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, and identical mutations have been described in both TMN and autosomal recessive Alport \200 \231s syndrome. TMN patients with such mutations can be considered as carriers of autosomal recessive Alport \200\231s syndrome. Approximately 20 COL4A3 and COL4A4 mutations have bee n identi \201 ed in families with TMN. The majority are sin- gle nucleotide substitutions that are different in each family. Recently the association of TMN, focal segmental glomeru - losclerosis and progressive CKD has been described in a cohort of patients with mutations in both COL4A3 and COL4A4 genes. In some families linkage with the COL4A3 and COL4A4 genes has not been found. Whereas some of these cases may be explained by de novo mutations or i ncomplete pen- etrance, it is probable that the remainder are due to the presence of furthe r TMN loci. Differential diagnosis The two principal differential diagnoses are: \200 \200 IgA nephropathy; Alport \200\231s syndrome. TMN can only be distinguished from IgAN by renal biopsy. TMN and IgAN may coexist; whether this is a true associa- tion or simply due to the coincidence of two common glomerular diso rders is unclear. TMN must be distinguished from Alport \200\231s syndrome (hereditary neph ritis with deafness), of which the com- monest form is X-linked. If there is a clear autoso mal dominant pattern of hematuria without renal insuf \201 ciency or extrarenal problems a clini- cal diagnosis of TMN may be established with reasonable con \201 dence, but a rena l biopsy in at least one family mem- ber is still preferable. Once the diagnosis is establi shed in a kindred, biopsy is not required unless there are unexpected clinical changes. Dif ferentiation from the less common autosomal forms of Alport \200\231s syndrome may be less straightforward. Subclinical deafness should be excluded by audiography if necessary. The r enal biopsy also requires careful assessment. In TMN there is uniform thinning; early in th e course of Alport \200\231s syndrome, even if the typical structural disruption of the GBM has not yet developed, marked variability in GBM width is typical. Staining of GBM for the chains of type IV collagen is highly informative: in X-linked Alport \200\231s the 3, 4 and 5 are absent (mosaic expression in female carriers); in autosomal recessive Alpo rt \200\231s the 3, 4 chains are absent; whereas in TMN normal chain distribution is preserved. Genetic testing for COL4A3 or COL4A4 mutations to diag- nose TMN is clinically not practical because of the huge size of these genes, their frequent polymorphisms, and th e likelihood of the existence of further gene loci. Clinical features TMN is the underlying diagnosis in 20 \200\22325% of patients presenting to a nephrologist with isolated microscopic hematuria. Autopsy and kidney transplant donor studies suggest that 5 \200\2239% of the population has TMN. It is an autosomal dominant co ndition but may also be sporadic. Persistent microscopic hematuria is typical and usually l ifelong. Episodic macroscopic hematuria may also occur in up to 1/5 of patients. Up to 30% of patients experience \202 ank pain. In a small number of cases TMN has been described i n patients with loin-pain hematuria syndrome. Hypertension may be more common than in the g eneral population although this is not con \201 rmed in all studies. Proteinuria is uncomm on and patients with nephrotic range proteinuria usually have a second, superadded diagnosi s. Progressive renal impairment is rare but has been described in a number of families. Dea fness and other extrarenal manifestations seen in Alport \200\231s syndrome are absent. The re is no speci \201 c treatment. Prognosis and follow-up The prognosis is excellent in the great majority of families with T MN, though there is a small but de \201 nite risk of CHAPTER 15.7 Thin membrane nephropathy 607 developing CKD, heralded by the onset of proteinuria and hypertension. Long-term follow-up of patients with TMN is therefore mandatory with urinalysis, blood pressure measurement and renal function testing recommended every 1 \200\2232 years. (a) Further reading Dische FE, et al. Incidence of thin membrane nephropathy: morpho- metric in vestigation of a population sample. J Clin Pathol 1990; 43: 457 \200\223460. Nieuwhof CM, deHeer F, de Leeuw P, van Brieda Vriesman PJ. Thin glomerular basement nephrop athy. Premature glomerular obso- lescence is associated with hypertension and late onset re nal failure. Kidney Int 1997; 515: 1596 \200\2231601. Tiebosch AT, et al. Thin basement membrane nephropathy in adults with persistent hematuria. New Engl J Med 1989; 320: 14 \200\22318. Tryggvason K, Patrakka J. Thin basement membrane nephropathy. J Am Soc Nephrol 2006; 17: 813 \200\223822. Internet resources Background information on Alport \200\231s and TMN: http://www.genetests.org/query?dz=alport See also Urinalysis and microscopy, p. 8 Renal biopsy, p. 32 Alport \200\231s syndrome, p. 606 IgA nephropathy and Henoch \200\223Sch nlein purpura, p. 100 (a)I (b) Fig. 15.7.1 Thin membrane nephropathy. (a) Electron micrograph of two capillary loops with abnormally thin basement membranes. The GBM is otherwise structurally normal. (a)I Measurem ent of the GBM shows that it is uniformly thinned. (b) Electron micrograph of two capillary loops with normal GBM for comparison. (Electron micrographs courtesy of Dr Nick Mayer, Con sultant Histopathologist, University Hospitals of Leicester, UK.) M. HALL 608 Alport \200\231s syndrome Introduction Alport \200\231s syndrome (also known as hereditary nephritis or Davidson \200 \231s nephritis) is an inherited syndrome of hematu- ria and progressive renal impairment d ue to defects in synthesis of type IV collagen. Type IV collagen is a hexamer (Fig. 15.8.1) and a major component of basement mem- branes, predominantly found in the glomerular base- ment membrane (GBM), tubular basement membranes, Bowman \200\231s capsule and skin. In add ition to the renal involve- ment there may be associated sensorineural deafness, anterior l entoconus and other ocular abnormalities. Proteinuria Autosomal recessive (AR) Alport \200\231s syndrome and males with X-linked Alpo rt \200\231s syndrome develop proteinuria in early adulthood. Nephrotic syndrome occurs in 40%. X-linked heterozygous females and AD Alport \200\231s syndrome rarely develop proteinu ria but when present it is associ- ated with worse prognosis. Excretory renal dysfunction Cases of AR Alport \200\231s syndrome and males with X-linked d isease progress to ESRD. Most patients reach ESRD in their third decade. Some kindreds prog ress more slowly, reaching ESRD in their 5th decade. X-linked disease in females and AD Alp ort \200\231s syndrome is generally benign. Proteinuria or diffuse GBM thickening on electr on micros- copy is associated with progressive renal failure. Epidemiology Alport \200\231s syndrome is rare, affecting 1 in 5000 live births. There is n o difference in inheritance by: \200 \200 \200 gender; geography; ethnicity. Males are more severely affected than females. Severity of disease is consistent within kin dreds but there is marked variability between families. Novel mutations account for 20% of cases. Patients with Alport \200\231s syndrome account for 2 \200\2233% of patients with ES RD. Hypertension With progressive proteinuria and renal dysfunction hyper- tension is common. Sensorineural deafness Alport \200\231s syndrome is associated with deafness in most males with X-linked disease and patients with AR Alport \200\231s syndrome. Hearing loss is progr essive and usually clinically signi \201 cant by the second decade. In females with X-link ed disease and AD Alport \200\231s syndrome hearing loss is less severe and develops later in life. Genetics The constitutive proteins are coded on six genes found on three different chromoso mes (Fig. 15.8.1). Genes are located on chromosomes 2, 13 and X. Theoretically these gene p roducts could polymerize in 46 656 combinations but in fact only three are found. Alport \200\231s syndrome can be inherited in three ways (Table 15.8.1): \200 \200 \200 Ocular defects Anterior lenticonus is associated with established progres- sion to ESRD and occurs in 15% of males with X-linked disease. Asymptomatic perimacular granulations can be observed in up to 30% of patients. X-linked (80% of cases); autosomal recessive (15% of cases); autosomal dominant (5% of case s). More than 200 distinct disease-causing mutations have been identi \201 ed resulting in def ects in type IV collagen (Fig. 15.8.2). X-linked Alport \200\231s syndrome is most prevalen t. Mutations in COL4A2 have thus far not been identi \201 ed in Alport \200\231s syndrome. Mutations in COL4A1 have recently been implicated in a novel syndrome of hematuria, cystic kidney disease, intrac- ranial aneurysms and muscle cramps. Related syndromes Defects in type IV collagen are found in other conditions bearing some si milarities to Alport \200\231s syndrome. Benign familial hematuria is etiologically identic al to AD Alport \200\231s syndrome and probably represents the most benign end of the spect rum of disease. Nail \200\223patella syndrome results from mutation of the LMX1B transcript ion factor altering expression of COL4A3 and COL4A4. Clinical features Hematuria Persistent microscopic hematuria can be seen from infancy. Uppe r respiratory tract infections may be associated with paroxysmal macroscopic hematuria. Mal e children without microscopic hematuria by the age of 10 years are unlikely to have Alport \200\231s syndrome. Affected female patients (X-linked heterozygous) and autosomal dominan t (AD) Alport \200\231s syndrome may have intermittent hematuria. Differential diagnoses \200 \200 \200 \200 \200 \200 \200 Thin membrane disease. IgA nephropathy. Familial membranous nephropathy. Focal segmental gl omerulosclerosis (FSGS). Epstein and Fechner \200\231s syndromes. Urogenital neoplasia. Uri nary calculi. CHAPTER 15.8 Alport \200\231s syndrome 609 Chromosome Gene Protein Collagen trimer Collagen IV hexamer 1, 1, 2 Chr13 1(IV) 1, 1, 2 COL4A1 1, 1, 2 13 2(IV) COL4A2 3, 4, 5 3(IV) COL4A3 Chr2 3, 4, 5 2 ChrX 3, 4, 5 4(IV) COL4A4 5(IV) 1, 1, 2 COL4A5 Chr13 5, 5, 6 X 5, 5, 6 6(IV) ChrX COL4A6 Fig. 15.8.1 The genetics of type IV collagen. Table 15.8.1 Patterns of inheritance of Alport \200\231s syndrome Inheritance Family history Prevalence Genetic defect Clinical features Yes 40% COL4A5 (Chr Xq22) Hematuria from \201 rst decade Proteinuria and progression to ESRD in 3rd decade Associat ed with leiomyomas if defect extends to COL4A6 gene X-linked males Yes 40% COL4A5 (Chr Xq22) More benign X-linked females Isolated microscopic hematuria may be the only manifestation Progression to ESRD occurs in 12% by 5th decade No 15% COL4A3 (Chr 2q35-q37) COL4A4 (Chr 2q35-q37) De novo mutation in COL4A5 (Chr Xq22) Similar to males with X-linked disease Autosomal recessive Yes 5% COL4A3 (Chr 2q35-q37) COL4A4 (Chr 2q35-q37) Marked heterogeneity Autosomal dominant Spectrum of disease from isolated microscopic hematuria to ESRD M. HALL 610 Investigations Alport \200\231s syndrome should be suspected in a patient with: \200 \200 \200 There are no randomized controlled trials of therapies to slow progression of CKD in Alport \200\231s syndrome. hematuria; deafness; family history of kidney disease. Ciclosporin and ACEIs/ARBs There is a single report of treatment with ciclosporin preservin g renal function for more than a decade in eight children. Data from a proteinuric animal m odel of Alport \200\231s syn- drome suggests that ACEIs may reduce proteinuria and slow dec line in renal excretory dysfunction. It is likely that treatment of high blood pressure wit h an ACEI and/or ARB will reduce proteinuria and delay pro- gression of renal decline in co mmon with other progres- sive renal diseases. Observational trials are in progress to asses s the ef \201 cacy of this approach. Biochemistry Biochemical investigations are not diagnostic of Alport \200\231s syndrome. Th ey do help identify and monitor degree of renal impairment: \200 \200 urea, creatinine and electrolytes; urine protein excretion: spot PCR or 24 h collection. Imaging Imaging of the renal tract in Alport \200\231s will be normal. Ultrasound examinati on of the urogenital tract is impor- tant to exclude alternative diagnoses for example stru c- tural abnormalities and neoplasia. Plain abdominal X-ray may identify calculi within the uro- genital system. Renal transplantation Renal transplantation is an effective treatment of ESRD in Alport \200\231s syndrome. Post-transplant renal outcomes are comparable to other populations with reported 1 year and 5 year graft survival of 87% and 66% respectively. Care must be taken when assessing potential living related donors. Genetic testing Genetic screening by linkage analysis or gene sequencing is possible. Howev er, this is time-consuming and often unreli- able due to the large number of disease-causin g muta- tions. It may be useful for prenatal diagnosis in previously charac- terized kindre ds. Post-transplantation anti-GBM disease Patients with Alport \200\231s syndrome are immunolog ically naive to subunits of type IV collagen. Following transplantation, exposure to these previously absent type IV collagen subu- nits in the renal allograft may trigger a signi \201 cant immune response. Post-transplantation anti-GBM disease is encountered in patients with Alport \200\231s syndrome, although it is less com- mon than one might expect. Antibo dies against components of type IV collagen can be identi \201 ed in up to 20% of renal al lograft recipients. Overt anti-GBM disease occurs in only 1.5 \200\2232.5%. Post-transplant ation anti-GBM disease differs from tradi- tional Goodpasture \200\231s disease: \200 \200 Renal biopsy Diagnosis is con \201 rmed by renal biopsy. Light microscopy There are no pathognomonic lesions of Alport \200\231s syndrome on light m icroscopy but this can exclude other potential diagnoses including FSGS, membranous nephrop athy and IgA nephropathy. GBM thickening, glomerular sclerosis and tubulointerstitial \201 brosis may be seen with progessive disease. Immuno \202 uorescence Direct immunofluorescence is unhelpful in diagnosing Alport \200 \231s syndrome but can exclude IgA nephropathy. Immunostaining for components of type IV co llagen can be diagnostic. Commercially available antibodies against A3(IV), A4(IV) and A5(I V) are available (Table 15.8.2). Some female patients with X-linked disease have a mosaic p attern of immunostaining for type IV collagen. the disease is always renal-limited; in traditional disease, antibodies usually form agains t the A3(IV) subunit of collagen but in patients with Alport \200\231s syndrome they may be against A3(IV), A4(IV), A5(IV) or A6(IV) depending on the genotype; laboratory testing for \200\230anti-GBM \200\231 antibodies is normally limited to A3(IV) collagen, so false-neg ative results may arise. Electron microscopy Lamellation of the GBM is strongly suggestive of Alport \200\231s syndr ome (Fig. 15.8.3). Other abnormalities include variability in thickness of the GBM with bot h abnormally thick and thin areas. Diagnosis is con \201 rmed by renal transplant biopsy showing linear IgG staining, crescen tic glomerulonephritis, segmen- tal necrosis and neutrophilic in \201 ltrates. There are n o randomized controlled trials for the treat- ment of post-transplantation anti-GBM disease . Graft outcomes are poor. A trial of immunosuppressive therapy and plasma exchange may be considered. Retransplantation of affected individuals is rarely success- ful and often asso ciated with more rapid acute vascular rejection. Skin biopsy Skin biopsy has been advocated by some as a less invasive alternative to renal biopsy. An absence of A5(IV) collagen in skin biopsies is diagnostic of X-linked Alport \200\231s syndrome in patients with hematuria and a positive family history. Treatment Slowing progression of renal failure There is no speci \201 c treatment for Alpo rt \200\231s syndrome. Follow-up Patients with AR Alport \200\231s syndrome or males with X-linked disease will pr ogress to ESRD. CHAPTER 15.8 Alport \200\231s syndrome 611 Autosomal recessive X-linked males Loss of 5(IV) Loss of 3(IV) or 4(IV) 3, 4, 5 1, 1, 2 3, 4, 5 3, 4, 5 3, 4, 5 5, 5, 6 1, 1, 2 1, 1, 2 1, 1, 2 5, 5, 6 1, 1, 2 1, 1, 2 No 3, 4, 5 or 6 in type IV collagen No 3 or 4 in type IV collagen Fig. 15.8.2 Phenotype of type IV collagen in Alport \200\231s syndrome. Table 15.8.2 Type IV collagen immunostaining patterns in Alport \200\231s syndrome A3(IV) A4(IV) A5(IV) Normal \234\223 \234\223 \234\223 X-linked males \234\230 \234\230 \234\230 X-linked females Mosaic pattern Autosomal recessive \234\230 \234\230 \234\230 Autosomal dominant Reduced or absent \234\223 \234\223 Fig. 15.8.3 Electron micrograph showing lamellation, thickening and thinning of the glomeru lar basement membrane in Alport \200\231s syndrome. (Courtesy of Nick Dr Mayer, Consultant Histopathologist, University Hospitals of Leicester, UK.) M. HALL 612 Timely treatment of complications of CKD (hypertension, anemia, renal bone disease) and pla nning for renal replace- ment therapy improves morbidity and mortality as with other kidney diseases. Pre-emptive renal transplantation is effective for patients with Alport \200\231 s syndrome. Relatives offering kidneys for transplantation should be carefully assessed to exclude covert disease. Patients should be offered genetic counseling if planning to start a family. Ophthalmology and audiology input is often indicated. Outcomes range from isolated microscopic hematuria to ESRD. Future prospects Bone marrow transplantation has been shown to amelio- rate renal disease i n a murine model of Alport \200\231s syndrome although we remain a long way from offering t his or other forms of gene therapy for the treatment of Alport \200\231s syndrome. Increase d use of ACEIs, ARBs with stringent BP control may slow progression of excretory dysfunctio n and delay the onset of ESRD but this still needs to be con \201 rmed. Prognosis Males with X-linked disease ESRD develops in 90% of patients by the 5th decade. P atients with deafness and ocular changes tend to progress more rapidly. Increasing proteinu ria and hypertension are associated with more rapid progression to ESRD. Life expectancy is shortened due to complications of transplantation and dialysis. Further reading Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Alport \200\231s syn drome, Goodpasture \200\231s syndrome and type IV collagen. N Engl J Med 2003; 348: 2543 \200\2232556. Plasier E, Gribouval O, Alamowitch S, et al. COL4A1 mutations and hereditary angiopathy, ne phropathy, aneurysms and muscle cramps. N Engl J Med 2007; 357; 2687 \200\2232695. Saito A, Yamazaki H, Nakagawa Y, Arakawa M. Molecular genetics of renal diseases. Intern Med 1993; 36: 81 \200\22386. Internet resources The Alport Syndrome Foundation: Females with X-linked disease This is usually a benign disorder of microscopic hematuria. P rogression to ESRD occurs in 12% by the 5th decade. Associated deafness, ocular disorders, proteinuria and hypertension are associated with worse prognosis. http://alportsyndrome.org/index.html National Kidney Federation: Alport \200\231s syndrome: http://www.kidney.org.uk/medical-info/alports/ See also Antiglomerular basement membrane disease, p. 124 Selection and preparation of reci pients, p. 544 Recurrent disease and de novo disease post renal trans- plantation, p. 566 N ail \200\223patella syndrome, p. 608 Autosomal recessive disease Outcomes are similar to males with X-linked disease. Absence of a family history and relative increase in severity in females may delay diagnosis. Autosomal dominant disease There is marked heterogeneity in clinical manifestations depende nt on genotype. This page intentionally left blank P. TOPHAM 614 Nail \200\223patella syndrome Introduction Nail \200\223patella syndrome (NPS) is an autosomal dominant disease character ized by dystrophic nails, hypoplastic or absent patellae, dysplasia of the elbows and iliac horns, and renal disease in some patients. Nail defects 80 \200\22390% of patients will have nail abnormalities. These are present at birth and tend to be bilateral and symmetrical. The \201 ngernails are more commonly affe cted than toenails with the thumb and index \201 nger particularly affected. The nails ma y be absent but are more often hypoplastic or dysplastic with discoloration, koilonychia, l ongitudinal ridges, or triangular lunulae. Epidemiology Estimated incidence of NPS is 22 pmp. NPS is described in populations througho ut the world. Equal gender distribution. Other defects Bony abnormalities of the feet and ankles, and scoliosis have been described. In addition, symptoms of irritable bowel syndrome and vasomotor dysfunction are occasional ly observed. Genetics NPS is caused by mutation of the LMX1B gene found on the long arm of chromosome 9 (9q34). LMX1B is a LIM homeodomain-type transcription factor that regulates the transcripti on of genes critical for glomer- ular basement membrane formation (GBM) and podocyte functi on. These are: \200 \200 \200 Renal pathology Light microscopy Essentially normal in those with normal renal function. He avy proteinuria and/or impaired renal function is mani- fested by basement membrane thicken ing and nonspeci \201 c focal and segmental glomerulosclerosis. type IV and probably type III collagen; podocin; CD2AP. Immuno \202 uorescence microscopy Usually negative apart from nonspeci \201 c IgM and C3 reac- tivity in sclerotic areas. Loss of regulated expression of these glomerular compo- nents leads to abnormal GBM product ion and podocyte dysfunction, leading to the renal phenotype described below. Electron microscopy Demonstrates irregular and lucent rarefactions of the lamina densa of t he basement membrane. These areas contain crossbanded collagen \201 brils that are best d emonstrated by staining with uranyl acetate and phosphotungstic acid. These lesions are pat hognomonic for NPS. They may involve the whole or just segments of the GBM, may be seen in the mesangium, but are never seen in the tubular basement membrane. These \201 brils have been shown to be comprised of type III collagen (Fig. 15.9.1). Note that these features ca n also be seen in NPS patients without clinical evidence of renal involvement and the sever ity of histological abnormality corre- lates poorly with clinical renal dysfunction in thos e with nephropathy. Clinical presentation Renal manifestations Renal disease is clinically apparent in less tha n one-half of patients with NPS. Approximately 10% of NPS patients with nephropathy will de velop ESRD. NPS-related nephropathy usually becomes apparent in late adolescence or young a dulthood. The features of nephropathy are variable and typically include microscopic hematu ria and low grade proteinuria, but may progress to nephrotic syndrome in association with h ypertension. Urine concentrating ability may also be affected. The frequency and severity o f renal involvement varies between families and also in affected individuals within familie s. Natural history End-stage renal disease develops in 10% of NPS patients with nephropathy. Mean age when ESRD develops is 33 18 years. The clinical course can be highly variable s uggesting that nongenetic factors in \202 uence outcome. Other glomerular diseases have be en described in patients with NPS-related nephropathy including: \200 \200 \200 \200 Extrarenal manifestations Skeletal defects 60% of patients have absent or hypoplastic patel lae that results in lateral slippage of the patella on knee \202 exion. Joint effusions a nd osteoarthritis leading to knee pain may result. Up to 80% of patients have iliac horns t hat are pathogno- monic of NPS. These are symmetrical osseous processes arising from the il iac wings. They are asymptomatic but may be detected on clinical examination. Elbow abnorma lities are also common. These include hypoplasia of the radial heads leading to elbow sublu xa- tion, hypoplasia of the distal humerus, and formation of posterior processes from the d istal humerus leading to limitations of extension, pronation and supination of the forearm. IgA nephropathy; membranous nephropathy; anti-GBM disease; pauci-immune vasculitis. Whether these diseases occur in NPS with increased fre- quency is unknown. CHAPTER 15.9 Nail \200\223patella syndrome 615 Renal transplantation is not associated with recurrent dis- ease and is not complicated by anti-GBM disease (in con- trast to Alport \200\231s syndrome). Further reading Bennett WM, Musgrave JE, Campbell RA, et al. The nephropathy of the nail \200\223patella syndrome. Clinicopathologic analysis of 11 kindred. Am J Med 1973; 54: 304. Bongers EM, Gubler MC, Knoers NV. Nail \200\223patella syndrome. Overview on clinical and m olecular \201 ndings. Pediatr Nephrol 2002; 17: 7037 \200\2237012. Dunston JA, Hamlington JD, Zaveri J, et al. The human LMX1B gene: transcription unit, promo ter, and pathogenic mutations. Genomics 2004; 84: 565. Sweeney E, Fryer A, Mountford R, Green A, McIntosh I. Nail patella syndrome: a review of th e phenotype aided by developmental biology. J Med Genet 2003; 40: 153 \200\223162. Internet resources Nail Patella Syndrome UK: http://www.npsuk.org/ Nail Patella Syndrome Worldwide: Fig. 15.9.1 Nail \200\223patella syndrome. Electron micrograph showing the characteristic c rossbanded collagen \201 brils in the glomerular basement membrane (arrowhead). http://www.nailpatella.org/ See also Proteinuria and/or hematuria, p. 76 Alport \200\231s syndrome, p. 606 Thin membran e nephropathy, p. 602 Treatment There is no speci \201 c treatment available. A generic treatment approach with blood pressure control, the use of ACEIs and/or ARBs, and cardiovascular risk management is appropriate. P. TOPHAM 616 Congenital and infantile nephrotic syndrome Introduction Congenital nephrotic syndrome by de \201 nition develops within the \201 rs t 3 months of life. The onset of nephrotic syndrome between 3 and 12 months of age is calle d infantile nephrotic syndrome. Genetic abnormalities underlie the majority of cases of nep hrotic syndrome that develop in the \201 rst year of life. The renal outcome is generally poor. Clinical features Prematurity (35 \200\22338 weeks) is usual. Babies are small for gestatio nal age. Cranial sutures are widely separated, the nose is small and ears are low-set. Flex ion deformities of hips, knees and elbows are common. The placenta is enlarged. Edema prese nt by the end of the 1st week of life in 50%. Severe nephrosis with ascites is invariably p resent by 3 months. Profound hypoalbuminemia and hypogammaglobulinemia develops. Growth is poor. Bacterial infections (peritonitis, respiratory infections) and thromboembolism may oc cur. Hypothyroidism is common (urinary loss of thyroxine- binding proteins). End-stage rena l failure develops at 3 \200\2238 years of age. Prolonged survival is possible with support ive treatment including dialysis and transplantation. Genetics More than 85% of cases of congenital nephrotic syndrome are due to mutations of th e following genes (Table 15.10.1): NPHS1 Encodes the slit diaphragm component nephrin; mutations result in congenital nephroti c syndrome of Finnish type. NPHS2 Encodes podocin; mutations result in familial FSGS. WT1 Encodes the Wilms \200\231 tumor suppressor gene; mutations result in the Denys \200 \223Drash and Frasier syndromes. LAMB2 Encodes 2-laminin; mutations result in the Pierson syndrome. Pathology Early changes are con \201 ned to mild mesangial hypercellular- ity with increas ed mesangial matrix expansion. Later with further mesangial matrix deposition progressive g lomerulosclerosis develops. Immune deposits are absent. On electron microscopy podocytes ha ve profound foot process effacement and slit-diaphragms are absent. Tubulointerstitial chan ges are prominent, with microcystic dilatation of tubules, progressive interstitial \201 brosis and tubular atrophy developing later in the course of disease. PLCE1 Encodes phospholipase C ; mutations result in early-onset diffuse mesangial sclerosi s. NPHS1 and NPHS2 mutations account for >90% of cases of congenital nephrotic syndrome. Co ngenital nephrotic syndrome may also result from non- genetic causes and these are listed i n Table 15.10.1. Congenital nephrotic syndrome of the Finnish type (CNF) This is most frequent in Finland. T he incidence is between 0.9 and 1.2 per 10 000 live births but is now falling due to the av ailability of prenatal screening. CNF has also been described in a variety of ethnic groups throughout the world. Treatment Glucocorticoids and immunosuppressive agents are ineffective. Management includes : \200 \200 \200 \200 \200 daily or alternate day albumin infusions; gammaglobulin replacement; high-protein, low-salt diet (tube feeding/parenterally); vitamin and thyroxine supplementation; infection and thr omboembolism prophylaxis. Pathogenesis CNF results from abnormalities of the NPHS1 gene. This gene encodes for nephri n which is a component of the podocyte slit diaphragm. The absence of nephrin from the slit diaphragm is thought to result in the breakdown of glomerular permselective function and t he free movement of plasma proteins into the urine. A wide variety of nephrin mutations has been described. However, 90% of Finnish CNF patients have either the Fin-major (nt121delC T) or Fin-minor (R1109X) mutations. In non-Finnish CNF patients >30 mutations have been ide nti \201 ed. In addition, a small number of patients with fea- tures of classical CNF have no identi \201 able NPHS1 muta- tions, suggesting that the disease can be induced by prom oter or intronic mutations or mutations of proteins that interact with nephrin. Bilateral surgical nephrectomy may be required since even maximal supportive therapy may no t avoid growth retarda- tion and intercurrent complications of nephrosis. The administratio n of indomethacin and ACEIs to reduce intraglomerular pressure is an alternative approach t o sur- gery. In a small number of cases this has led to substantial reduction in proteinuri a and subsequently an improvement in nutritional status and growth. Renal transplantation c an be undertaken once the child reaches a weight of 8 \200\2239 kg. Recurrence of nephrotic syndrome can occur in 20 \200\22325% of transplants. This is more common in Fin-major rec ipi- ents (nephrin is absent in native kidneys) and has been shown to be due to the presenc e of circulating anti-nephrin CHAPTER 15.10 Congenital and infantile nephrotic syndrome 617 sclerosis may also be seen as part of Denys \200\223Drash syn- drome resulting from a mutat ion in the WT1 gene. PLCE1 encodes phospholipase C which is an enzyme that catalyzes the hydrolysis of phosphoinositides and results in the generation of signaling molecules. The m echanism through which aberrant phospholipase C activity leads to podocyte dysfunction is unclear but a causal role is supported by the observation that targeted deletion of PLCE1 gene in zebra \201 sh leads to glomerular dysfunction. Table 15.10.1 Causes of congenital nephrotic syndrome