# 615721

RENAL HYPODYSPLASIA/APLASIA 2; RHDA2


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
8p22 ?Renal hypodysplasia/aplasia 2 615721 AR 3 FGF20 605558
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Face
- Potter facies
RESPIRATORY
Lung
- Pulmonary hypoplasia
GENITOURINARY
Kidneys
- Bilateral renal aplasia
Ureters
- Bilateral ureteral aplasia
SKELETAL
Feet
- Pes varus
SKIN, NAILS, & HAIR
Skin
- Redundant skin
PRENATAL MANIFESTATIONS
Amniotic Fluid
- Anhydramnios
MISCELLANEOUS
- One family has been reported (last curated March 2014)
- Death in utero
MOLECULAR BASIS
- Caused by mutation in the fibroblast growth factor 20 gene (FGF20, 605558.0002)

TEXT

A number sign (#) is used with this entry because of evidence that renal hypodysplasia/aplasia-2 (RHDA2) is caused by homozygous mutation in the FGF20 gene (605558) on chromosome 8p22. One such family has been reported.


Description

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).

For a discussion of genetic heterogeneity of renal hypodysplasia/aplasia, see RHDA1 (191830).


Clinical Features

Barak et al. (2012) reported a highly consanguineous Caucasian family in which 2 pairs of sib fetuses related as first cousins had bilateral renal agenesis associated with anhydramnios. All the pregnancies were terminated. Postmortem examination of 1 affected fetus showed the Potter sequence, with redundant skin, varus feet, and pulmonary hypoplasia. Internal examination showed bilateral renoureteral agenesis; other organs were normal. Neuropathologic examination showed no brain or eye abnormalities.


Inheritance

The transmission pattern of RHDA2 in the family reported by Barak et al. (2012) was consistent with autosomal recessive inheritance.


Molecular Genetics

In 3 affected fetuses from a consanguineous family with bilateral renal aplasia, Barak et al. (2012) identified a homozygous frameshift mutation in the FGF20 gene (605558.0002). The mutation, which was found using a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Loss of Fgf20 and Fgf9 (600921) in mice resulted in kidney agenesis, supporting the pathogenicity of the mutation in this family (see ANIMAL MODEL).


Animal Model

In the developing mouse kidney, Barak et al. (2012) demonstrated that Fgf9 and Fgf20 act as ligands for the niche signal required to maintain stem cells in the progenitor state. Studies of mutant mice with various combinations of loss of Fgf20 and Fgf9 showed that these 2 genes acted redundantly and were essential for kidney development. Reduction of Fgf20 and Fgf9 levels resulted in a reduction in kidney size and fewer glomeruli resulting from a smaller progenitor pool that differentiated normally. One wildtype Fgf20 allele in Fgf9-null embryos was enough to support normal kidney development, but Fgf20-null embryos with 1 wildtype Fgf9 allele had a more severe phenotype, suggesting that Fgf20 has a more dominant role than Fgf9 in the kidney. Fgf20-null kidneys with 1 wildtype Fgf9 allele were characterized by a loss of progenitor cells and the presence of premature differentiation of functional nephrons. Fgf20 was expressed exclusively within nephron progenitors, whereas Fgf9 was expressed mostly in the ureteric bud with signaling to the metanephric mesenchyme. In vitro studies indicated that Fgf20 or Fgf9, alone or together with Bmp7 (112267), maintained isolated metanephric mesenchyme and nephron progenitors that remained competent to differentiate.


REFERENCES

  1. Barak, H., Huh, S.-H., Chen, S., Jeanpierre, C., Martinovic, J., Parisot, M., Bole-Feysot, C., Nitschke, P., Salomon, R., Antignac, C., Ornitz, D. M., Kopan, R. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell 22: 1191-1207, 2012. [PubMed: 22698282, images, related citations] [Full Text]

  2. 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, images, related citations] [Full Text]

  3. 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, related citations] [Full Text]


Creation Date:
Cassandra L. Kniffin : 3/31/2014
carol : 01/08/2019
carol : 06/27/2017
carol : 05/07/2014
carol : 4/8/2014
mcolton : 4/4/2014
mcolton : 4/4/2014
ckniffin : 4/3/2014

# 615721

RENAL HYPODYSPLASIA/APLASIA 2; RHDA2


ORPHA: 1848, 411709;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
8p22 ?Renal hypodysplasia/aplasia 2 615721 Autosomal recessive 3 FGF20 605558

TEXT

A number sign (#) is used with this entry because of evidence that renal hypodysplasia/aplasia-2 (RHDA2) is caused by homozygous mutation in the FGF20 gene (605558) on chromosome 8p22. One such family has been reported.


Description

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).

For a discussion of genetic heterogeneity of renal hypodysplasia/aplasia, see RHDA1 (191830).


Clinical Features

Barak et al. (2012) reported a highly consanguineous Caucasian family in which 2 pairs of sib fetuses related as first cousins had bilateral renal agenesis associated with anhydramnios. All the pregnancies were terminated. Postmortem examination of 1 affected fetus showed the Potter sequence, with redundant skin, varus feet, and pulmonary hypoplasia. Internal examination showed bilateral renoureteral agenesis; other organs were normal. Neuropathologic examination showed no brain or eye abnormalities.


Inheritance

The transmission pattern of RHDA2 in the family reported by Barak et al. (2012) was consistent with autosomal recessive inheritance.


Molecular Genetics

In 3 affected fetuses from a consanguineous family with bilateral renal aplasia, Barak et al. (2012) identified a homozygous frameshift mutation in the FGF20 gene (605558.0002). The mutation, which was found using a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Loss of Fgf20 and Fgf9 (600921) in mice resulted in kidney agenesis, supporting the pathogenicity of the mutation in this family (see ANIMAL MODEL).


Animal Model

In the developing mouse kidney, Barak et al. (2012) demonstrated that Fgf9 and Fgf20 act as ligands for the niche signal required to maintain stem cells in the progenitor state. Studies of mutant mice with various combinations of loss of Fgf20 and Fgf9 showed that these 2 genes acted redundantly and were essential for kidney development. Reduction of Fgf20 and Fgf9 levels resulted in a reduction in kidney size and fewer glomeruli resulting from a smaller progenitor pool that differentiated normally. One wildtype Fgf20 allele in Fgf9-null embryos was enough to support normal kidney development, but Fgf20-null embryos with 1 wildtype Fgf9 allele had a more severe phenotype, suggesting that Fgf20 has a more dominant role than Fgf9 in the kidney. Fgf20-null kidneys with 1 wildtype Fgf9 allele were characterized by a loss of progenitor cells and the presence of premature differentiation of functional nephrons. Fgf20 was expressed exclusively within nephron progenitors, whereas Fgf9 was expressed mostly in the ureteric bud with signaling to the metanephric mesenchyme. In vitro studies indicated that Fgf20 or Fgf9, alone or together with Bmp7 (112267), maintained isolated metanephric mesenchyme and nephron progenitors that remained competent to differentiate.


REFERENCES

  1. Barak, H., Huh, S.-H., Chen, S., Jeanpierre, C., Martinovic, J., Parisot, M., Bole-Feysot, C., Nitschke, P., Salomon, R., Antignac, C., Ornitz, D. M., Kopan, R. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Dev. Cell 22: 1191-1207, 2012. [PubMed: 22698282] [Full Text: https://doi.org/10.1016/j.devcel.2012.04.018]

  2. 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]

  3. 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]


Creation Date:
Cassandra L. Kniffin : 3/31/2014

Edit History:
carol : 01/08/2019
carol : 06/27/2017
carol : 05/07/2014
carol : 4/8/2014
mcolton : 4/4/2014
mcolton : 4/4/2014
ckniffin : 4/3/2014