http://www.kidney.org.uk/medical-info/kidney- disease/pckd.html NIH (NIDDK) Information Cle aring House: Takei R, Ubara Y, Hoshino J, et al. Percutaneous transcatheter hepatic artery embolization for liver cysts in autosomal dominant polycystic kidney disease. Am J Kidney Dis 2007; 49: 744 \200\223752. http://kidney.niddk.nih.gov/kudiseases/pubs/ polycystic/ Polycystic Kidney Disease Foundati on: Torres VE, Harris PC. Mechanisms of disease: autosomal dominant and recessive polycystic ki dney diseases. Nature Nat Clin Prac Nephrol 2006; 2: 40 \200\22354. http://www.pkdcure.org Walz G. Therapeutic approaches in autosomal dominant polycystic kidney disease (ADPKD): is there light at the end of the tunnel? Nephrol Dial Transplant 2006; 21: 1752 \200\2231757. See also Polycystic kidney disease in children, p. 586 Tuberose sclerosis and von Hippel \200\223Lindau disease, p. 598 Medullary sponge kidney, p. 664 Nephronophthisis, p. 600 Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intracra- nial aneurysms: natural history, clinical outcome, and risks of sur- gical and endovascular treatment. Lancet 2003; 362: 103 \200\223110. Internet resources The Polycystic Kidney Disease Charity: http://www.pkdcharity.co.uk/ This page intentionally left blank H. MORGAN 598 Tuberous sclerosis Introduction Tuberous sclerosis complex (TSC) is a multisystem disease associated with the growth of hamartomatous lesions in multiple organs. A de \201 nitive clinical diagnosis re quires the presence of two major criteria or one major and two minor criteria: Renal involvement Renal involvement occurs in 60% of patients: \200 renal angiomyolipoma (AML)(70 \200\22380%); \200 renal cysts (30 \200\22345%); \200 renal cell carcinoma (4% ). There is a clear genotype/phenotype correlation with TSC2 mutations having a more severe re nal phenotype: \200 \200 Major criteria \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 TSC2 60% AML vs TSC1 22% AML; TSC2 31% renal cysts vs TSC1 15% renal cysts. Cardiac rhabdomyoma. Cerebral cortical tuber. Hypomelanotic macule. Retinal hamartoma. Faci al angio \201 broma. Shagreen patch. Subependymal nodule. Subependymal giant-cell tumor. R enal angiomyolipoma. Ungual \201 broma. Lymphangiomyomatosis. With more numerous and bilateral lesions of both types with TSC2 mutations. Angiomyolipoma These are benign tumors composed of abnormal blood vessels, immature smooth muscle cells and fat cells. They commonly appear by 7 years of age. They may present with f rank hematuria (uncommon occurring in 4 \200\2239%). Life-threatening hemorrhage may occur. Like sporadic cases, AML in TSC are more common and more numerous in females. The presence of multiple AML is a reliable indicator of TSC. They are more likely than not to grow in s ize. They become more vascular as they increase in size. AML >4 cm are at increased risk of hemorrhage, 50% will bleed vs 5% <4 cm. AML are unlikely to develop in an individual who has not developed them by early adulthood. It is unlikely that TSC-related AML progress to carcinoma. Minor criteria \200 \200 \200 \200 \200 \200 \200 \200 Multiple renal cysts. Multiple pits in dental enamel. Hamartomatous rectal polyps. Bone cys ts. Cerebral white-matter radial migration lines. Gingival \201 bromas. Retinal achromic patch. \200\230Confetti \200\231 skin lesions. Epidemiology Incidence: 1 in 6000 to 10 000 live births. Prevalence: 1 in 23 000 from 15 to 45 years Renal cysts Cysts commonly appear by age 9 years. They are often single or small and multip le. A contiguous deletion of TSC2 and autosomal dominant polycystic kid- ney disease (PKD1) on chromosome 16 leads to early- onset polycystic kidney disease. These cysts are numerous and large. Cysts are more often associated with hypertension and renal impairment than AML but the majority are asymptomatic. TSC should always be included in the differential diagn osis of cystic kidney disease. 1 in 97 000 age >45 years. Genetics Autosomal dominant disorder resulting from inactivating mutations in two genes: \200 \200 TSC1 : chromosome 9q34, encoding hamartin; TSC2 : chromosome 16p13, encoding tuberin. More than 200 mutations have been identi \201 ed. \200 26% of patients have mutations in TSC1 ; \200 55% of patients have mutations in TSC2; \200 20% of patients have no identi \201 ed mutation. Renal cell carcinoma The mean age of occurrence is 28 years compared with 53 years in the g eneral population. There are variable histological subtypes; clear cell, papillary, chromop hobe and oncocytomas are reported. A germline (inherited) mutation inactivates one allele and a somatic mutation or loss of he terozygosity inactivates the remaining allele. New mutations (sporadic cases) account for 6 5% of patients. TSC1 and TSC2 proteins function as tumor suppressors; they form heterodimer s that integrate growth factors, nutrients and the cell cycle via the mammalian target of r apamycin (mTOR). Mutations lead to increased activity of mTOR which has a central role in t he control of cell growth and proliferation. Chronic kidney disease Renal impairment is an uncommon initial presentation of TSC (<1%). C KD may occur as a consequence of renal compression by AML, treatment of AML or glomeruloscl erosis but most commonly due to the polycystic phenotype. Overall 1% of patients will devel op ESRD with a mean age of onset of 36 years. The TSC2 polycystic phenotype is more likely to be symp- tomatic and lead to CKD. Clinical features Most patients are identi \201 ed due to central nervous system (CNS) dis ease (epilepsy or learning dif \201 culties) and skin lesions. Renal manifestations are of ten identi \201 ed during screening. CHAPTER 15.4 Tuberous sclerosis 599 Investigations Renal angiomyolipoma AML need to be 0.4 \200\2230.5 cm in diameter to be rel iably detected on USS. They are seen as hyperechoic lesions, equal to renal sinus fat. Fat is an important identifying feature of AML. On CT scan there should be attenuation equal to that of subcutaneous fat and no enhancement with contrast. MRI scans show high signal on T 1-weighted images. Diagnostic dif \201 culty can arise due to fat-poor AML that resemble c arcinoma on imaging. In cases of diagnostic doubt, surgical exploration should be considere d, not percutaneous biopsy. There is a signi \201 cant risk of bleeding from vascular AML and seeding of malig- nant tumors. Indeterminate AML on imaging studies often have indeter- minate pathology and may be mistakenly diagnosed as malignant lesions. In female patients aged >16 years AML are associated with pulmonary lymphangiomyomatosis. Due to the signi \201 cant morbidity, lung function and chest imaging should be undertaken. Renal transplantation There is no signi \201 cant increased risk of malignancy. In the lim ited number of reported patients followed long term, no malignancy occurred. The native kid neys do not need to be removed before transplant. There is no evidence that neurological fe atures worsen after renal transplantation. Follow-up Baseline renal USS should be performed in all patients before 5 years. If normal it should be repeated every 2 \200\2233 years. If abnormal it should be repeated every 12 m onths. If suspicious of carcinoma, MRI or CT is required and this should be repeated after 6 months. Prognosis Overall life expectancy is normal. Renal manifestations are the second most commo n cause of death after complica- tions of CNS disease. Progression of AML and cysts is dif \201 cult to predict but lesions become more numerous with age. Renal lesions may develop in adulthood after normal imag- ing in childhood (3% of cases with renal involvement). Morb idity from renal involvement is low, <10% require intervention. Renal cysts Cysts are sharply circumscribed smooth-walled anechoic structures on USS with w ater attenuation or \202 uid signals on CT/MRI. Complex lesions are not commonly seen in TSC and suggest carcinoma. Genetic testing In view of the genotype/phenotype correlation, blood for genetic mutation a nalysis should be taken. Future prospects Detailed understanding of TSC1 and TSC2 interactions with multiple cellula r pathways may identify potential anti- tumoral targets. The consequences of mTOR inhibitio n (sirolimus) require further study. Treatment A multidisciplinary team approach is required to effectively manage patients with TSC. CNS symptoms often predomi- nate; epilepsy is frequently the most prevalent and chall eng- ing clinical manifestation, occurring in 70 \200\22380% of patients. Young patients an d those with learning disability are likely to require general anesthetic for investigation and treatment. Further reading Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis com- plex. N Engl J Med 2006;355:1345 \200\2231356. Rakowski SK, Winterkorn EB, Paul E, et al. Renal manifestations of tuberous sclerosis compl ex: incidence, prognosis, and predictive factors. Kidney Int 2006;70:1777 \200\2231782. Angiomyolipoma Nephron-sparing strategies are required since renal involvement is typically bilateral. Treatment should be considered for: AML >4 cm in diameter; symptomatic AML of a ny size; rapidly growing asymptomatic AML. Internet resources UK Tuberous Sclerosis Association: \200 \200 www.tuberous-sclerosis.org TS Alliance (North America): www.tsalliance.org Selective arterial embolization is the treatment of choice. In experienced hands this allow s almost complete preser- vation of surrounding normal parenchyma. Embolization can be perf ormed on large AML, >20 cm. Pharmacological therapy is currently under investigation. Sirol imus, an inhibitor of mTOR, is being trialed in a multi- center phase II study of AML in TS C patients. See also Polycystic kidney disease in children, p. 586 Autosomal dominant polycystic kidney disease, p. 590 Tumors of the kidney, p. 668 Renal cysts Cysts rarely require treatment and may be managed as simple renal cysts. H. MORGAN 600 von Hippel \200\223Lindau disease Introduction von Hippel \200\223Lindau disease (VHL) is a familial, autosomal dominant, mul tisystem cancer syndrome. Patients develop multiple benign and malignant tumors in many org ans. The CNS, kidneys, adrenal glands and pancreas are most com- monly affected. A clinical diagnosis generally requires one major manifesta- tion in a patient with a positive family history or two major manifestations (including one retinal or CNS) in isolated cases. Cysts grow slowly (0.5 cm in diameter per year) and some may involute. Foci of cancer are f ound in cyst walls but transition to solid RCC is rare. Cysts generally precede the develop ment of RCC by 5 years. Renal cell carcinoma This is uncommon before 18 years. It occurs at a younger age and is mo re frequently bilateral or multicentric than sporadic cases. It often remains asymptomatic for long periods of time. Large tumors present with hematuria, \202 ank pain or abdom- in al mass. Neoplastic lesions uniformly enlarge (1.6 cm in diameter per year). Histologically all are clear cell subtype. Multiple (up to 600) microscopic tumors are present throughout both kidneys. Small carcinomas, <3 cm, tend to be low grade and rarely, if ever, metastasi ze. RCC is the leading cause of mortality for VHL patients. Most will develop recurrence po ssibly requiring the removal of all renal tissue. Major manifestations \200 \200 \200 \200 \200 Retinal hemangioblastoma. CNS hemangioblastoma. Renal cell carcinoma. Pheochromocytoma. Pan creatic tumor. Other manifestations \200 \200 \200 \200 Renal cysts. Pancreatic cysts. Endolymphsac tumor. Epididymal cystadenoma. Epidemiology Incidence: 1 in 36 000 live births. 90% penetrance by 65 years. End-stage renal disease One fourth (23%) of patients develop ESRD as a result of treatment of RCC. Genetics The VHL gene, on chromosome 3p25-26, encodes a tumor suppressor protein. Most pati ents (80%) inherit a germline mutation from an affected parent and normal wild type allele from an unaf- fected parent. Tumors develop after inactivation of the wild type allele in s usceptible organs. The same gene is inacti- vated in sporadic renal cell carcinoma (RCC) an d CNS hemangioblastoma. The VHL gene product, pVHL, is pivotal in angiogenesis via an oxyge n-sensing pathway involving hypoxia-inducible factor (HIF). Defective pVHL leads to increas ed acti- vation of HIF and overproduction of vascular growth factors. pVHL has multiple oth er functions with site-speci \201 c tumor risks dependent on the degree of expression. Investigations Renal ultrasound should be used to screen for renal involvement. Cysts are t hin-walled and have no solid component. Complex cystic and solid lesions suggest RCC and re quire CT or MRI. Lesions suspicious for RCC have attenuation greater than water and enhance with contrast. Pheochromocytoma should be excluded, by 24 h urine collection for catechola mines and metanephrines, prior to surgery or pregnancy. DNA should be sent for VHL gene mut ation analysis. Treatment A multidisciplinary team approach is required. The manage- ment of progressive, m ultiple tumors in various organs must be co-ordinated with treatment of the renal involveme nt. Clinical features Renal involvement occurs in up to 60% of patients and is found in the maj ority of patients as a result of screening: \200 \200 \200 renal cysts (50 \200\22370%); renal cell carcinoma (25 \200\22345%); end-stage renal diseas e (20 \200\22325%). Renal cell carcinoma Nephron-sparing surgical techniques should be employed; the goal is to remove lesions that could metastasize. Treatment should be considered for RCC >3 cm in dia meter. Smaller lesions should be followed until >3 cm. Arterial embolization, radiofrequenc y ablation, partial nephrectomy and tumor enucleation have been success- fully employed. Ph armacological agents blocking downstream targets of HIF have shown promise in early phase I studies. Renal cysts Cysts are usually few in number. They are typically asymptomatic and rarely bec ome infected or lead to hypertension and renal impairment. VHL should be included in the di fferential diagnosis of cystic kidney disease. The presence of numerous pancreatic cysts he lps to iden- tify VHL. CHAPTER 15.5 von Hippel \200\223Lindau disease 601 Future prospects Antiangiogenic therapies and speci \201 c inhibitors of HIF may be used f or the treatment of VHL-related RCC and spo- radic cases. Renal transplantation Graft and patient survival is similar to that of matched con- trols. (Note: overall survival is better with surveillance and nephron-sparing surgery.) A waiting period of 2 years to exclude recurrence of RCC should be considered. This may not be requi red in patients with low grade asymptomatic tumors found dur- ing screening. Excluding VHL mutations in family members, by genetic screening, will allow living related donor transpla ntation. Further reading Lonser RR, Glenn GM, Walther M, et al. von Hippel \200\223Lindau disease. Lancet 2003; 361: 2059 \200\2232067. Shuin T, Yamasaki I, Tamura K, et al. Von Hippel \200\223Lindau disease: molecular patholog ical basis, clinical criteria, genetic testing, clinical features of turmors and treatment. Jpn J Clin Oncol 2006; 36: 37 \200\22343. Follow-up Annual blood pressure from 5 years. Renal imaging: \200 \200 \200 Internet resources von Hippel \200\223Lindau Family Alliance: www.vhl.org Cancerbackup: renal USS from 8 years and annually thereafter; abdominal CT with contrast from 16 years; M RI as clinically indicated. http://www.cancerbackup.org.uk/home Annual 24 h urine for catecholamines and metanephrines from 11 years. See also Polycystic kidney disease in children, p. 586 Autosomal dominant polycystic kidney disease, p. 590 Tumors of the kidney, p. 668 Prognosis Any renal involvement is usually apparent between 18 and 30 years. An initial ons et after 60 years is very rare. ESRD develops due to repeated surgical removal of renal tis sue for the treatment of recurrent and multiple RCC. M.A. SALEEM 602 Nephronophthisis Introduction Nephronophthisis (NPHP), historically termed \200\230familial juvenile nephro nophthisis \200\231, is a chronic tubulointerstial nephritis and frequent cause of CKD in c hildren and ado- lescents. Inheritance is autosomal recessive, and consti- tutes the most f requent genetic cause for ESRD in the \201 rst three decades of life. which manifest with ESRD at the median ages of 1, 13 and 19 years, respectively. Symptoms Initial symptoms are relatively mild (except in infantile NPHP type 2). Typically it presents after 6 years of age through adolescence, but may become apparent in early chil dhood. At an average age of 9 years, a slightly raised serum Cr is noted. The clinical pres entation is insidious, and the early symptoms of polyuria and polydipsia are often overlook ed in the presence of a relatively normal urinalysis and in the absence of proteinuria, ure mia, and hypertension. Other typical symptoms to look out for include secondary enuresis an d anemia. Thus most patients are not diagnosed until after the onset of renal failure. If a patient presents with mild renal impairment, ESRD invariably develops within a few years. These children are excellent candidates for transplantation. Disease recurrence has never b een reported in kidneys that were transplanted to patients with NPHP. Epidemiology NPHP is the commonest cause of genetic ESRD in children and is commonly associ ated with nonrenal abnormalities. NPHP1 is the commonest form, with an incidence of 1:5000, and constitutes 25% of NPHP cases. NPHP1 and medullary cystic kidney disease (MCKD) accou nt for 10 \200\22320% of children with CKD and for 1 \200\2235% of all children undergoing dialysis or transplantation. Genetics Positional cloning has revealed seven monogenic recessive genes to date (NPHP1-6 a nd AHI1), suggesting that muta- tions in each of these genes is suf \201 cient to cause NP HP, and mammalian data suggest that the encoded proteins func- tion together. Syndromic associations NPHP is associated with several extrarenal features, often coming un der eponymous names according to the systems involved. These syndromes include: NPHP1 Mutations in NPHP1 were identi \201 ed as causing juvenile NPHP type 1. NPHP1 encode s nephrocystin-1, a protein that interacts with components of cell \200\223cell and cell \200\223matrix signaling. It also interacts with the products of other NPHP genes, such as nephrocystin-2/inversin, nephrocystin-3, and nephrocystin-4. Polymerase chain reaction test ing for the gene deletion causing type 1 disease is available. Senior \200\223L ken syndrome (SLSN) Retinal dystrophy, retinitis pigmentosa. Joubert syndrome ( JBTS) Retinal degeneration, cerebellar vermis aplasia, diffuse hypotonia and mental retardation. Cogan syndrome Ocular motor apraxia. NPHP2 The renal cystic changes of infantile NPHP (NPHP type 2) combine clinical features of NPHP and of polycystic kidney disease (PKD). Mutations in human inversin (INVS, the pro- t ein product of NPHP2) cause infantile NPHP (type 2) with and without situs inversus. Invers in interacts with nephro- cystin-1 and with -tubulin, which constitutes the microtu- bule axoneme of primary cilia (see below). In particular, inversin/NPHP2 function has been impl icated in signaling mechanisms of planar cell polarity. Mainzer \200\223Saldino syndrome Retinal pigmentary dystrophy, cerebellar ataxia and skelet al dysplasia (cone-shaped epiphyses of the hands). Leber \200\231s congenital amaurosis Retinal dystrophy. Jeune syndrome Asphyxiating thoracic dysplasia. NPHP3 By positional cloning in a large Venezuelan kindred, mutations in NPHP3 have been sho wn to be responsible for adolescent NPHP. The protein product is termed nephrocystin-3. Ellis \200\223van Creveld syndrome Chondroectodermal dysplasia. RHYNS syndrome Retinitis pigmentosa, hypopituitarism, NPHP, and skeletal dysplasia. NPHP4 Mutations in NPHP4 were identi \201 ed by homozygosity map- ping and total genome se arch for linkage. The encoded protein, nephrocystin-4/nephroretinin, is in a complex with o ther proteins that are involved in cell adhesion and actin cytoskeleton organization, such as nephrocystin-1, p130Cas, Pyk2, tensin, \201 lamin, and -tubulin. In polarized epithe lial cells, nephrocystin-4 localizes to primary cilia, basal bodies, and the cortical actin cytoskeleton, whereas in dividing cells, it localizes to centrosomes. Alstr m syndrome Retinitis pigmentosa, deafness, obesity, and diabetes with- out mental de fect, polydactyly, or hypogonadism. Meckel \200\223Gruber syndrome Additional NPHP-associated disorders are Sensenbrenner syndrome (cranioectodermal dysplasia ) and Arima syn- drome (cerebro-oculo-hepato-renal syndrome). NPHP has also been described in association with ulcerative colitis. As can be seen in this chapter, the delineation of the genes responsible for these disorders is clarifying the pheno- typing and classi \201 cation of the disease. In some instances, there seems to be a genotype/phenotype correlatio n. NPHP5, 6 and AHI1 \200\223 see below Clinical features (overview) Three clinical forms of NPHP have been distinguished by onset of ESRD: infantile, juvenile, and adolescent NPHP, CHAPTER 15.6 Nephronophthisis 603 For instance, there is involvement of the retina in all known cases with mutations of NPHP5 or NPHP6. In other instances, such as NPHP1 mutations, the eyes are involved in <10% of pa tients. The molecular basis of eye involve- ment is unknown. with bile duct ectasia. Bile duct involvement in these cystic kidney diseases may be explai ned by the ciliary theory, because the epithelial cells lining bile ducts (cholangi- ocytes ) possess primary cilia. Patients develop hepatomegaly and moderate portal \201 bro- sis with mild bile duct proliferation. This pattern differs from that of classical congenital h epatic \201 brosis, whereby biliary dysgenesis is prominent. A recessive mutation in the NPHP3 gene has been described in a patient with NPHP and liver \201 brosis. Hepatic invol vement in NPHP type 2 (infantile NPHP) seems to involve only transient elevation of transam inases. Extrarenal features NPHP is variably associated with conditions affecting extrarenal organs , such as retinitis pigmentosa (SLSN) and ocular motor apraxia (Cogan syndrome). Eyes The renal \200\223retinal involvement in SLSN can be explained by the fact that the pr imary cilium of renal epithelial cells is a structural equivalent of the connecting cilium of photore- ceptor cells in the retina. SLSN has been associated with NPHP1, 3, 4 and 5, an d it has been suggested to use the nomenclature SLSN1, SLSN2, SLSN4 and SLSN5 to corre- spo nd to the associated NPHS gene mutation. Similarly, patients with NPHP1 mutations as well a s those with NPHP4 mutations have been described with Cogan syn- drome, highlighting a poss ible pleiotropic effect of NPHP mutations. The heterogeneity of the renal \200\223retinal s yndrome is indi- cated by the variable age of onset of the retinal abnormality. In some fam ilies it is congenital, whereas in others it behaves like isolated recessive retinitis pigm entosa. In children with recessive mutations in the NPHP1, 2, 3, and 4 genes, retini- tis p igmentosa occurs in 10% of all affected families, with- out any obvious genotype/phenotype correlation. Three different terms have been used in the literature to describe the retina l \201 ndings of SLSN: retinitis pigmentosa, tapetoretinal degeneration, and retinal \200 \223renal dysplasia. This most likely re \202 ects a spectrum within the pathogene- sis th at includes developmental defects (dysplasia) as well as defects of tissue maintenance (deg eneration). In the retinal dysplasia of NPHP, pale optic nerve head and attenuated blood ve ssels are seen, as in other forms of chorioretinal degeneration. Fundoscopic alterations ar e present in all patients with late-onset SLSN by the age of 10 \200\223years. The late-ons et form manifests \201 rst with night blindness, followed by development of blindness dur ing school age. Retinal degeneration is characterized by a constant and complete extinction of the electroretinogram, which pre- cedes the development of visual and fundoscopic signs of retinitis pigmentosa. The kidney involvement in SLSN is identical clinically to what is known from patients with NPHP without ocular involvement regarding age of onset, symptoms, and histology of renal disease. Leber \200\231s congenital amaurosis is characterized by m oderate to severe visual impairment identi \201 ed at or within a few months of birth, inf antile nystagmus, sluggish pupillary responses (and occasionally a paradoxical pupil respon se), and absent or poorly recordable electroretinographic responses early in life. Addition al features include symmet- ric midfacial hypoplasia with enophthalmos and hyperme- tropic refractive errors. Congenital oculomotor apraxia (in Cogan syndrome), is a condition charac terized by (1) defective or absent horizon- tal voluntary eye movements, and (2) defective or absent horizontal ocular attraction movements. Central nervous system Recent \201 ndings suggest that oculomotor apraxia type Cogan (ass ociated with NPHP1 and NPHP4 mutations), cerebellar vermis hypoplasia (in JBTS), and mental retarda- tion (in NPHP type 6) may be due to defects in microtu- bule-associated functions during neurite outgrowth and axonal guidance. Cardiac The phenotypic combination of NPHP2, situs inversus, and cardiac septal defect (one patient with a VSD has been reported) on the basis of inversin mutations is observed in hu mans, mice, and zebra \201 sh. Clinical features according to genotype NPHP1 (juvenile form) In the various reports, anemi a, polyuria, polydipsia, and death in uremia have been features. Hypertension and proteinur ia are conspicuous by their absence. Excessive urinary loss of sodium accounts for the rari ty of hypertension. It has also been reported that decreased urine-concentrating ability mi ght be a manifestation of heterozygotes. Histologically the kidneys show morphologic change s affecting tubular basement membranes of all segments of the nephron, with or without cyst s. These included extreme thinning and attenuation, layering, and thickening. Also reported are interstitial lymphohistiocytic cell in \201 ltration, and development of cysts at the corticomedullary border of the kidneys. NPHP2 (infantile form) The speci \201 c clinical features of this disease are its early on set and rapid progression to ESRD. It presents within the \201 rst months of life with se vere renal failure and acidosis, associated with hypertension and polyuria in the majority. In addition, some patients display severe cholestatic liver disease though others may have hepatomegaly without his- tological disease. Renal ultrasound will con \201 rm lack of di stinct cysts, and some kindreds have been reported with enlarged and echogenic kidneys that lack corticomedullary differentiation. Renal biopsy is characterized by a diffuse chronic tubu- lointerstitial nephritis and particularly by the presence of microcystic dilatation o f proximal tubules and Bowman space. Pathologically, it differs from later-onset NPHP by th e absence of medullary cysts and thickened tubular basement membranes and by the presence o f cortical microcysts. NPHP3 (adolescent form) The history is similar to juvenile NPHP. Most patients suffer from anemia when they \201 rst come to medical attention. Liver Both NPHP and Bardet \200\223Biedl syndrome can be associated with liver \201 brosi s. Autosomal recessive PKD is also associated M.A. SALEEM 604 In adolescent NPHP, onset of ESRD occurs signific- antly later (median age 19 years; quarti le borders, 16.0 and 25.0 years) than in juvenile NPHP (median age 13.1 years; quartile bor ders, 11.3 and 17.3 years). Histologic \201 ndings in adolescent NPHP are generally not d istinguishable from those of juvenile NPHP. Renal pathol- ogy is thus characterized by alte rations of tubular base- ment membranes, tubular atrophy and dilatation, sclerosing tubuloi nterstitial nephropathy, and renal cyst development predominantly at the corticomedullary j unction. Genetics of MCKD There are now known to be 2 types of MCKD, 1 and 2, distinguished by chrom osomal localization, with one form of medullary cystic kidney disease (MCKD2) known to be c aused by mutation in the gene encoding uromodulin (UMOD), which is also the site of mutatio ns causing juve- nile hyperuricemic nephropathy. Pathology: the ciliopathies The cilium is a hair-like structure that extends from the cell surface into the extracellular space. The interaction and colocalization to cilia of nephro cystin-1, inversin, and -tubulin provide a functional link between the pathogenesis of NP HP, the pathogenesis of PKD (polycystic kidney disease), primary cilia function, and left \200\223 right axis determination. The functional relationship between ciliary expression o f these so-called \200\230cystoproteins \200\231 (proteins mutated in cystic kidney diseas e) and the renal cystic phenotype, however, is still somewhat unclear. One of the \201 rs t concepts for this relationship proposes that cilia may act as mechano- sensors to sense \202 uid movement in the kidney tubule, where polycystin-1 (the protein product of PKD1) t rans- mits the signal to polycystin-2, which is a TRP type calcium channel. This would prod uce suf \201 cient calcium in \202 ux to induce calcium release from intracellular storag e, which then regulates numerous intracellular signaling activities that are linked to the regulation of cell cycle and planar cell polarity. Taken together, these \201 ndings indi cate that the nephrocys- tin proteins are involved in functions of sensory cilia, cell pola rity, and cell division. NPHP4 This gene locus was discovered in patients without NPHP1 \200\2233, with clinical and biopsy features of NPHP and ESRD commencing within a wide age range, 11 \200\22334 years. This was additionally found to be a new locus for SLSN, an NPHP variant associated with ret initis pigmentosa. NPHP5 Overall, one in 10 individuals with NPHP has retinitis pig- mentosa, constituting SLS N. However, all individuals with NPHP5 mutations have retinitis pigmentosa, suggesting that mutation in NPHP5 is the most frequent cause of SLSN. Eight different mutations in the NPH P5 gene have been identi \201 ed in patients with SLSN and NPHP mapping to chromosome 3q21 .1 (SLSN5). All patients have early-onset retinitis pigmentosa with no signs of cerebellar vermis aplasia or oculomotor apraxia (Cogan syndrome, associated with NPHP1 and 4). NPHP6 Recently, recessive truncating mutations in a novel gene NPHP6/CEP290, which encodes a centrosomal protein, were identi \201 ed as the cause of NPHP type 6 and Joubert syndrom e type 5. The clinical features of NPHP type 6 include renal cysts, retinitis pigmentosa, a nd cerebellar vermis aplasia. Treatment No speci \201 c prophylaxis or treatment is available for NPHP currently. The on ly therapeutic options are supportive treatment once CKD has developed and dialysis and tra ns- plantation for ESRD. AHI1 Mutations in AHI1, encoding jouberin, have been detected in patients with Joubert synd rome with and without renal involvement. Patients reported with renal involvement develop E SRD in their 20s. Follow-up Genetic counseling is important for this group of diseases. Genetic mutation anal yzes are increasingly being offered by genetics departments in major centers. Other renal syndromes associated with NPHP Bardet \200\223Biedl syndrome (BBS) BBS exhibits renal histology that is similar to NPHP. Positional cloning of recessive genes that are mu tated in BBS has revealed that the molecular relation between NPHP and BBS may lie in coexp ression of the respective gene products in primary cilia, basal bodies, and centro- somes o f renal epithelial cells. Prognosis In both nephronophthisis (NPHP) and medullary cystic kidney disease (MCKD) patien ts typically progress to ESRD within 5 \200\22310 years of presentation. Retinal involvemen t is very variable, and long-term infor- mation on outcome is not available. Liver function at the time of renal failure is usually normal despite histological changes, though longer -term liver out- come may become a more signi \201 cant feature as these patients survive longer. Distinction from MCKD NPHP has previously been grouped together with the clinical entity of medullary cystic kidney disease (MCKD) because of similarities of clinical and pathologic features. Both have normal or slightly small kidneys with corticome- dullary cysts. However , MCKD follows autosomal domi- nant inheritance, and is due to mutations in MCKD1 and MCKD2 genes. In MCKD ESRD occurs in the 4th decade and later. In MCKD there is no extrarenal inv olvement other than hyperuricemia and gout. Future prospects The delineation of the biology underlying this group of conditions in rece nt years will lead to exciting potential advances in treatment. For example the renal cysti c pheno- type of pcy mice, which is the equivalent of human NPHP type 3, can be strongly mi tigated or even reversed by treat- ment with the vasopressin V2 receptor antagonist OPC3126 0. CHAPTER 15.6 Nephronophthisis 605 Table 15.6.1 Principal features of the different types of nephronophthisis Nomenclature Gene Protein Renal manifestations Extrarenal manifestations NPHP 1 Juvenile NPHP Type 1 Nephrocystin-1 Presents at 4 \200\2236 years with ESRD at 13 years Renal \200\223retinal syndrome (retinitis pigmentosa, tapetoretinal degeneration). Joubert syndrome (uncommon) NPHP 2 Infantile NPHP Type 2 Inversin Presents at 1 \200\2232 months with ESRD at 1 year Retinitis pigmentosa. Hepatomegaly. Cholestatic liver disease. Situs inversus. NPHP3 Adolescent NPHP Type 3 Nephrocystin-3 Presents at 4 \200\2236 years ESRD at 19 years Tapetoretinal degeneration and hepatic \201 brosis, cerebellar ataxia, cone-shaped epiphy ses, congenital oculomotor apraxia. NPHP4 Type 4 Nephrocystin-4 or nephroretinin Wide range of ESRD onset, 11 \200\22334 years Tapetoretinal degeneration; retinitis pigmentosa. Retinitis pigmentosa in all patients Nephrocystin-5 Renal involvement in all. ESRD by second decade of life. Type 5 NPHP5 also known as IQCB1 NPHP6 Type 6 Nephrocystin-6 Either severe or absent Retinitis pigmentosa; cerebellar vermis aplasia; Leber \200\231s congenital amaurosis. AHI1 Joubert syndrome Jouberin ESRD in the 3rd decade of life, if renal involvement Joubert syndrome: aplasia of the cerebellar vermis, ataxia, abnormal eye movements, an abno rmal breathing pattern in the neonatal period and psychomotor mental retardation. Further reading Chang B, Khanna H, Hawes N, et al. In-frame deletion in a novel centrosomal /ciliary protein CEP290/NPHP6 perturbs its interac- tion with RPGR and results in early-ons et retinal degeneration in the rd16 mouse. Hum Mol Genet 2006; 15: 1847 \200\2231857. Parisi MA, Doherty D, Eckert ML, et al. AHI1 mutations cause both retinal dystrophy and ren al cystic disease in Joubert syndrome. J Med Genet 2006; 43: 334 \200\223339. Sayer JA, Otto EA, O \200\231Toole JF, et al. The centrosomal protein nephrocystin-6 is mut ated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 2006; 38 674 \200\223681. Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. Yang H, Wu C, Zhao S, et al. Identi \201 cation and characterization of D8C, a novel domai n present in liver-speci \201 c LZP, uromodulin and glycoprotein 2, mutated in familial ju venile hyperuricaemic nephropathy. FEBS Lett 2004; 578: 236 \200\223238. J Am Soc Nephrol 2007; 18: 1855 \200\2231871. Hildebrandt F, Otto E, Rensing C, et al. A novel gene encoding an SH3 domain protein is mut ated in nephronophthisis type 1. Nat Genet 1997; 17: 149 \200\223153. Mangos JA, Opitz JM, Lobeck CC, et al. Familial juvenile nephro- nophthisis. An unrecognize d renal disease in the United States. Pediatrics 1964; 34: 337 \200\223345. Internet resources Joubert Syndrome Foundation: Olbrich H, Fliegauf M, Hoefele J, et al. Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal dege- neration and hepatic \201 brosis. Nat Genet 2003; 34: 455 \200\223459. http://www.jsfrcd.org/ Genetic & Rare Diseases Information Center: http://rarediseases.info.nih.gov Otto E, Hoefele J, Ruf R, et al. A gene mutated in nephronophthisis and retinitis pigmentos a encodes a novel protein, nephroretinin, conserved in evolution. Am J Hum Genet 2002; 71: 1161 \200\2231167. Otto EA, Schermer B, Obara T, et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic dis- ease to the function of primary c ilia and left \200\223right axis determina- tion. Nat Genet 2003; 34: 413 \200\223420. See also Rare syndromes with renal involvement, p. 640 Polycystic kidney disease in childre n, p. 586 CKD in children, p. 462 Otto EA, Loeys B, Khanna H, et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior \200\223L ken syndrome and inter- acts with RPGR and calmodulin. Nat Genet 2005; 37: 282 \200\223288. P. TOPHAM 606 Thin membrane nephropathy Pathology The pathological \201 ndings in TMN are limited to diffuse thinning of the GBM which is otherwise morphologically normal (Fig. 15.7.1). This contrasts with Alport \200 \231s syndrome in which the GBM is thickened and lamellated and the normal lamina densa of the GBM is disrupted. The normal range for GBM thickness must be determined in each laborat ory because of the in \202 uence of techniques used for \201 xing the biopsy, but typica lly normal GBM thick- ness is 350 \200\223450 nm and a reduction to <250 nm involving >50% of the GBM is diagnostic of TMN. An accurate assessment of GBM thickness can only be made o n glutaraldehyde- \201 xed renal tissue. Reprocessing of formalin- \201 xed tissue for el ectron microscopy (for example when the glutaraldehyde- \201 xed sample contains no glomer uli) results in artifactual thinning of the GBM which precludes the accurate diagnosis of T MN. Thin membrane nephropathy (TMN) is a common auto- somal dominant inherited glomerular disor der that results in persistent microscopic hematuria. TMN is characterized by glomerular ba sement mem- branes (GBMs) which are thin but otherwise morphologi- cally normal. The term \200\230benign familial hematuria \200\231 was previously used in an era before the GBM abn ormality had been identi \201 ed. Genetics The similarity between the basement membrane changes seen in early Alport \200\231 s syndrome and those seen in TMN suggested the presence of a similar underlying genetic def ect. 40% of families with TMN have hematuria that segregates with the COL4A3/COL4A4 locus,