Ocular abnormalities were found in 44 of 50 patients diagnosed with CHARGE syndrome. The majority had retinochoroidal colobomata with optic nerve involvement, but only 13 patients had an iris defect. Two patients had atypical iris colobomata with normal fundi. Additional features were microphthalmos in 21 patients, optic nerve hypoplasia in 4, nystagmus in 12, and a vertical disorder of eye movement in 4 of the 22 cases with facial palsy (25). Of the 24 patients who underwent renal ultrasound, 10 (42%) were diagnosed with urinary tract anomalies, including a solitary kidney, hydronephrosis, renal hypoplasia and duplex kidneys. Further evaluation revealed vesicoureteral reflux, neurogenic bladder secondary to spinal dysraphism, nephrolithiasis, ureteropelvic junction obstruction, and a nonfunctioning upper pole in both duplex kidneys (26). COACH Syndrome (OMIM 216360). COACH syndrome is characterized by hypoplasia of cerebellar vermis, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis. The occurrence of multiple cases in single sibships suggests an autosomal recessive inheritance. Progressive renal insufficiency with fibrocystic changes on renal biopsy is found as a common manifestation of COACH syndrome (27). Nephronophtisis, fibrocystic renal disease, oligophrenia, and small medullar cysts have also been described. Aniridia. Aniridia is a severe eye disease characterized by iris hypoplasia. Both sporadic and familial cases with autosomal dominant inheritance have been reported. Mutations in the Pax6 gene have been shown to be the genetic cause of the disease (OMIM 106210). Other ocular findings include decreased vision, cataract, glaucom, Peter's anomaly (congenital anomaly of the anterior segment), and corneal clouding. Some of the sporadic cases are caused by large chromosomal deletions, some of which also include the Wilms tumor gene (WAGR syndrome), resulting in an increased risk of developing Wilms tumor (28). A variety of WT1 mutations induces renal development defects such as the dominant Wilms tumor/aniridia/genital anomaly/mental retardation syndrome (WAGR syndrome; OMIM 194072), Denys-Drash syndrome (DDS; OMIM 194080), and Frasier syndrome (FS; OMIM 136680). Wilms tumor (nephroblastoma) is a childhood tumor of the kidney (1/10,000 live births) originating from the metanephric blastema. Patients with Wilms tumor are at an increased risk for developing ocular disorders, including aniridia and, less frequently, optic nerve hypoplasia resulting from inactivation of the aniridia gene Pax6, which lies telomeric of WT1 on chromosome 11p13 (29). Unlike the genetic mechanism leading to the development of retinoblastoma, an embryonal tumor of childhood affecting the retina, which only requires the inactivation of one single gene, the biological pathways leading to the development of Wilms tumor are complex and likely involve several genetic loci (30). Denys-Drash Syndrome. On 100 reports of intragenic WT1 mutations, the accompanying clinical phenotypes revealed 5% of sporadic Wilms tumours and >90% of patients with the DDS (renal nephropathy, severe hypertension, a steroid-resistant nephrotic syndrome that rapidly progresses to end-stage renal disease before the age of 5 yr, male pseudohermaphrodism, predisposition to Wilms tumor [31]). Renal biopsy showed diffuse mesangial sclerosis and focal segmental sclerosis. Podocytes exhibit decreased or absent WT1 expression but persistent Pax2 expression. It is proposed that patients with early onset, rapidly progressive nephrotic syndrome and diffuse mesangial or focal segmental sclerosis should be tested for WT1 mutations to identify those at risk for developing Wilms tumor (32). Frasier Syndrome. FS includes a slowly progressing nephrotic syndrome attributable to minimal glomerular changes or focal segmental glomerulosclerosis and complete male or female gender reversal in 46 XY patients but no signs of Wilms tumor. In contrast to DDS, end-stage renal disease develops more slowly and at a later stage in life (3). Eya1 Gene The Drosophila eyes absent gene (eya) is involved in the formation of compound eyes. Flies with loss-of-function mutations of this gene develop no eyes and form the ectopic eye in the antennae and the ventral zone of the head on target expression. A highly conserved homologous gene in various invertebrates and vertebrates has been shown to function in the formation of the eye. In contrast, a human homologue, EYA1, has been identified by positional cloning as a candidate gene for branchio-oto-renal (BOR) syndrome (OMIM 113650), in which phenotypic manifestations are restricted to the areas of branchial arch, ear, and kidney, with usually no anomalies in the eye. The EYA1 gene is expressed very early, between the 4th and 6th weeks of human development. Deafness relates to abnormalities in the three ossicles of the middle ear derived from the first and second branchial arches, whereas the branchial fistulae relates to abnormalities of the second, third, and fourth arches. In the embryonic human kidney, the EYA1 gene is expressed strongly; in the BOR syndrome, there is an inductive fault between the ureteric bud and the metanephric mesenchymal mass as the ureteric bud branches into the renal parenchyma (33). Mutations in human EYA1 gene are mapping on chromosome 8q13.3. The BOR syndrome is an autosomal dominant disease characterized by hearing loss of early onset, preauricular pits, branchial clefts, and early progressive chronic renal failure in up to 40% of family affected members (33). Azuma et al. (34) identified three novel missense mutations in patients who had congenital cataracts and ocular anterior segment anomalies. One of the patients had clinical features of BOR syndrome as well. The most important renal abnormalities that lead to end-stage renal disease include unilateral renal agenesis with controlateral hypodysplasia characterized by decreased renal volume and size, loss of ultrasound normal corticomedullary differenciation, and hyperechogenicity of the renal cortex. Histologically there is glomerular hyalinization, mesangial proliferation, and basement membrane splitting. Bilateral renal agenesis is the extreme, leading to miscarriage or immediate neonatal death. Other renal abnormalities include bifid kidneys with double ureters, cystic dysplasia, vesico-ureteric reflux, and pelviureteric stenoses (33). The BOR syndrome should be included in the differential diagnosis of deafness and chronic renal failure in childhood and adolescence.Table 1: Oculorenal syndromesaTable 1: Oculorenal syndromesa (cont'd)BMP7 Mutation (OMIM 600779) The bone morphogenetic proteins are members of the TGF-β superfamily purified by Ozkaynak et al. (35). Hahn et al. (36) mapped the BMP7 gene to human chromosome 20 by study of human-rodent somatic cell hybrid lines with cDNA probes. Marker et al. (37) suggested that the human BMP7 gene may be on 20q13.1–q13.3, extrapolating from the fact that the BMP7 gene in the mouse is between Ada (localized to 20q12–q13.11) and Pck1 (localized to 20q13.2–q13.31). BMP-7 and Kidney Development. During vertebrate development, the metanephric mesenchyme undergoes an epithelial transformation to form the glomerulus and the tubules of the nephrons. This nephrogenic process begins at 11.5 days post conception (dpc) with mesenchymal condensation and is initiated by signals coming from the ureteric bud such as growth factors. Observations reported suggest that BMP-7 is an early inducer of nephrogenesis. Moreover, deletion of BMP-7 in mice results in failure of the metanephric mesenchyme and leads to loss of mesenchymal cell condensation around the ureteric bud and eventually to glomerular and tubular agenesis and severely hypoplastic kidneys. In addition to its role as a renal morphogen, BMP-7 probably is a critical renal tubular differentiation factor determining epithelial cell phenotype. In the absence of BMP-7, only incomplete mesenchymal condensations are identified in the kidney at 12.5 dpc and the metanephric mesenchymal cells died before 14.5 dpc, a phenomenon that is also observed when the metanephric mesenchyme is cultured in the absence of proper inductive tissues (38). BMP-7 and Eye Development. Lens formation is the result of reciprocal inductive interaction between the optic vesicle and the surface ectoderm. Genetic evidence has demonstrated that the optic vesicle is required for lens formation in mice (39). This reciprocal interaction leads to the formation of the lens vesicle from the surface ectoderm at ∼10.5 dpc (40). In about 35 % of BMP-7m1/BMP-7m1 embryos, interaction between the optic vesicle and the surface ectoderm did not occur properly, resulting in the unilateral or bilateral absence of lens formation in these animals. The expression of BMP-7 during eye development suggests that it is involved directly in lens formation. The importance of BMP-7 during eye development has also been suggested by in vitro culture experiments showing that anti-BMP-7 antibodies can block lens formation in cultured rat embryos. However, 86% of the BMP-7m1 embryos did develop lens (or lenses), indicating that genes segregating in the F2 animals can suppress this aspect of the BMP-7–deficient phenotype. Renal Cyst and Ocular Abnormalities Alagille Syndrome (AGS; OMIM 118450). In addition to neonatal jaundice, features of this syndrome include posterior embryotoxon and retinal pigmentary changes and: In the heart: pulmonic valvular stenosis as well as peripheral arterial stenosis In the bones: abnormal vertebrae (butterfly vertebrae) and decrease in interpediculate distance in the lumbar spine In the nervous system: absent deep tendon reflexes and poor school performance In the facies: broad forehead, pointed mandible, and bulbous tip of the nose In the fingers: varying degrees of foreshortening (41,42) The syndrome has an autosomal dominant inheritance, and the gene is located at 20p12 (43). Most often, AGS leads to chronic liver disease in childhood with severe morbidity and a mortality of 10 to 20%. LaBrecque et al. (44) described 15 affected persons in four generations. They all presented with renal dyslasia and renal artery stenosis associated in some cases with hypertension. Simple ophthalmic examination of children with neonatal cholestatic jaundice and their parents should allow early diagnosis of AGS, eliminating the need for extensive and invasive investigations. The most common ocular abnormalities in patients were posterior embryotoxon (95%), iris abnormalities (45%), diffuse fundus hypopigmentation (57%), speckling of the retinal pigment epithelium (33%), and optic disc anomalies (76%). Microcornea was not associated with large refractive errors, and visual acuity was not significantly affected by these ocular changes. Martin et al. (45) described three children with Alagille syndrome, in two of whom a unilateral multicystic dysplastic kidney was detected by prenatal ultrasound. In the third child, a solitary cortical cyst was detected later in childhood. All had normal renal function, growth, and liver synthetic function but continued to have clinical and biochemical signs of cholestasis. Thus the authors concluded that AGS should be included in the differential diagnosis of cystic kidney disorders associated with cholestatic liver disease. A mesangiopathic glomerulopathy with fibrillary deposits and foam cells and medullar cysts have been described (46). Other renal lesions include membranous nephropathy and lamellated glomerular basement membrane (47). Cystic renal disease with or without renal dysplasia, tubulointerstitial nephritis, renal tubular acidosis, renal artery stenosis, renovascular hypertension, horseshoe kidney, and vesicoureteric reflux have also been reported in association with AGS. Woolfenden et al. (48) described two children with sporadic AGS associated with moya-moya. They interpreted this finding as indicating that AGS is a vasculopathy. Li et al. (49) demonstrated that AGS is caused by mutations in the human homolog of Jagged-1 (Jag1), which encodes a ligand for Notch1. They concluded that AGS is caused by haploinsufficiency of Jag1. They mapped the human Jag1 gene (OMIM 601920) to the AGS critical region within 20p12. Giannakudis et al. (50) detected parental mosaicism for a Jag1 mutation in 4 of 51 families in which mutations had been identified in the AGS patients and where parental DNA was available. The co-localization and genetic interaction of Jag1 and Notch2 (OMIM 600275) imply that this ligand and this receptor physically interact, forming part of the signal transduction pathway required for glomerular differentiation and patterning. Notch2(del1)/Notch2(del1) homozygotes also display myocardial hypoplasia, edema, and hyperplasia of cells associated with the hyaloid vasculature of the eye. These data identify novel developmental roles for Notch2 in kidney, heart, and eye development (51). Zellweger Syndrome (OMIM 214100). Zellweger syndrome is a fatal recessively inherited disease with disturbed function of many organs. The disease is caused by a defect of peroxisomes, subcellular organelles, which are absent in these patients. Several genes are necessary for the formation and function of the peroxisomes. The clinical picture of Zellweger syndrome can be caused by defects in a number of genes. Ophthalmic manifestations include corneal opacification, cataract, glaucoma, pigmentary retinopathy, tapetoretinal degeneration, and optic atrophy (52). Polycystic kidneys with adequate functional renal parenchyma and cortical renal cysts were described. The Zellweger gene is on chromosome 7q11.13. Autosomal Dominant Polycystic Kidney Disease (OMIM 601313, 173910). Autosomal dominant polycystic kidney disease (ADPKD) is a frequent genetic disorder affecting 1 out of 1000 individuals. The predicted protein has been named polycystin. Cell-matrix interactions have been suggested to be important for kidney development (53), and there is some evidence that laminin-1 and its receptors could be involved (54). It has been determined that the embryogenetic stages of eye and kidney development occur rather simultaneously (55). From the 7th to the 10th week, the development of the ocular architecture progresses in parallel with the differenciation of the kidney tubules (56). It is conceivable that the unknown factor leading to the development of renal tubular cysts in utero might simultaneously affect the eye and the kidney. Meyrier et al. (57) reported a strongly association between ADPKD and blepharochalasis. Other ocular abnormalities including severe myopia, cataracts, papilledema, and peripheral retinal pigmentation have also been described in association with ADPKD (58). Mutant mice that develop severe kidney phenotypes as adults include the Bcl-2 mutant mice with polycystic kidneys (59), the s-liminin/laminin β2 mutant mice, which develop massive proteinuria (60), the epidermal growth factor receptor mutant mice with cystic dilations of the collectiong ducts (61), the tensin mutant mice, which develop progressive kidney degeneration (62), and the cyclooxygenase 2 mutant mice, which die from chronic renal failure most likely as a result of reduced nephron mass (63). Digenic inherantance have been reported for polycystic kidney disease, where it was hypothesized that cyst formation results from the inheritance of one germinal mutation in one of two PKD1 or PKD2 genes, and the occurrence of a second-hit, somatic mutation in the other interacting gene, thereby generating a trans-heterozygous situation in the affected cystic cell (64). von Hippel Lindau Disease (OMIM 193300). The von Hippel-Lindau (vHL) syndrome is transmitted as an autosomal dominant trait with variable penetrance. Its clinical manifestations include cerebellar and retinal hemangioblastomas, pancreatic cysts, carcinoma, renal cell carcinoma, and pheochromocytoma (65). The vHL gene is on chromosome 3 (3p25-26) (66) and functions normally as a tumor suppressor by inhibiting transcription elongation (67). The classic ophthalmologic finding is heamanglioblastoma, a round, red tumor of the retina with a pair of feeding vessels showing an increase in diameter and tortuosity. Angiomatosis retinae may cause severe impairment of vision as a result of retinal detachment. Blindness or near-blindness typically happens without preceding symptoms and without pain. Capillary hemangioma of the retina may occur as either an isolated retinal vascular abnormality or as one of the many systemic abnormalities of vHL disease. Progressive intraretinal and subretinal exudation occurs as the angioma develops. If it remains untreated, either exudative or tractional retinal detachment or retinoschisis may result (68). Retinal telangiectasis associated with facioscapulohumeral muscular dystrophy (69) and Alport syndrome may also cause massive outpouring of exudate into the outer retinal layers and may result in exudative retinal detachment. Kidney disorders have been found in up to 60% of vHL subjects at autopsy. The mean age at detection of renal lesions is approximately 35 yr (65). Loin pain or complaints of an abdominal mass and, infrequently, gross hematuria have been reported, mainly in patients with large tumors. Hypertension, renal function deterioration, and proteinuria have rarely been observed in vHL patients with renal lesions. Cysts as numerous as in polycystic kidney disease are very seldom too (65). Renal cysts and angiomas develop in approximately two thirds of cases (70) and include benign cysts and renal cell carcinoma. In addition, renal adenomas, hemangiomas, and adrenal cell carcinoma occur but are rare. Simple cysts are most frequent and are observed in about 75% of patients. Renal cell carcinoma tends to occur in younger patients, has an equal gender distribution, and is usually bilateral and multicentric. The clear cell type of renal cell carcinoma is the most common type of cancer in vHL. Carcinomas occur in about one fourth of cases, metastasize in about half of those, and cause death in about one third (71). It is estimated that renal carcinoma will develop in approximately 70% of patients who survive to age 60 yr (70). Computer tomography scanning, which is more sensitive, should be performed every 3 yr or more frequently in patients with multiple cysts (70). The renal lesions, depending or the sign and the number of the angiomata, could generate enlargement of the kidney and may cause renal failure. Pheochromocytoma, which is often asymptomatic, may occur with equal frequency. Pheochromocytoma occurs in 10 to 19% of vHL patients. There is usually bilateral involvement. The median age is 28 yr. Polycythemia, due to the ectopic production of erythropoietin by the hemangioblastoma or carcinoma, is occasionnally present and may disappear after the excision of the tumor (72). Sturge-Weber-Krabble Syndrome (Phacomatosis Pigmentovascularis; OMIM 185300). Sturge-Weber syndrome (SWS) or encephalotrigeminal syndrome is a dermato-oculo-neural syndrome involving cutaneous facial nevus flammeus in the area of the first and/or second division of the trigeminal nerve, ipsilateral glaucoma, ipsilateral diffuse cavernous hemangioma of the choroid, and ipsilateral leptomeningeal hemangioma (73). The classical cutaneous feature of SWS is facial nevus flammeus, which is usually unilateral and may be associated with hypertrophy of the involved skin of the face. One of the ocular manifestations of SWS is diffuse choroidal hemangioma (74), usually on the same side as facial nevus flammeus. The ocular component