iBet uBet web content aggregator. Adding the entire web to your favor.
Link to original content: http://omim.org/entry/191830
Alternative titles; symbols
ORPHA: 1848, 411709; DO: 14766;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10p13 | Renal hypodysplasia/aplasia 1 | 191830 | Autosomal recessive | 3 | ITGA8 | 604063 |
A number sign (#) is used with this entry because renal hypodysplasia/aplasia-1 (RHDA1) is caused by homozygous or compound heterozygous mutation in the ITGA8 gene (604063) on chromosome 10p13.
Renal hypodysplasia/aplasia belongs to a group of perinatally lethal renal diseases, including bilateral renal aplasia, unilateral renal agenesis with contralateral dysplasia (URA/RD), and severe obstructive uropathy. Renal aplasia falls at the most severe end of the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT; 610805), and usually results in death in utero or in the perinatal period. Families have been documented in which bilateral renal agenesis or aplasia coexists with unilateral renal aplasia, renal dysplasia, or renal aplasia with renal dysplasia, suggesting that these conditions may belong to a pathogenic continuum or phenotypic spectrum (summary by Joss et al., 2003; Humbert et al., 2014).
Genetic Heterogeneity of Renal Hypodysplasia/Aplasia
See also RHDA2 (615721), caused by mutation in the FGF20 gene (605558) on chromosome 8p22; RHDA3 (617805), caused by mutation in the GREB1L gene (617782) on chromosome 18q11; and RHDA4 (619887), caused by mutation in the GFRA1 gene (601496) on chromosome 10q25.
Bilateral renal agenesis in utero results in oligohydramnios, and affected infants are noted at birth to have a characteristic facial phenotype known as 'Potter facies.' This association was described by Potter (1946) in newborns with bilateral renal agenesis or other kidney abnormalities, including renal aplasia, dysplasia, hypoplasia, or multicystic disease. The typical 'Potter facies' is characterized by wide-set eyes, flattened nose, receding chin, and large, low-set ears deficient in cartilage. The characteristic phenotype of these infants is independent of the origin of the renal abnormality and results from the decreased volume of amniotic fluid and consequent restricted fetal movement. Thus, 'Potter syndrome,' which also included lung hypoplasia and clubfeet, is not a distinct etiologic entity and can have different origins (summary by Schmidt et al., 1982).
Hack et al. (1974) reported 2 Jewish Iraqi brothers with bilateral renal agenesis. The unaffected parents were unrelated. Both infants showed typical Potter facies with pulmonary hypoplasia and died soon after birth.
Schmidt et al. (1982) reported ultrasonographic findings of fetuses with severe kidney disease from 23 families. Most had persistent oligohydramnios, severely decreased or absent renal function, and features of Potter syndrome, including dysmorphic facies and clubfeet. Diagnoses included bilateral renal agenesis, unilateral renal agenesis and contralateral renal dysplasia, renal dysplasia with multicystic kidneys and deformations of the urogenital tract, bilateral renal hypoplasia, and cystic dysplasia or polycystic kidney disease. Schmidt et al. (1982) noted that the most severely affected infants usually died within hours to days after birth.
Yates et al. (1984) reported monozygotic twin girls with bilateral renal agenesis. The parents were unrelated. The twins were born at 36 weeks' gestation and showed breech presentation with very little amniotic fluid. Both died in the perinatal period. Both had Potter facies, large spade-like hands, and talipes equinovarus. Postmortem examination showed bilateral renal agenesis with complete absence of the ureters and bladder, and hypoplastic lungs. The fallopian tubes and uterus were hypoplastic, but ovaries and female external genitalia were normal.
Monn and Nordshus (1984) reported a family in which 4 individuals spanning 3 generations had hereditary renal adysplasia. In 2 affected members, a small tissue bud with a ureteric remnant was observed. There was minimal compensatory hypertrophy of the normal kidney.
By means of gray-scale ultrasonography, Roodhooft et al. (1984) evaluated 71 parents and 40 sibs of 41 index patients with bilateral renal agenesis, bilateral severe dysgenesis, or agenesis of 1 kidney and dysgenesis of the other. Asymptomatic renal malformations, most often unilateral renal agenesis, were found in 10 (9%) of 111 first-degree relatives (9%). The 4.5% frequency of renal agenesis was contrasted with the 0.3% frequency among 682 adults (p less than 0.004).
In a population-based family study of 221 patients with perinatal lethal renal disease in the State of Victoria, Australia, 1961 to 1980, Bankier et al. (1985) observed 134 cases of bilateral renal agenesis (BRA), 34 cases of unilateral agenesis with dysplasia of the other kidney (URA/RD), 42 cases of bilateral renal dysplasia (BRD), and 11 cases of renal aplasia. The highest frequency in sibs (8%) was observed when the index case had BRA and urogenital defects. When BRA was part of a multiple malformation syndrome in a proband, none of the sibs had BRA, although 5 of 40 (12.5%) had a similar pattern of malformations. The findings confirmed that BRA and URA are genetically related.
Selig et al. (1993) reported a family in which 4 successive offspring had a combination of congenital lethal renal disorders, including bilateral renal dysplasia, megalocystis secondary to urethral obstruction, and sirenomelia with associated renal agenesis. The parents were not related, and renal ultrasound revealed that both had 2 normal kidneys.
Humbert et al. (2014) reported a large consanguineous Roma Gypsy family originating from Serbia and Spain in which 3 couples had 1 to 4 terminations of pregnancy for bilateral renal agenesis associated with the Potter sequence due to anhydramnios, characterized by facial dysmorphism, pulmonary hypoplasia, and clubbed feet. In another unrelated family from West Africa, 2 sibs were similarly affected: a fetus spontaneously aborted at 24 weeks' gestation due to bilateral renal agenesis with anhydramnios, and a boy died perinatally with bilateral renal agenesis and cryptorchidism.
Buchta et al. (1973) coined the term hereditary renal 'adysplasia,' which combines the terms aplasia and dysplasia.
In the family reported by Humbert et al. (2014), RHDA was transmitted as an autosomal recessive trait.
Madisson (1934) reported bilateral renal agenesis in sibs.
Baron (1954) described bilateral agenesis of the kidneys in 2 consecutive infants in a family.
Davidson and Ross (1954) noted 6 twin pairs in which only 1 twin had bilateral absence of the kidney.
Kohn and Borns (1973) and Zonana et al. (1976) each described a father with a single kidney and offspring with bilateral renal agenesis.
Prenatal Diagnosis
Schmidt et al. (1982) reported prenatal diagnosis of kidney diseases by ultrasonography in 23 families.
Morse et al. (1987) reported bilateral renal aplasia in 3 consecutive sibs. Renal ultrasound studies on both parents and a surviving child were normal. Ultrasound was used prenatally to diagnose BRA in both recurrences, and autopsy confirmed the diagnosis in otherwise normal fetuses.
Bankier et al. (1988) cautioned that renal ultrasound examination of parents of offspring with perinatal lethal renal disease cannot be depended on to exclude the presence of a genotype that could lead to recurrence in a later-born sib. For that reason, couples who have had an affected pregnancy should rely on ultrasound screening of subsequent pregnancies between 16 and 18 weeks of gestation.
Joss et al. (2003) described bilateral renal aplasia diagnosed in a fetus by ultrasound at 29 weeks' gestation. Bilateral absence of renal tissue and very low volume of amniotic fluid were the basis of the diagnosis. Labor was induced at 32 weeks of age and the baby died shortly after birth. He had features typical of Potter sequence, including a flattened nose, large squashed ears, rocker-bottom feet, and marked skin laxity over the trunk and limbs. A de novo translocation (1;2)(q32;p25) was found.
Pending Confirmation
Sanna-Cherchi et al. (2012) examined the burden of large rare copy number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD), including renal aplasia, agenesis, hypoplasia, and dysplasia. They replicated findings in 330 RHD cases from 2 independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnically matched controls (p = 4.8 x 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. In total, 55 of 522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 x 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, revealing 38 potential novel or rare genomic variants for this trait. Deletions at the HNF1B (189907) locus and the DiGeorge/velocardiofacial locus (see 192430) were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary tract defects; 14 individuals harbored 2 or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort had previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. Sanna-Cherchi et al. (2012) concluded that CNV analysis should be performed in individuals with severe renal disorders to make specific syndromic diagnoses and to evaluate for the possibility of later developmental delay.
In 3 fetuses of Roma Gypsy descent with bilateral renal hypodysplasia/agenesis-1, Humbert et al. (2014) identified a homozygous splice site mutation in the ITGA8 gene (604063.0001), predicted to result in a loss of function. The fetuses were offspring of a large consanguineous Roma Gypsy family originating from Serbia and Spain; several other fetuses were similarly affected, but their DNA was not studied. The mutation, which was found in the first fetus by whole-exome sequencing, was confirmed by Sanger sequencing. The 2 other affected fetuses were homozygous for the mutation, and 1 unaffected mother was heterozygous for the mutation. Whole-exome sequencing of another affected family with a similar phenotype identified compound heterozygous mutations in the ITGA8 gene (604063.0002 and 604063.0003), which were demonstrated to cause a loss of protein function. Humbert et al. (2014) noted that Itga8-null mice also display renal agenesis (Muller et al., 1997), further supporting the findings in these families.
Associations Pending Confirmation
For a possible association between renal hypodysplasia/aplasia and variation in the SLIT3 gene, see 603745.0001.
Inductive interactions between the ureteric epithelium and metanephric mesenchyme are essential for kidney morphogenesis. Using immunohistochemistry, Muller et al. (1997) demonstrated that in mouse, integrin alpha-8/beta-1 (ITGB1; 135630) is expressed in many developing organs and particularly in the kidney, in mesenchymal cells bordering on epithelial cell sheets that undergo branching morphogenesis. By gene targeting, they produced mice lacking the alpha-8 gene. The mutant mice showed severe deficits in kidney morphogenesis due to reduced growth of the ureteric bud toward the metanephric mesenchyme, reduced branching of the ureteric epithelium within the mesenchyme, and defective epithelialization of kidney mesenchymal cells. Muller et al. (1997) concluded that ITGA8/ITGB1 plays a crucial role in epithelial-mesenchymal interactions during kidney morphogenesis.
Wiedemann (1994) gave a short biography of Edith Potter (1901-1993), who worked as a pathologist at the Chicago Lying-In Hospital for over 3 decades.
Bain et al. (1964) noted that 'Potter syndrome' can be seen in infants with normal kidneys but prolonged leakage of amniotic fluid; Potter syndrome is not pathognomonic of renal anomalies.
Scott and Goodburn (1995) found no renal malformations in 50% of autopsied second- or third-trimester fetuses with features of Potter syndrome. There was a high incidence of chorioamnionitis, suggesting that the mechanism of oligohydramnios was occult amniotic fluid leakage.
Two sisters reported by Schmidt et al. (1952) as having renal aplasia belonged to a family later described (Winter et al., 1968) as having 4 sisters affected with a syndrome that, in addition to renal hypoplasia or aplasia, showed vaginal atresia and anomalies of the otic ossicles (see 267400).
Bain, A. D., Smith, I. I., Gauld, I. K. Newborn after prolonged leakage of liquor amnii. Brit. Med. J. 2: 598-599, 1964. [PubMed: 14171064] [Full Text: https://doi.org/10.1136/bmj.2.5409.598]
Bankier, A., de Campo, M., Newell, R., Rogers, J. G., Danks, D. M. A pedigree study of perinatally lethal renal disease. J. Med. Genet. 22: 104-111, 1985. [PubMed: 3886908] [Full Text: https://doi.org/10.1136/jmg.22.2.104]
Bankier, A., Sheffield, L. J., Danks, D. M. Renal ultrasound examination of parents in dominantly inherited renal adysplasia: a note of caution. (Letter) Am. J. Med. Genet. 29: 695-696, 1988. [PubMed: 3287926] [Full Text: https://doi.org/10.1002/ajmg.1320290336]
Baron, C. Bilateral agenesis of the kidneys in two consecutive infants. Am. J. Obstet. Gynec. 67: 667-670, 1954. [PubMed: 13138668] [Full Text: https://doi.org/10.1016/0002-9378(54)90059-9]
Buchta, R. M., Viseskul, C., Gilbert, E. F., Sarto, G. E., Opitz, J. M. Familial bilateral renal agenesis and hereditary renal adysplasia. Z. Kinderheilk. 115: 111-129, 1973. [PubMed: 4744207] [Full Text: https://doi.org/10.1007/BF00440537]
Cain, D. R., Griggs, D., Lackey, D. A., Kagan, B. M. Familial renal agenesis and total dysplasia. Am. J. Dis. Child. 128: 377-380, 1974. [PubMed: 4413435] [Full Text: https://doi.org/10.1001/archpedi.1974.02110280107016]
Carter, C. O., Evans, K., Pescia, G. A family study of renal agenesis. J. Med. Genet. 16: 176-188, 1979. [PubMed: 469895] [Full Text: https://doi.org/10.1136/jmg.16.3.176]
Davidson, W. M., Ross, G. I. M. Bilateral absence of the kidneys and related congenital anomalies. J. Path. Bact. 68: 459-471, 1954. [PubMed: 14354552] [Full Text: https://doi.org/10.1002/path.1700680220]
Hack, M., Jaffe, J., Blankstein, J., Goodman, R. M., Brish, M. Familial aggregation in bilateral renal agenesis. Clin. Genet. 5: 173-177, 1974. [PubMed: 4829427] [Full Text: https://doi.org/10.1111/j.1399-0004.1974.tb01679.x]
Humbert, C., Silbermann, F., Morar, B., Parisot, M., Zarhrate, M., Masson, C., Tores, F., Blanchet, P., Perez, M.-J., Petrov, Y., Khau Van Kien, P., Roume, J., and 9 others. Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans. Am. J. Hum. Genet. 94: 288-294, 2014. Note: Erratum: Am. J. Hum. Genet. 94: 799 only, 2014. [PubMed: 24439109] [Full Text: https://doi.org/10.1016/j.ajhg.2013.12.017]
Joss, S., Howatson, A., Trainer, A., Whiteford, M., FitzPatrick, D. R. De novo translocation (1;2)(q32;p25) associated with bilateral renal dysplasia. (Letter) Clin. Genet. 63: 239-240, 2003. [PubMed: 12694239] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00037.x]
Kohn, G., Borns, P. The association of bilateral renal aplasia in the same family. J. Pediat. 83: 95-97, 1973. [PubMed: 4797640] [Full Text: https://doi.org/10.1016/s0022-3476(73)80324-5]
Madisson, H. Ueber das Fehlen beider Nieren (Aplasia renum bilateralis). Centrabl. Path. Anat. 60: 1-8, 1934.
Monn, E., Nordshus, T. Hereditary renal adysplasia. Acta Paediat. Scand. 73: 278-280, 1984. [PubMed: 6741530] [Full Text: https://doi.org/10.1111/j.1651-2227.1984.tb09946.x]
Morse, R. P., Rawnsley, E., Crowe, H. C., Marin-Padilla, M., Graham, J. M., Jr. Bilateral renal agenesis in three consecutive siblings. Prenatal Diag. 7: 573-579, 1987. [PubMed: 3317388] [Full Text: https://doi.org/10.1002/pd.1970070808]
Muller, U., Wang, D., Denda, S., Meneses, J. J., Pedersen, R. A., Reichardt, L. F. Integrin alpha-8/beta-1 is critically important for epithelial-mesenchymal interactions during kidney morphogenesis. Cell 88: 603-613, 1997. [PubMed: 9054500] [Full Text: https://doi.org/10.1016/s0092-8674(00)81903-0]
Potter, E. L. Facial characteristics of infants with bilateral renal agenesis. Am. J. Obstet. Gynec. 51: 885-888, 1946. [PubMed: 20984673] [Full Text: https://doi.org/10.1016/s0002-9378(16)39968-9]
Rizza, J. M., Downing, S. E. Bilateral renal agenesis in two female siblings. Am. J. Dis. Child. 121: 60-63, 1971. [PubMed: 5539818] [Full Text: https://doi.org/10.1001/archpedi.1971.02100120096015]
Roodhooft, A. M., Birnholz, J. C., Holmes, L. B. Familial nature of congenital absence and severe dysgenesis of both kidneys. New Eng. J. Med. 310: 1341-1345, 1984. [PubMed: 6717505] [Full Text: https://doi.org/10.1056/NEJM198405243102101]
Sanna-Cherchi, S., Kiryluk, K., Burgess, K. E., Bodria, M., Sampson, M. G., Hadley, D., Nees, S. N., Verbitsky, M., Perry, B. J., Sterken, R., Lozanovski, V. J., Materna-Kiryluk, A., and 44 others. Copy-number disorders are a common cause of congenital kidney malformations. Am. J. Hum. Genet. 91: 987-997, 2012. [PubMed: 23159250] [Full Text: https://doi.org/10.1016/j.ajhg.2012.10.007]
Schinzel, A., Homberger, C., Sigrist, T. Bilateral renal agenesis in male sibs born to consanguineous parents. J. Med. Genet. 15: 314-316, 1978. [PubMed: 712765] [Full Text: https://doi.org/10.1136/jmg.15.4.314]
Schmidt, E. C. H., Hartley, A. A., Bower, R. Renal aplasia in sisters. AMA Arch. Path. 54: 403-406, 1952. [PubMed: 12984947]
Schmidt, W., Schroeder, T. M., Buchinger, G., Kubli, F. Genetics, pathoanatomy and prenatal diagnosis of Potter I syndrome and other urogenital tract diseases. Clin. Genet. 22: 105-127, 1982. [PubMed: 7151297] [Full Text: https://doi.org/10.1111/j.1399-0004.1982.tb01422.x]
Scott, R. J., Goodburn, S. F. Potter's syndrome in the second trimester: prenatal screening and pathological findings in 60 cases of oligohydramnios sequence. Prenatal Diag. 15: 519-525, 1995. [PubMed: 7544896] [Full Text: https://doi.org/10.1002/pd.1970150604]
Selig, A. M., Benacerraf, B., Greene, M. F., Garber, M.-F., Genest, D. R. Renal dysplasia, megalocystis, and sirenomelia in four siblings. Teratology 47: 65-71, 1993. [PubMed: 8475459] [Full Text: https://doi.org/10.1002/tera.1420470111]
Wiedemann, H.-R. Edith Potter (1901-1993). Europ. J. Pediat. 153: 471, 1994.
Wilson, R. D., Baird, P. A. Renal agenesis in British Columbia. Am. J. Med. Genet. 21: 153-165, 1985. [PubMed: 4003440] [Full Text: https://doi.org/10.1002/ajmg.1320210123]
Winter, J. S. D., Kohn, G., Mellman, W. J., Wagner, S. A familial syndrome of renal, genital, and middle ear anomalies. J. Pediat. 72: 88-93, 1968. [PubMed: 5634940] [Full Text: https://doi.org/10.1016/s0022-3476(68)80404-4]
Yates, J. R. W., Mortimer, G., Connor, J. M., Duke, J. E. Concordant monozygotic twins with bilateral renal agenesis. J. Med. Genet. 21: 66-67, 1984. [PubMed: 6694189] [Full Text: https://doi.org/10.1136/jmg.21.1.66]
Zonana, J., Rimoin, D. L., Hollister, D. W. Renal agenesis--a genetic disorder? (Abstract) Pediat. Res. 10: 420, 1976.