Introduction and definition 1 2 http://www.marchofdimes.com 3 PAX2 4 EYA1 PAX2 5 1 Primary renal agenesis 6 Primary renal hypoplasia and dysplasia Strictly speaking, renal hypoplasia is defined as a small kidney, which contains intact nephrons that are reduced in number, whereas a dysplastic kidney contains disorganized elements and maldifferentiated tissue. Noninvasive imaging studies such as ultrasounds and dimercaptosuccinic acid (DMSA) scan offer limited information to help distinguish a hypoplastic kidney from a dysplastic one. Unequivocal distinction between these two entities therefore depends on histological examination of renal tissue obtained from kidney biopsy or surgical nephrectomy, which are rarely performed. A further confounding factor is the reduction of kidney size due to chronic injury and scarring from VUR. Most of the time, a DMSA scan helps differentiate primary hypoplasia or dysplasia from small kidneys secondary to VUR. However, a DMSA scan has a low negative predictive value in distinguishing primary hypoplasia or dysplasia from a secondary reduction in kidney size from VUR when scars or areas of negative isotope uptake are present. In practice, the diagnosis of primary renal hypoplasia is favored when the following criteria are satisfied: (a) a reduction of renal size by 2 standard deviations (SDS) from the mean size for the age, (b) exclusion of renal scarring by DMSA scan, and (c) a presence of compensatory hypertrophy of the contralateral kidney. In all cases, the exclusion of renal cysts by ultrasonography is mandatory to avoid confusion with primary renal hypoplasia associated with fibrosis and cysts, nephronophthisis being the most pertinent example. The presence of VUR and/or ureteropelvic junction obstruction (UPJO) does not automatically exclude the diagnosis of hypoplasia, as both conditions are frequently associated with primary renal-size defects. It is clear that this problem is difficult to resolve if the ureteral defect presents ipsilateral to renal hypoplasia. For example, severe antenatal hydronephrosis due to UPJO can determine the involution of the renal parenchyma and lead to an erroneous diagnosis of primary renal agenesis after birth. In bilateral cases, syndromic traits as well as inherited disorders such as medullary cystic kidney disease/nephronophthisis have to be excluded. Unequivocal exclusion of renal dysplasia is usually not feasible except in rare cases for which histology is available. It is possible that in the near future, molecular genetic advances could modify our present understanding and allow for a more direct separation of the two pathological entities based on laboratory tests. These challenges in clinical diagnosis of renal hypoplasia complicate studies attempting to discover new genes underlying this anomaly. For research purposes, we utilize a tentative classification scheme for categorizing our subjects for genetic studies: (1) isolated bilateral hypoplasia/dysplasia, (2) isolated unilateral hypoplasia/dysplasia, and (3) hypoplasia/dysplasia associated with lower tract abnormalities such as VUR or UPJO. Once the genetic basis of different subsets of urinary tract malformations is identified, the classification will likely be retrospectively changed and improved. Kidney development and mouse models 7 8 1 RET WNT11 GDNF WT1 EYA1 PAX2 7 9 GDNF RET 10 Gdnf Ret Gdf11 Six1 Gdnf/Ret Wnt 1 Table 1 Principal genes targeted in mice leading to renal agenesis, hypoplasia, dysplasia Gene Human homolog Kidney phenotype Reference Foxd1 FOXD1 Small, fused, undifferentiated kidneys 59 Eya1 EYA1 Absent kidneys 60 61 Emx2 EMX2 Absent kidneys 62 Hoxa11/Hoxd11 HOXA11/HOXD11 Small or absent kidneys 63 Lhx1 LHX1 Absent kidneys 64 Pax2 PAX2 Small or absent kidneys 65 Wt1 WT1 Absent kidneys 66 Agtr2 AGTR2 Multiple urinary tract malformations 67 Bmp4 BMP4 Altered ureteric bud (UB) branching 68 Bmp7 BMP7 Disrupted nephrogenesis 69 Wnt4 WNT4 Undifferentiated kidneys 70 Ret RET Absent kidneys, severe dysgenesis 71 Gdnf GDNF Absent kidneys, severe dysgenesis 72 73 74 Six1 SIX1 Absent kidneys 75 Six2 SIX2 Small kidneys 76 Sall1 SALL1 Absent kidneys 77 Fgfr1/Fgfr2 FGFR1/FGFR2 Absent kidneys 78 Slit3 SLIT3 Small or absent kidneys 79 Pbx1 PBX1 Small or absent kidneys 80 Fgf8 FGF8 Small kidneys 81 Rara/Rarb2 RARA/RARB2 Small kidneys 82 Lim1 LIM1 Absent kidneys 83 The interdependence between developmental pathways explains why defects in different genes result in similar phenotypes and why morphologic classification of abnormalities alone cannot predict the location or nature of primary defects. Available data thus suggest a large list of candidate genes for human renal and urologic malformations, highlighting the potential for genetic heterogeneity of the trait. Genetic contribution to human renal agenesis/hypoplasia and dysplasia A genetic contribution to the development of renal hypoplasia/dysplasia has been recognized for many years. For the isolated, nonsyndromic renal agenesis/hypoplasia and dysplasia, only segregation studies have been performed, and no loci and/or genes have been mapped so far. Much more is known about rare syndromic forms, for which several genes have been already implicated. Syndromic forms 11 2 4 12 13 14 15 3 2 3 Table 2 List of human malformation syndromes with kidney hypoplasia/dysplasia Gene Human syndrome Kidney phenotype OMIM JAG1, NOTCH2 Alagille syndrome MCDK, kidney dysplasia, kidney mesangiolipidosis #118450 #610205 BBS1-BBS11 Bardet-Biedl syndrome Renal dysplasia and calyceal malformations #209900 EYA1, SIX1, SIX2 Branchiootorenal syndrome Renal agenesis/dysplasia #113650 SOX9 Campomelic dysplasia Diverse renal malformations #114290 CHD7 CHARGE syndrome Diverse urinary tract malformations #214800 Del. 22q11 Di George syndrome Renal agenesis, dysplasia, VUR #188400 GATA3 Hypothyroidism, sensorial deafness, renal anomalies (HDR) Renal agenesis, dysplasia, VUR #146255 DNA repair Fanconi anemia Renal agenesis #227650 FRAS1, FREM2 Fraser syndrome Renal agenesis, dysplasia #219000 KALL1, FGFR1 Kallman’s syndrome Renal agenesis, dysplasia #308700, #147950 PAX2 Renal coloboma syndrome Renal hypoplasia, MCDK, VUR #120330 TCF2 Renal cysts and diabetes syndrome Renal dysplasia, cysts #137920 GPC3 Simpson-Golabi-Behmel syndrome Renal dysplasia, cysts #300209 DHCR7 Smith-Lemli-Opitz syndrome Renal dysplasia, cysts #270400 SALL1 Townes-Brocks syndrome Renal dysplasia, lower urinary tract malformations #107480 LMX1B Nail-patella syndrome Glomerulus malformation, renal agenesis #161200 NIPBL Cornelia de Lange syndrome Renal dysplasia #122470 CREBBP Rubinstein-Taybi syndrome Renal agenesis #180849 WNT4 Rokitansky syndrome Renal agenesis #277000 PEX-family Zellweger syndrome Renal dysplasia, cysts #214100 GLI3 Pallister-Hall syndrome Renal agenesis, dysplasia #146510 p57(KIP2) Beckwith-Wiedemann syndrome Renal dysplasia #130650 SALL4 Okihiro syndrome Renal ectopia with or without fusion, lower urinary tract malformations #607323 TBX3 Ulnar-Mammary syndrome Renal agenesis #181450 MCDK VUR Table 3 Common chromosomal disorders associated with urinary tract anomalies Chromosomal disorders Renal agenesis Hypoplasia Other associated anomalies Patau syndrome (trisomy 13) +  Holoprosencephaly, midline anomalies, cleft lip/palate Miller-Dieker syndrome (17p13 deletion) +  MR, lissencephaly, microgyria, agyria, typical facie, seizures Edward syndrome (trisomy 18) 18q deletion +  IUGR, CHD, clenched hands, rocker bottom feet SS, MR, microcephaly, narrow external ear canals, long hands Down syndrome (trisomy 21) +  MR, hypotonia, CHD, typical face, clinodactyly Cateye syndrome (tetrasomy 22p) +  MR, CHD, colobomas, anal/digital anomalies Velocardiofacial syndrome (22q11 deletion) + + Conotruncal CHD, thymic aplasia, typical face, cleft palate Turner syndrome (45,X or 46,X,i(Xq)) + + SS, amenorrhea, webbed neck, cubitus valgus, hypogonadism MR  IUGR  CHD SS Nonsyndromic forms 6 16 17 16 18 19 Strategies for gene discovery Strategies to find genes causing renal agenesis/hypoplasia and dysplasia vary significantly depending on the characteristics of the study population available. Different data sets of patients have potential advantages and possible pitfalls. Candidate gene studies 20 http://www.hgmd.cf.ac.uk/ac/index.php 21 22 23 24 28 PAX2 TCF2 5 29 30 RET RET 31 Traditional linkage studies and genetic isolates 32 33 PAX2 TCF2 34 35 36 38 39 41 42 Genome-wide association studies http://www.ncbi.nlm.nih.gov/projects/SNP/ 43 44 45 46 47 48 TCF7L2 49 50 Search for structural variations in the genome 51 52 53 54 55 57 CHD7 58 Conclusions Renal agenesis/hypoplasia and dysplasia still represents a challenge for both the clinicians who attempt a precise diagnosis and for the geneticists who try to unravel the genetic basis. Genetic and clinical approaches are now converging toward a common goal, which is the discovery of genetic markers, to make the diagnosis of this trait easier. The final objective is to improve classification, to make a reliable prognosis, and to attempt prevention. Based on advances from the last few years, the goal appears to be more feasible with large multicentric collaborative groups that share the same objectives and resources.