A number sign (#) is used with this entry because of evidence that congenital anomalies of the kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay (CAKUTHED) is caused by heterozygous mutation in or deletion of the PBX1 gene (176310) on chromosome 1q23.

Some individuals with the CAKUTHED phenotype have deletion of several genes in this region, consistent with a contiguous gene deletion syndrome.

CAKUTHED is an autosomal dominant highly pleiotropic developmental disorder characterized mainly by variable congenital anomalies of the kidney and urinary tract, sometimes resulting in renal dysfunction or failure, dysmorphic facial features, and abnormalities of the outer ear, often with hearing loss. Most patients have global developmental delay (summary by Heidet et al., 2017 and Slavotinek et al., 2017).

Le Tanno et al. (2017) reported 8 unrelated patients with a syndromic form of CAKUT associated with variable deletions of chromosome 1q23.3-q24.1; the patients were collected through several microarray databases with a focus on CAKUT. One of the patients (PT3) had previously been reported by Mackenroth et al. (2016). Seven of the patients described by Le Tanno et al. (2017) presented either at birth or in infancy with kidney defects, including renal hypoplasia (6), renal dysplasia (3), renal ectopia (2), and/or horseshoe kidney (1); the eighth patient presented at 18 months with normal kidney morphology, but other urinary tract abnormalities, including bifid ureter, small urethral valve, renal pelvis dilatation, and vesicoureteral reflux. Three patients had chronic kidney disease during childhood. One 42-year-old patient (PT6) with the longest follow-up had end-stage renal disease requiring dialysis at age 16 and subsequently had 2 kidney transplants. Three of 4 males had cryptorchidism. Although the patients were ascertained for their renal phenotype, all had significant additional abnormal features. Seven had global developmental delay, often with speech delay; 1 (PT4) had only motor delay with normal speech. Five had hearing impairment, 3 had hypotonia, and 2 had autism spectrum disorder. Seven patients had highly variable dysmorphic facial features, such as broad nasal bridge, anteverted nares, hypertelorism, strabismus, prominent philtrum, or thin upper lip. A common abnormality found in almost all patients was abnormal outer ears that were low-set, hypoplastic, abnormally hemmed, and anteverted or crumpled; the helices were thickened or hypoplastic. Other organ malformations were rarely reported: 4 patients had heart malformations, mainly septal defects; 4 had neurologic abnormalities, including sacral pit (3), spina bifida occulta (1), and corpus callosum hypoplasia (1); and 2 had anal malposition. Le Tanno et al. (2017) noted that 6 of the 8 patients had deletions of several contiguous genes, which may also have contributed to the extrarenal symptoms. However, the 2 patients with isolated deletion of PBX1 had similar extrarenal manifestations.

Heidet et al. (2017) reported 3 unrelated patients with truncating point mutations in the PBX1 gene. One patient (K175) was a 21-year-old woman with renal hypoplasia resulting in renal insufficiency, deafness, and scoliosis. The second patient (K179) was an 11-year-old girl presenting with small hyperechogenic kidneys with cystic dysplasia resulting in renal insufficiency; she also had developmental delay, growth retardation, and long and narrow face. The third patient (K186) was a fetus with renal hypoplasia, oligonephronia, and oligohydramnios. Three additional patients with larger deletions involving several genes were also reported. One of these patients (K181) was a 39-year-old woman with a small dysplastic horseshoe kidney and absence of corticomedullary differentiation resulting in renal failure, and profound deafness. The second was an infant (K136) with a single small hyperechogenic kidney, but normal renal function at age 18 months. This child also had developmental delay, microcephaly, and dysmorphic facial features, including long, narrow face and abnormal ear lobes. The third patient was a 10-year-old boy with small hyperechogenic kidneys, rapidly progressive renal failure, developmental delay, and dysmorphic facial features.

Slavotinek et al. (2017) reported 8 unrelated patients with a pleiotropic developmental disorder associated with de novo heterozygous point mutations in the PBX1 gene. Seven of the patients were under the age of 3 years, whereas the remaining patient was 27 years old. Some of the pregnancies were complicated by oligohydramnios or variable abnormal findings on ultrasound. Most of the patients had delayed development with delayed walking and poor speech. The 27-year-old patient had severe intellectual disability, behavioral abnormalities, and poor eye contact. Among the patients, features included poor growth, short stature, hypotonia, poor feeding necessitating tube placement, and respiratory insufficiency sometimes requiring ventilation. Each had variable abnormalities including craniofacial, ear, branchial arch, cardiac, pulmonary, diaphragmatic, renal, and/or genital systems. Craniofacial anomalies present in some patients did not delineate a recognizable phenotype. Renal anomalies comprised renal hypoplasia, pyelocaliectasis, dilated fetal ureters, and increased echogenicity, as well as recurrent urinary tract infections. Four males with karyotype 46,XY had cryptorchidism and 2 males had atypical sexual development: 1 with intraabdominal testes and retained Mullerian structures, and the other with micropenis and undervirilized male external genitalia, a vaginal introitus, and uterus didelphys.

The heterozygous mutations in the PBX1 gene that were identified in patients with CAKUTEHD by Heidet et al. (2017) occurred de novo.

In 8 unrelated patients with CAKUTHED, Le Tanno et al. (2017) identified 8 different heterozygous deletions of chromosome 1q23.3-q24.1. The deletions ranged from 276 kb to 9.21 Mb, and the minimum region of overlap included only the PBX1 gene. The deletions in 2 patients (PT4 and PT8) only affected the PBX1 gene. The deletions were confirmed to occur de novo in 6 patients; the inheritance status of the remaining 2 patients could not be determined.

In 2 of 204 unrelated patients with CAKUT who underwent next generation sequencing of candidate genes, Heidet et al. (2017) identified 2 patients with de novo heterozygous deletions of 1q23 including the entire PBX1 gene. The deletions were 2.46 Mb, including 7 additional genes, and 9.1 Mb, including 130 other genes. A third patient with a de novo 6.2-Mb deletion including PBX1 who had similar features was subsequently identified.

In 3 of 204 unrelated patients with CAKUT who underwent next generation sequencing of candidate genes, Heidet et al. (2017) identified 3 different de novo heterozygous point mutations in the PBX1 gene, all of which resulted in a truncated protein (176310.0001-176310.0003). The mutations were confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function and haploinsufficiency.

In 8 unrelated patients with CAKUTEHD, Slavotinek et al. (2017) identified 7 different de novo heterozygous mutations in the PBX1 gene (see, e.g., 176310.0004-176310.0007). There were 5 missense mutations, 1 frameshift mutation, and 1 nonsense mutation. In vitro functional expression studies of 5 of the mutations showed variable disturbances in protein function. In the presence of endogenous wildtype PBX1, all 5 mutant proteins exhibited a significant decrease in transactivation capability, despite different locations of the mutations within the protein domains. These results suggested that the mutant proteins might either be directly responsible for the decrease of transactivation activity observed or might affect the capability of the endogenous protein to transactivate target genes, resembling PBX1 haploinsufficiency. Similar studies of the mutant proteins in cells with marked reduction of wildtype PBX1 showed that only 2 of the variants exhibited significantly diminished transactivation activity, suggesting that these mutations directly affect the intrinsic capability of PBX1 to transactivate downstream transcriptional targets. In addition, 2 of the variants showed decreased nuclear localization. Overall, the findings indicated that disruption of PBX1 target genes can cause variable aberrations in normal embryonic development. Slavotinek et al. (2017) noted that the pleiotropic defects observed in patients reflect the broad expression of Pbx1 during murine embryogenesis and are consistent with the multiple organ systems affected in Pbx1-knockout mice.

Schnabel et al. (2003) found that Pbx1-null mouse embryos died at about E15.5. The kidneys were reduced in size and axially mispositioned, had fewer nephrons than controls, and sometimes showed unilateral agenesis. The mutant kidneys had expanded regions of mesenchymal condensates in the nephrogenic zone. Decreased branching and elongation of the ureter were also observed. These findings established a role for Pbx1 in mesenchymal-epithelial signaling, and indicated that Pbx1 is an essential regulator of mesenchymal function during renal morphogenesis.