Phosphoribosyl pyrophosphate synthetase (PRPS) superactivity This much rarer condition has some clinical similarities to HPRT de \201 ciency, as it is again sex-linked, leads to ura te overproduction, and there may be a neurological com- ponent to the disease. The enzyme P RPS catalyzes the transfer of the pyrophosphate group of ATP to ribose 5-phosphate to form PP-ribose-P in the de novo pathway leading to purine synthesis (Fig. 15.15.1). The mutation leads to PRPS overactivity and overproduction of urate. Kelley \200\223Seegmiller syndrome (KLS) Partial enzyme defects may be associated only with uric acid overproduction and its consequences may present (usually with gout) in adolescen ce or early adulthood; this is sometimes known as the Kelley \200\223Seegmiller syndrome. Presentation In addition to crystalluria, gout and renal impairment, affected children may present with dysmorphic features, sometimes inherited nerve deafness, a family history of r epeated attacks of bronchopneumonia and death in early infancy as well as developmental ret ardation. A much milder phenotype presents later in adolescence with kid- ney stones or sev ere gout. Presentation All degrees of HPRT de \201 ciency may present in the \201 rst weeks of lif e with crystalluria, gout and AKI, sometimes leading to ESRD or death in infancy. Diagnosis The diagnosis can be advanced by measurement of plasma urate, remembering that th e fractional excretion of \201 ltered urate (FEurate) is much higher in infants and child ren, and the plasma urate correspondingly lower than in adults. Renal failure leads to a ri se in plasma urate concentration. A better guide to diagnosis is the excretion fo urate whi lst taking a low-purine diet, to demonstrate over-production. Finally, diagnosis can be con \201 rmed by using an enzyme assay on red cell lysates. Carrier detection is unsatisfacto ry with a low yield, but preimplantation diagnosis and chori- onic villous sampling are pos sible. Diagnosis Although this defect is X-linked, it should be suspected in any child, female, or young adult of either sex with marked hyperuricemia and/or hyperuricosuria, but with norma l HPRT activity in lysed red cells. The heterozygote females can be severely affected also, particularly mothers of male children with neurological de \201 cits or urate overproduct ion who themselves have gout. These female carriers may also have sensorineural deafness. Treatment Allopurinol, again used with care to avoid xanthine neph- ropathy, will control p lasma uric acid in patients with nor- mal renal function and gout or kidney stones. A high \202 uid intake and alkalinization of the urine may help, and in CKD Treatment The elevated uric acid concentrations in either complete or partial de \201 cien cies may be controlled by a high \202 uid intake, together with alkali and allopurinol. CHAPTER 15.15 Inherited disorders of purine metabolism and transportation 637 DNA de novo ATP synthesis PRPS adenylate inosinate guanylate guanosine adenosine HPRT APRT inosine guanine hypoxanthine adenine XOR XOR 2,8-diOH adenine uric acid xanthine XOR Fig. 15.15.1 Purine metabolism in summary. The reactions catalyzed by the enzymes HPRT, PRP S, APRT, and XOR are indicated by stippled arrows. XOR, xanthine oxidoreductase; PRPS, phos phoribosyl pyrophosphate synthetase; HPRT, hypoxanthine-guanine phosphoribosyltransferase; APRT, adenine phosphoribosyltransferase; DNA, deoxyribonucleic acid; ATP, adenosine triphos phate. Table 15.15.1 Common defects of purine metabolism Homo-/hemizygote frequency Insoluble purine in crystals/stones Associated features Enzyme defect Abbreviation Gene location and mode of inheritance Uric acida HPRT Xq 1:380 000 (1/3 new mutations) Hypoxanthine-guanine ribosyltransferase de \201 ciency Choreoathetosis Self-mutilation Developmental arrest Sex-linked Uric acida PRPS Xq.21ptr (PRS1) Xp.22.3 (PRS2) ? Dysmorphia Developmental arrest Deafness Phosphoribosyl pyrophosphate synthetase overactivity Sex-linked Adenine phosphoribosy ltransferase de \201 ciency APRT 16q24 Autosomal recessive 1:33 000 to 1:250 000 2,8-Dihydroxyadenosine None Xanthine oxidoreductase de \201 ciency XOR 2p22 Autosomal recessive 1:45 000 Xanthine None a Also contain xanthine and/or oxypurinol in those treated with allopurinol. J.S. CAMERON 638 recipients will continue to need treatment with allopurinol; therefore, azathioprine should be avoided. If used, the dose of both drugs should be reduced (up to 200 mg for allopu- ri nol and 25% of the daily dose for azathioprine). the allopurinol dose must be reduced even further as indi- cated above. To date, no success ful therapy for the associated neuro- logical complications in severe cases has been devise d, and unfortunately death in childhood is frequent. Prognosis for patients presenting in a dolescence is good. Hereditary xanthinuria De \201 ciency of xanthine oxidoreductase (XOR) results in an inabi lity to oxidize hypoxanthine and xanthine to uric acid (Fig. 15.15.1). This leads to accumu lation of xanthine (and to a lesser extent hypoxanthine) in place of uric acid. Xanthine co ncentrations in plasma and especially urine are increased. The nephrotoxicity of this purin e, like that of 2,8-dihydroxyadenine, is due to its insolubility, which unlike uric acid ca n barely be increased by alkalinizing the urine. By contrast, hypoxanthine is very soluble and poses no problem. Xanthine lithiasis, like uric acid lithiasis, is climate dependent, b eing much more prevalent and associated with more severe renal complications in countries w hich fringe the Mediterranean. Adenine phosphoribosyltransferase (APRT) de \201 ciency APRT is the companion salvage enzy me of HPRT which catalyzes the conversion of adenine to AMP using PP-ribose-P (Fig. 15.15.1 ). Its prime function is the removal of adenine arising as a metabolic waste product from t he polyamine pathway. In the congenital absence of APRT, adenine accumulates in quantity an d is oxidized by xan- thine dehydrogenase to 8-hydroxyadenine and then the very insoluble 2 ,8-dihydroxyadenine. 2,8-Dihydroxyadenine is extremely insoluble at any pH, and has a high renal clearance: 2,8-dihydroxyadenine is pro- tein-bound but is actively secreted by the hu man kidney. The stones, unlike the hard, compact, yellowish urate stones, are bluish or put ty-colored and crumbly, but often have been misidenti \201 ed as uric acid because of thei r identi- cal chemical behavior, giving positive tests in both the colorimetric and murexid e reactions for urate. Type 1 xanthinuria Typically nonsense, missense, or frame-shift mutations are found in the XOR gene in patients with \200\230classical \200\231 type 1 xanthinuria. In most homozygot es uric acid is virtually undetectable in plasma and urine on a purine-free diet, and is re placed in the urine by xanthine and, to a lesser extent, hypoxanthine (which is extensively salvaged) in a ratio of 3 \200\2234:1. The potential toxicity of xanthine in xanthinuric s ub- jects relates to its high renal clearance by \201 ltration with little or no tubular reabsorption. In XOR-de \201 cient homo- zygotes with normal renal function, plasma and ur inary xanthine concentrations are generally well in excess of the solubility of xanthine in urine (0.9 mmol/L), even at pH 7.0. Therefore the potential for precipitation in the kidne y or urinary tract is high.The condition predominates in males. Type I APRT de \201 ciency Subjects are predominantly Caucasian and have no detect- able A PRT activity in lysed erythrocytes. Various substitu- tions, insertions, and deletions have been identi \201 ed in non-Japanese patients. Type II APRT de \201 ciency Subjects have an erythrocyte lysate APRT activity up to 25% of normal, found almost exclusively in Japan, where APRT de \201 ciency is common. A single mutation accounts for 70% of Japanese patients. Differentiation of these two types of defe ct requires intact cell studies. Type 2 xanthinuria (associated lack of aldehyde oxidase; MoCo de \201 ciency) Xanthinuria, as well as resulting from an isolated de \201 ciency of XOR (type 1), may also arise from a dual de \201 ciency of XOR and the related enzyme aldehyde oxidase (type 2). Aldehyde o xidase (AO), like XOR, contains molybdenum and a defect in the synthesis of the sulfide lig and of the molybdenum cofactor (MoCo) common to both enzymes deletes the activity of both \200\223 but leaves the activity of asso- ciated sul \201 te oxidase intact. This dual enz yme de \201 ciency may account for up to 50 per cent of cases with supposed \200\230class ical \200\231 xanthinuria. These subjects are at special risk for drugs that are normally m etabolized by aldehyde oxidase, which include allopurinol, azathioprine, cyclophosphamide, methotrexate, and quinine. A few infants have a de \201 ciency of all three enzymes (XOR, AO and sul \201 te oxidase), due to the absence of MoCo from several genetic defects, with severe clinical features of sul \201 te oxidase de \201 ciency (severe neonatal \201 t ting, microcephaly, and other speci \201 c neurological de \201 cits) which overshadow th ose of classical xanthinuria, although multiple renal cal- culi have been observed by ultra sonography. Presentation At least 15% of cases are without symptoms, which occur only when 2,8-dihydrox yadenine stones or crystals are formed. The picture may vary from benign to life-threaten- ing. The age of onset of symptoms for both defects has varied from birth to the 7th decade. Crystalluria and renal damage may be worsened by a diet high in adenine. Both AKI from sto nes, and CKD may occur, and in some patients the diagnosis is only made following transplan tation, some- times with loss of the allograft. Diagnosis Renal USS may provide the \201 rst clue to the underlying crystal nephropathy i n patients with AKI but in others it has taken more than 50 years before the nature of the kid- ney stones was recognized. Subjects with complete APRT de \201 ciency generally have normal amounts of uric acid in plasma and urine, in con- trast to HPRT de \201 ciency and PRPS superactivity. Presentation Although the age of onset of nephrotoxicity has varied from the \201 rst yea r of life to the 8th decade, nearly half of the cases presenting with urolithiasis have bee n children aged \211 10 years. Symptoms present from birth have included persistent vomiti ng, poor weight gain and urinary tract infection; irritability, sleeplessness, and gross he matu- ria have also been noted. Despite the insolubility of xanthine, Treatment Treatment with allopurinol is highly effective, immediately and in the long term, with the usual proviso relating to allopurinol dose reduction in CKD. Unlike uric acid, al kali will not increase the solubility of 2,8-dihydroxyadenine. If ESRD occurs because of la te diagnosis, renal transplanta- tion can be successful. The allograft remains at risk, and CHAPTER 15.15 Inherited disorders of purine metabolism and transportation 639 it is likely that up to half of XOR-de \201 cient homozygotes never present with symptoms, and are picked up inciden- tally or not at all. Nevertheless, renal damage can be severe, leading in some to ESRD, nephrectomy and even death. Adults with the more serious renal com plications frequently have a history of recurrent urolithiasis dating back to early childho od. part of the syndrome of hepatocyte nuclear factor-1 , which can include medullary cystic k idney disease. Patients, especially those with FJHN, show hyperuricemia and in some familie s gout. A low FEurate ( \211 3%) is present throughout the course of the condition until re nal failure supervenes, and presents before any other signs of the condition are found in c hildren; but the relationship between this and the uromodulin abnormalities remains obscure , since all major urate handing mechanisms so far de \201 ned seem to be present only in t he proximal tubule, whereas uromodulin is found only in the thick ascending limb of the loo p of Henle. There is some evidence also that treatment with allopurinol, if begun early, ma y be renopro- tective, but this is disputed by others. If so, this would sug- gest some maj or role for urate in the pathogenesis of the condition. Otherwise, it may merely be a side- effect of sec- ondary polyuria and volume contraction \200\223 features not particularly e vident in the majority of patients, and urate deposits are in general absent from the kidne ys. Moreover, inherited nephrogenic DI is not associated with renal fail- ure, although gou t may occur. Otherwise onset or presentation may be from childhood to middle age, and femal es are equally affected as males, as one would expect of a dominantly inherited condition. Hypertension is usually absent, unless and until renal fail- ure supervenes. Inherited disorders of renal urate handling Several inherited conditions arising from defec ts in the bidirectional transportation of urate in the renal tubule lead to decreased or in creased excretion of urate, with concomi- tant alterations in plasma urate concentrations. Hypouricemia of renal tubular origin Urate, being an anion, is handled mainly if not exclus ively in the proximal nephron by a number of channels and trans- porters of varying speci \201 cities. Thus, among those patients noted to have hypouricemia (usually on screening, 0.5% of the population) are some who have inherited disorders of these transportation syste ms. Some of these patients are found to have full Fanconi syndrome, with hypouricemia repre senting only one aspect of the generalized proximal tubular dysfunction present, e. g. cyst inosis or Lowe \200\231s syndrome. Mutations in URAT-1 URAT-1 is a relatively speci \201 c reabsorptive proximal tubu- lar tr ansporter of urate, mutations of which lead to a recessively inherited hyperuricosuria and hypouricemia. These individuals are usually without symptoms, but may suffer urate crystall uria, stones or exercise-associated AKI. This disorder is particularly common in Japan, whe re a sin- gle point mutation is usually (80%) responsible. The cause of the AKI episodes re mains obscure \200\223 urate crystals have been found in the kidney only occasionally. The FEurate usually varies from 35 to 80%, but in some instances may exceed the GFR. Some othe r forms of renal hypouricemia may relate to mutations in others of the many transportation systems which handle urate, but none have yet been proven to be impli- cated in non-URAT-1 cases. Further reading Becker MA. Hyperuricemia and gout. In: Scriver CR, Beaudet AL, Sly WS, Vall e D (eds), The metabolic and molecular basis of inherited disease, 8th edn. New York: McGra w-Hill; 2001. pp. 2513 \200\2232535. Cameron JS, Moro F, Simmonds HA. Inherited disorders of purine metabolism and transportatio n. In: Davison AM, Cameron JS, Gr nfeld JP, et al. (eds), Oxford textbook of clinical neph rology, 3rd edn, Oxford: Oxford University Press; 2005. pp. 2381 \200\2232395. Raivio KO, Saksela M, Lapatto R. Xanthine oxidoreductase \200\223 role in human pathophysi ology and in hereditary xanthinuria. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds), The metabolic and molecu- lar basis of inherited disease, 8th edn. New York: McGraw-Hill; 2001 . pp. 2639 \200\2232652. Sahota AS, et al. Adenine phosphoribosyltransferase de \201 ciency and 2,8-dihydroxyadenin e lithiasis. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds), The metabolic and molecular basis of inherited dis- ease, 8th edn. New York: McGraw-Hill; 2001. pp. 2571 \200\2232584. Familial hyperuricemia and gout A group of related, dominantly inherited, disorders has bee n described including hyperuricemia and gout in a pro- portion of family members. These dis orders include the symptom complexes of familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease type 2 (MCKD2). They have been shown to be the result o f mutations either of the gene for the major urinary protein uromodulin on chromosme 16p11- 12 (UMOD), present in some 30 \200\22340% of families; or presumptively of some other gene( s) which is/are concerned with uromodulin assembly, traf \201 c or excretion, since these other families generally show, as in those with a UMOD mutation, a low urinary excretion of uromodulin and abnormal patterns of uro- modulin staining in their renal tubules. Loci hav e been iden- ti \201 ed tentatively on chromosomes 1 and 7, the latter as Scriver CR, Beaudet AL, Sly WS, Valle D (eds), The metabolic and molecular basis of inherit ed disease, 8th edn. New York: McGraw- Hill; 2001. Internet resources Purine Research Society: http://www.purineresearchsociety.org/ Lesch \200\223Nyhan Disease International Study Group : http://www.lesch-nyhan.org/ See also Medical management of stone disease, p. 270 Isolated defects of tubular function, p. 200 R. HOLT 640 Rare syndromes with renal involvement There are between 250 and 300 syndromes with recognized renal anomalies. Each of these synd romes may be individu- ally rare, but collectively patients with syndromic conditions are s een relatively commonly in pediatric practice. The disorders in this chapter have been sele cted for their broad relevance. With improved survival, it is likely that some of these con ditions will be encountered by nephrol- ogists in adult practice more frequently. General features: affects 1 in 13 700 individuals; macro- somia (birth weight and length t ypically 97th centile, adult height 50 \200\22397th centiles); macroglossia (particularly notable in infancy); unusual skin creases on ear lobe and indenta- tions on outer rim of ea r pinna; omphalocele/umbilical hernia; visceromegaly, including pancreatic hyperplasia (ass ociated with hyperinsulinemia and neonatal hypoglyc- emia); hemihypertrophy; increased risk of embryonal tumors (e.g. hepatoblastoma). Nephrourological features: nephronomegaly with renal medullary dysplasia; Wilms \200\231 tumor predisposition (occurs in 7% of cases); hy percalciuria is an occasional feature. Additional notes: in view of risk of Wilms \200\231 tumor and other embryonal tumors, USS screening recommended at 3 \200\2234 month intervals until age 7 \200\2238 years. Alagille syndrome Synonym: arteriohepatic dysplasia. Genetic basis: mutation of JAG1 gene ( 20p12), which encodes a ligand in the Notch signaling pathway involved in early determinati on of cellular fate during development. Inheritance pattern: autosomal dominant (AD). Gener al features: characteristic facies (broad forehead, long nose, prominent chin in adults); o cular abnormalities (posterior embryotoxon); vertebral anomalies (butter \202 y vertebrae) ; right-sided congenital cardiac defects (periph- eral pulmonary artery stenosis, tetralogy of Fallot); intrahe- patic bile duct hypoplasia and chronic cholestasis (frequently presen ting as prolonged neonatal jaundice); abdominal aor- tic coarctation has been documented in some cases. Nephrourological features: variable \200\223unilateral renal agenesis; renal d ysplasia; renal artery stenosis; renal abnormalities are thought to occur in 10% of affect ed individuals. Branchio-oto-renal (BOR) syndrome Synonym: Melnick \200\223Fraser syndrome. Genetic basis: mutations of the EYA1 gene (8q13) account for \211 50% of cases (type 1); cases of BOR syn drome type 2 are due to mutation of the SIX5 gene (19q13). Inheritance pattern: AD. General features: BOR syndrome affects 1 in 40 000 peo- ple; hearing loss (90% of cases may be se nsorineural, con- ductive or mixed pattern); abnormal ear pinna (may be cup-shaped, \202 attened or hypoplastic); structural defects of middle ear, vestibular system and cochlea ma y be demonstrable on CT scan; pre-auricular pits (80%) or, less commonly, skin tags; branch ial \201 stulae or cysts (50%); see Fig. 15.16.2. Nephrourological features: spectrum of abnormalities includes unilateral or bilateral renal agenesis; renal hypo- plasia or dyspla sia ( 65% of cases); cysts; pelviureteric duplication; VUR. Additional notes: branchio-otic syndrome type1 and oto- facio-cervical syndrome result from different mutations of the EYA 1 gene; these disorders have phenotypic overlap with branchio-oto-renal syndrome, but do no t include renal abnormalities. Bardet \200\223Biedl syndrome Genetic basis: genetically heterogeneous disorder, involv- in g at least 12 loci (BBS1 \200\22312). Experimental studies suggest that the BBS genes may b e involved in ciliary function. Other genes are thought to have a role in modifying express ion of the BBS phenotype. Inheritance pattern: generally regarded as autosomal recessive (A R). In some cases, clinical manifestation of the BBS phenotype may require two abnormal all eles of one BBS gene and a third mutation in another BBS gene (triallelic inheritance). Gen eral features: incidence <1 in 100 000 in UK, but higher in some ethnic groups; short statu re; obesity; postaxial polydactyly; ocular abnormalities (pigmentary retinopathy causing pr ogressive visual impairment, Fig. 15.16.1); hypog- onadism; developmental delay/learning di f \201 culties. Nephrourological features: >95% of affected individuals have demonstrable renal abnormalities, which may include: persistent fetal lobulation; abnormal calyces; rena l dyspla- sia; renal scarring; pelviureteric duplication; vesicoureteric re \202 ux (VUR); urinary concentrating de \201 cit; renal tubular acidosis; progressive CKD, leading to ES RD in a minority of patients ( 4%). Additional notes: heterozygous relatives are thought to have a higher frequency of congenital renal malformations and an increased incidence of re nal cell carcinoma, com- pared with the general population. CHARGE syndrome Genetic basis: most affected individuals have mutations of the chromodomain helicase binding protein 7 (CHD7) gene on 8q12; the phenotype may also be caused by mutati ons of the semaphorin-3E gene (SEMA3E) on 7q21. Inheritance pattern: generally sporadic. Ge neral features: affects 1 in 12 000 individuals; CHARGE is an acronym representing the pri ncipal features; Coloboma; Heart defects; Atresia choanae; Retardation of growth and develo pment; Genital anomalies and hypogo- nadism; Ear abnormalities deafness. Nephrourologica l features: include renal agenesis; ectopic kidney; renal hypoplasia/dysplasia; lower urina ry tract abnormalities (e.g. VUR). Beckwith \200\223Wiedemann syndrome Genetic basis: related to abnormalities of imprinted gr owth-regulation genes clustered on 11p15, including uni- parental disomy and abnormalities of DNA methylation. Inheritance pattern: 85% sporadic; 15% AD. Denys \200\223Drash syndrome Genetic basis: mutations of the WT1 gene (11p13), usually loca ted in exons 7 \200\22310, which encode the DNA-binding domains of a transcription factor e xpressed in renal and genitourinary tract tissues; a different type of WT1 muta- tion gives rise to Frasier syndrome. CHAPTER 15.16 Rare syndromes with renal involvement 641 Fig. 15.16.1 Pigmentary retinopathy is associated with renal abnormalities in a number of c onditions, including Bardet \200\223Biedl syndrome and Senior \200\223L ken syndrome (Reti nal photograph courtesy of Dr Alan Fryer, Consultant in Clinical Genetics, Cheshire and Mer seyside Clinical Genetics Service, Liverpool, UK). General features: incidence 1 in 800 live births; short stat- ure; characteristic facial a ppearance; developmental delay/ learning dif \201 culties; congenital cardiac defects in 4 0 \200\22350% of affected individuals (notably septal defects); hypothyroidism in 20 \200 \22340%; epilepsy in 8%; increased incidence of duodenal atresia, Hirschsprung \200\231s di sease and several other congeni- tal anomalies; also increased risk of leukemia (affects 1 \200\2232%); ligamentous laxity, associated with risk of atlanto-axial sub- luxation (often asymptomatic, may rarely cause spinal cord compression with alteration of bladder/bowel fu nction or motor de \201 cits; usually occurs prior to age 10 years). Nephrourological feat ures: may occur in 20% of affected individuals and include: renal hypoplasia/dysplasia; pe lviu- reteric junction obstruction; vesicoureteric junction obstruction; VUR; posterior ure thral valves. Additional notes: in the absence of signi \201 cant comorbidity, Down syndro me is not considered to be a contraindica- tion to successful management of ESRD. Inheritance pattern: usually due to new mutation (nonpen- etrance in carrier parent has bee n reported in some cases). Nephrourological features: the classic triad consists of: 1. Ext ernal genital abnormalities (variable severity; hypos- padias and cryptorchidism may result in the appearance of pseudohermaphroditism in males). 2. Wilms \200\231 tumor predisposition. 3. Proteinuric nephropathy with progressive renal i mpair- ment (diffuse mesangial sclerosis histology on renal biopsy). Additional notes: \200 Karyotype should be checked in phenotypic females pre- senting with proteinuric nephropathy and diffuse mesangial sclerosis histology, to exclude male pseudo- hermaphroditism. In vie w of the Wilms \200\231 tumor predisposition, bilateral nephrectomy is advocated in Denys \200\223Drash syndrome. The proteinuric nephropathy does not appear to recur after renal tr ansplantation. Frasier syndrome Genetic basis: mutation of the WT1 gene (11p13), which encodes a transcrip tion factor expressed in renal and geni- tourinary tract tissues; alternative splicing of m RNA tran- scripts leads to the production of four isoforms of the transcription factor; in Frasier syndrome, a mutation in intron 9 causes a splice site change, altering the ratio of Down syndrome Genetic basis: chromosomal (trisomy 21 in 95%; remainder due to mosaicism, tr anslocation or complex chromosomal rearrangements). R. HOLT 642 in 50%; rhizomelic limb shortening; pelvic skeletal abnor- malities; biliary dysgenesis wit h periportal hepatic \201 brosis; pancreatic cysts and \201 brosis in a minority of cas es; retinal degeneration. Nephrourological features: cystic renal dysplasia; pro- gressive chronic renal impairment may manifest in early childhood; renal transplantation has been pe rformed suc- cessfully in affected individuals. MURCS Association Genetic basis: unknown. Inheritance pattern: usually sporadic, but famili al cases have been reported in siblings. General features: MURCS is an acronym representing the principal features: M \234llerian duct anomalies (absent/hypo- plastic uterus and abse nt upper 2/3 of vagina \200\223known as the Rokitansky defect); Renal anomalies; Cervicotho racic Somite dysplasia (Klippel \200\223Feil anomaly); many patients are diagnosed followin g investigation of primary amenorrhea (normal female secondary sexual characteristics devel op, as the ovaries are present). Nephrourological features: unilateral renal agenesis, rena l dysplasia or ectopia are found in 88% of cases. Neuro \201 bromatosis type 1 Synonym: von Recklinghausen disease. Genetic basis: mutation in the NF1 gene (17q11), which encodes neurofibromin, a GTPase-activating protein involved in cell cycle regulation. Inheritance pattern: AD, but 50% of cases are due to new mutation s. General features: birth incidence 1 in 2500 and preva- lence 1 in 4000; common feature s: caf -au-lait spots (six or more; \211 0.5 cm before puberty or \211 1.5 cm after pube rty); axillary/groin freckling; neuro \201 bromas (skin, spi- nal, visceral); Lisch nodule s (benign hamartomas of iris); distinctive dysplastic lesions of sphenoid or long bones; le arning dif \201 culties affect 33%; less common features include scoliosis, epilepsy and tumor predisposition (optic gliomas in early childhood; CNS tumors, malignant periph- eral nerve sheath tumors and rhabdomyosarcomas in adulthood); endocrine tumors occur in 3% (e.g . pheo- chromocytomas). Nephrourological features: neuro \201 bromas may occur in the kidn eys or bladder; renal artery stenosis occurs in 2% of affected individuals. Additional not es: regular blood pressure checks are rec- ommended in all age groups; when hypertension is detected, it is important to investigate appropriately for renal artery stenosis and pheoc hromocytoma. Fig. 15.16.2 Careful examination may be required to detect subtle features of branchio-oto- renal syndrome: note the pre- auricular pit. (Photograph courtesy of Dr Alan Fryer, Consult ant in Clinical Genetics, Cheshire and Merseyside Clinical Genetics Service, Liverpool, UK. ) these isoforms (in contrast, exon mutations of WT1 result in structurally abnormal transcri ption factor in Denys \200\223 Drash syndrome). Inheritance pattern: new mutation. Nephrour ological features: male pseudohermaphro- ditism (normal female external genitalia with 46XY karyotype); childhood-onset proteinuric glomerulopathy with nephrotic syndrome (focal segm ental glomeruloscle- rosis his tology on renal biopsy), progressing to ESRD in adolescence or early adulthood; streak gonads with predis- position to gonadoblastoma (hence gonadectom y is usu- ally advocated); relatively small increased risk of Wilms \200\231 tumor. Additio nal notes: the proteinuric nephropathy does not appear to recur after renal transplantation . Noonan syndrome Genetic basis: genetically heterogeneous; 50% of cases are due to mutation of the PTPN11 gene (12q24), which encodes a tyrosine phosphatase involved in multiple cell u- lar cascades. Inheritance pattern: AD. General features: affects 1 in 2500 people; shor t stature; characteristic facial appearance (hypertelorism, epican thic folds, low-set ears , low posterior hair-line with short or webbed neck); cardiac defects in 50 \200\22380% (no tably pulmonary valve stenosis, septal defects); thrombocytopenia or coagu- lation defects occur in up to 50% of cases; cryptorchidism Jeune syndrome Synonym: Asphyxiating thoracic dystrophy. Genetic basis: not fully elucidate d; linkage to 15q13. Inheritance pattern: AR. General features: normal facial appearance; s hort stature; long narrow thorax with short ribs, associated with lung hypoplasia (may be f atal in infancy, due to respiratory insuf- \201 ciency, particularly during viral respira tory tract infec- tions; for those who survive, there is a gradual improvement in the relat ive growth of the thorax); postaxial polydactyly CHAPTER 15.16 Rare syndromes with renal involvement 643 is common in males; lymphatic abnorma lities are associ- ated with dorsal edema of the hand s and feet. Nephrourological features: renal dysplasia and ureteric abnormalities (duplicat ion, VUR) are recognized in some cases. Inheritance pattern: AR. General features: pigmentary retinopathy; in the early stages, imp aired function of the rod photoreceptors manifests as reduced vision in dim illumination ( \200\230night blindness \200\231); this is followed by restriction of peripheral visual \201 elds and progressive visual loss; fundal examination shows pigmentary changes in the m idperipheral retina (Fig. 15.16.1). Nephrourological features: nephronophthisis; the earlie st detectable clinical feature may be impaired urinary con- centrating ability, manifesting as polyuria and polydipsia; followed by progressive CKD in childhood/adolescence. Prune belly syndrome Synonyms: Eagle \200\223Barrett syndrome; early urethral obstruc- tion sequence; (triad of megacystis-megaureter, cryp- torchidism, de \201 cient anterior abdom inal wall musculature). Genetic basis: unknown; occurrence in one member of a monozygotic t win pair suggests that nongenetic factors may be relevant. Inheritance pattern: generally c onsidered sporadic. General features: incidence 1 in 30 000; male predomi- nance (>95%); o ligohydramnios during pregnancy may lead to pulmonary hypoplasia and skeletal abnormalities (congenital talipes equinovarus and developmental dyspla- sia of the hip); cardiac anomali es are found in 10% of cases. Nephrourological features: urethral narrowing/atresia may be present; bladder is typically large volume and low pressure with poor contractility; ureter s typically dilated and tortuous with high grade VUR; in a minority of cases, there may be ureteric obstruction due to kinking or stenosis; renal dysplasia of variable severity; cryp - torchidism and infertility in males; females may have vaginal atresia or uterine abnormal ities; decompression of dis- tended bladder and de \201 cient abdominal wall musculature l ead to the classical wrinkled \200\230prune belly \200\231 appearance in infants. Addition al notes: poor detrusor contractility and VUR con- tribute to incomplete bladder emptying a nd UTI risk; expert urological management is essential; the combina- tion of renal dysplasi a and acquired scarring may lead to progressive CKD; ESRD management may be successfully un dertaken, but it is necessary to ensure adequacy of urinary drainage prior to renal transpl antation. Townes \200\223Brock syndrome Genetic basis: mutation of SALL1 gene (16q12), which encodes a zinc \201 nger transcription factor. Inheritance pattern: AD; high proportion of cases are due to new mutations. General features: ear anomalies (dysplastic ears, pre-auric- ular tags) with sensorineural hearing loss; various hand malformations (notably triphalangeal t humb or hypoplastic thumb; preaxial polydactyly); imperforate anus. Nephrourological featur es: renal malformations (variable \200\223 may include: renal agenesis; unilateral or bila teral dysplas- tic/hypoplastic kidneys); lower urinary tract abnormalities (VUR; posterior urethral valves; urethral meatal stenosis; hypospadias; bi \201 d scrotum); CKD occurs in some cases; life-long monitoring of renal function is recommended. Turner syndrome Genetic basis: chromosomal (karyotype 45X in 50% of cases; remaining cases involve various combinations of mosaicism). General features: affects 1 in 2500 live femal e births; phe- notype is highly variable and features may be very subtle in some individual s; signi \201 cant short stature (may be treated with growth hormone therapy); neck may be broad and webbed, with low posterior hair-line; cardiovascular abnor- malities are present in 15 \200\22350% (notably aortic coarctation and ventricular septal defects; adults have an increased risk of aortic root dilatation and aortic dissection \200\223 regular sur- ve illance is advised); lymphatic abnormalities are associated with edema of hands and feet, s een most commonly in newborn period but may be present at any age; gonadal dysgenesis leads to absent or limited spontaneous puber- tal development and infertility in the majority of cases (estrogen treatment required from adolescence); other problems in adulthood include risk of osteoporosis and susceptibility to autoimmune diseases (hypothyroidism, diabetes me llitus, in \202 ammatory bowel disease, chronic liver disease); mosaic 45X/46XY individual s have an increased risk of gonadoblastoma. Nephrourological features: congenital renal ano malies are found in 1/3 of cases (notably horseshoe kidney; unilat- eral renal agenesis; r enal dysplasia/hypoplasia; pelviureteric duplication; VUR); hypertension may be more common than in the general adult population. Renal \200\223Coloboma syndrome Synonym: Papillorenal syndrome. Genetic basis: mutation of paired box gene 2 (PAX2, 10q24). Inheritance pattern: AD. General features: wide range of o cular abnormalities, from mild optic disc dysplasia (dif \201 cult to recognize, no func- tional consequences) to colobomas of optic nerve and retina; high frequency sensorineural h earing loss in some affected individuals; Chiari malformation with hydrocepha- lus has been reported. Nephrourological features: VUR; renal hypoplasia; CKD may progress to ESRD in ch ildhood or adult life. Senior \200\223L ken syndrome Synonym: juvenile nephronophthisis with Leber amaurosis; ren al \200\223retinal syndrome. Genetic basis: genetically heterogeneous; Senior \200\223L ke n syndrome 1 is due to mutations in the nephrocystin gene (NPHP1, 2q13); mutations in NPHP4 (1p36), NPHP5 (3q21) and possibly NPHP3 (3q22) are also associated with the Senior \200 \223L ken phenotype; other mutations in these genes may result in juvenile nephronophthisi s without ocular abnormalities. VATER/VACTERL association Genetic basis: unknown; more frequent in offspring of dia- betic mothers. Inheritance pattern: sporadic. R. HOLT 644 lateral renal agenesis; pelvic kidney; VUR; bladder diverticu- lae; urethral stenosis); hyp ercalciuria may be present even in the absence of hypercalcemia and may lead to nephro- cal cinosis; renal artery stenosis affects 40%; nonrenovascu- lar hypertension is also recogniz ed; ESRD has been successfully managed by renal transplantation. General features: incidence 1.6 in 10 000; VATER/ VACTERL are acronyms representing the pr incipal fea- tures: Vertebral defects (typically hemivertebrae or fused vertebrae in thorac ic or lumbar regions); Anal atresia; Cardiac abnormalities (80% of cases, various types); T racheo-esophageal \201 stula with Esophageal atresia; Renal anomalies; radial upper Limb defects; a secure diagnosis requires at least one defect each in limbs, thorax and lower ab domen/pelvis (probable diagnosis may be based upon two anomalies in each of two of these re gions). Nephrourological features occur in 80% of cases and may include: unilateral renal a genesis; renal dysplasia/hypoplasia; pelviureteric duplication; VUR; urethral atresia/steno sis; external genital defects (e.g. hypospadias, bi \201 d scrotum). Additional notes: ext ensive surgical treatment may be required over many years (neonatal repair of tracheo- esop hageal \201 stula and esophageal atresia, colostomy, uro- logical procedures), but most a ffected individuals achieve normal cognitive development; dialysis and renal transplan- tat ion are established treatments for those patients who progress to ESRD. 22q11 deletion syndrome Synonyms: velocardiofacial syndrome; DiGeorge syndrome. Genetic bas is: 96% of patients have hemizygous 1.5 \200\2233 Mb deletions of 22q11, including 24 \200 \22330 genes; other patients have speci \201 c deletions, translocations or point mutation s of the TBX1 gene, which lies within this chromosomal region. Inheritance pattern: 94% of cases are due to new dele- tions; 6% inherited in AD pattern (although there is intrafa- m ilial variability in phenotypic expression). General features: growth retardation/short sta ture; char- acteristic facial appearance (prominent wide nasal bridge and root, small mouth , round ears); velopharyngeal insuf \201 - ciency cleft palate; congenital heart diseas e in 75% of cases (notably tetralogy of Fallot and other malformations of the cardiac out \202 ow tract); variable defect in cell-medi- ated immunity (usually mild and improving in \201 rst 2 years of life; a minority have a persistent profound T-cell dysfunc- tion); 60 % are hypocalcemic at some stage (notably during neonatal period, but also during later chi ldhood or preg- nancy); several of these features (velopharyngeal defects; thymic and parat hyroid abnormalities; cardiac out \202 ow tract malformations) are attributed to abnormal develop- ment of the derivatives of the third and fourth branchial arches. Nephrourological features: structural renal tract anomalies are found in 36% of cases (renal agenesis; mult icystic dys- plastic kidney; hydronephrosis; VUR).