Urofacial Syndrome 1

A number sign (#) is used with this entry because urofacial syndrome-1 (UFS1) is caused by homozygous or compound heterozygous mutation in the HPSE2 gene (613469) on chromosome 10q24.

Description

The urofacial syndrome (UFS) is a rare autosomal recessive disease characterized by a severe and early-onset form of dysfunctional urinary voiding. Affected individuals usually present prenatally or in early childhood with grossly distorted renal tracts, comprising dysmorphic bladders and dilatation of the ureter and renal pelvis. They are at high risk of vesicoureteral reflux (VUR), with ascending bacterial infection leading to kidney damage, hypertension, and renal failure. One-third of UFS children also experience constipation or fecal soiling, suggesting that the pathophysiology of the syndrome encompasses a broader functional impairment of elimination. In addition, affected individuals have a characteristic facial grimace when trying to smile (summary by Daly et al., 2010).

Genetic Heterogeneity of Urofacial Syndrome

Urofacial syndrome-2 (UFS2; 615112) is caused by mutation in the LRIG2 gene (608869) on chromosome 1p13.

Clinical Features

In 3 unrelated families Elejalde (1979) observed 7 children with hydronephrosis, hydroureter and a peculiar facial expression, mainly when smiling or crying. Urethral valves, as well as urethral obstruction, were demonstrated in some. All 3 males had cryptorchidism. One instance of first-cousin parents suggested autosomal recessive inheritance. However, Elejalde (1979) favored autosomal dominant inheritance because the paternal grandfather in that instance was said to have had the same facies and 2 grandsons by another son had the full syndrome and because the proportion of affected sibs was 7 of 13 (closer to 50% than 25%). The last is not a compelling argument. Elejalde (1979) called the disorder the Ochoa syndrome and thanked Dr. Bernardo Ochoa for referring the patients for study. Ochoa and Gorlin (1987) stated that between 1965 and 1986 they saw 36 children with enuresis and urinary tract infection in association with 'inversion' of facial expression when laughing. Mild neuropathic bladder was demonstrated in all cases, with severe urinary tract damage in most. About two-thirds of the patients had moderate to severe constipation. The occurrence of the disorder in multiple sibs with normal parents and increased consanguinity, as well as an equal distribution according to sex, support autosomal recessive inheritance.

Teebi et al. (1989) described a case in a Arab child with consanguineous parents. The patient had early urologic evaluation because he showed the characteristic 'inverted' facial expression, i.e., when smiling or laughing, he appeared to be crying. Investigations at age 6 showed minor changes, indicating the probable importance of detecting the abnormality through the facial expression at an early age.

Garcia-Minaur et al. (2001) described a Spanish boy and 2 Irish sisters with urofacial syndrome. The 12-year-old boy, who was born of consanguineous parents, presented at 3 years of age with a urinary tract infection, and ultrasonography revealed an enlarged left kidney with ureteral, pelvic, and calyceal dilation; voiding cystourethrography showed a trabeculated bladder with narrowing of the urethra and 'massive' left vesicoureteral reflux. Sphincter electromyography at 9 years of age showed severe lack of coordination between detrusor muscle contraction and urethral sphincter relaxation, with significant residual urine after voiding. Other features included a slow growth rate, with height and weight in the 3rd centile, a tendency to constipation, and electrocardiographic changes suggestive of Wolff-Parkinson-White syndrome (see 194200). He did not have cryptorchidism. His father was reported to have multiple urinary tract infections but urologic investigations were normal and he did not show the characteristic grimace. In the Irish family, 1 sister was the offspring of a twin pregnancy; her twin brother died in the neonatal period of unclear causes. She had constipation and several urinary tract infections in the first years of life, and evaluation at 3 years of age showed unusual facial grimacing and a grossly trabeculated bladder on cystoscopy. Intravenous pyelography (IVP) showed gross dilation of the left collecting system and a nonfunctioning left kidney, with some evidence of right hydronephrosis and hydroureter. She underwent multiple urologic surgeries, and at the time of the report had a reduced glomerular filtration rate (GFR; 40 ml/min) and was maintained on self-catheterization and prophylactic antibiotics. She had normal external ocular movements but bilateral weakness in the distribution of the seventh cranial nerve. Her asymptomatic sister, who had been noted to have similar facial movements, was diagnosed at age 25 years: she had had several urinary tract infections which responded to antibiotic treatment, urea and creatinine serum levels were normal, and IVP showed some clubbing of the upper pole of the right kidney. Cranial nerve examination was normal.

Derbent et al. (2009) studied a 16-year-old Turkish girl, born of first-cousin parents, with recurrent urinary tract infections and persistent enuresis in childhood who at 10 years of age was found to have moderate bilateral hydronephrosis and a trabeculated bladder with urinary retention, and underwent surgery for vesicoureteral reflux. Upon evaluation at 16 years of age, the patient showed the characteristic 'inverted' facial expression of UFS upon attempting to smile, and ultrasonography revealed bilateral hydroureteronephrosis with postvoiding dilation of the renal pelvises and bladder. Her glomerular filtration rate was within normal limits, as were routine biochemistry results, including urea and creatinine levels. Examination and electromyography of facial nerves were normal. Derbent et al. (2009) stated that this was the first UFS case reported from Turkey.

Aydogdu et al. (2010) described 10 Turkish patients from 4 families and 1 sporadic patient with UFS. In 1 family, 2 male cousins were affected, 1 of whom displayed only the characteristic facial grimace when attempting to smile, but had no symptoms of elimination dysfunction and showed normal findings on ultrasound, dimarcaptosuccinic acid (DMSA) scan, uroflowmetry, and videourodynamics. In another family in which 2 male cousins were affected, 1 of them had no facial abnormalities but a history of febrile urinary tract infections since birth with severe incontinence, a low-capacity bladder, and bilateral grade 3 reflux.

Daly et al. (2010) reported 3 British Pakistani sibs with urofacial syndrome, born of unaffected first-cousin parents. The proband presented at 2 years of age in acute renal failure with urinary sepsis and was found to have a hypercontractile bladder, bilateral vesicoureteral reflux, and hydronephrotic scarred kidneys; he underwent a surgical ileal loop urinary diversion procedure. At 11 years of age, he had a low-normal glomerular filtration rate with mild proteinuria, and required treatment for hypertension. At age 6, his sister was found to have dysfunctional voiding with a hypocontractile bladder and VUR; she did not have surgery and her kidney function remained normal. A younger brother presented with renal pelvis dilation on antenatal ultrasound, and postnatally was found to have a low-capacity trabeculated bladder with VUR; he underwent surgical urinary diversion, and at age 10 years he had a low-normal GFR and mild proteinuria but was normotensive. All 3 sibs had the characteristic UFS grimace upon smiling.

Mapping

To map the UFS gene, Wang et al. (1997) used a genome screen combining homozygosity mapping and DNA pooling strategies. They found that marker D10S677 was linked to and associated with UFS, as suggested by a significant excess of homozygosity in patients compared with that in unaffected relatives, as well as by the allele-frequency differences between patient pool and control pools. All 31 patients were found to be homozygous for 2 closely linked markers, D10S1726 and D10S198, located approximately 5 cM telomeric to D10S677, whereas only 12% of the unaffected relatives were homozygous for both markers. Several patients were heterozygous at 2 markers immediately flanking D10S1726/D10S198, 1 on the centromeric side and 1 on the telomeric side. These recombinational events placed the UFS gene within a 1-cM interval on 10q23-q24. Wang et al. (1999) narrowed the UFS critical region to an interval between markers D10S198 and D10S2494. This region was entirely covered by one YAC clone of approximately 1,410 kb. The gene for glutamate oxaloacetate transaminase (GOT1; 138180) was also located within this YAC clone, but was excluded as a candidate for the UFS gene by mutation analysis.

Wang et al. (2003) constructed a genomic sequence map covering the entire UFS critical region and narrowed the disease interval to a 220-kb region that harbors the ACDP1 gene (CNNM1; 607802) in addition to part of the GOT1 gene, which had already been excluded as a candidate for UFS. Extensive search for mutations in the coding region, the 5-prime and 3-prime untranslated regions, the promoter region, and the exon/intron junctions failed to identify a pathogenic mutation in the CNNM1 gene in UFS patients.

Chauve et al. (2000) described an affected French family, the first reported European cases of UFS. They compared haplotype analyses in this family with those previously described in Colombian families (Wang et al., 1997) and American families of Irish descent (Wang et al., 1999). The results were compatible with the same localization of the critical region and favored the hypothesis of genetic homogeneity. Wang et al. (2003) also showed that the same gene on 10q was responsible for all UFS patients from multiple ethnic groups.

To redefine the disease interval for urofacial syndrome, Pang et al. (2010) performed haplotype analysis in 7 UFS families with recombination events on both ends of the previously defined disease interval, and delineated an expanded disease region between markers D10S1433 and D10S603, containing 17 genes and 2 unnamed transcripts.

Daly et al. (2010) performed homozygosity mapping in a consanguineous British Pakistani family with UFS and identified a 16.65-Mb homozygous region flanked by rs17346680 and rs10786808 that encompassed the critical interval previously identified by Wang et al. (2003) on chromosome 10q23-q24.

Molecular Genetics

In a patient from a Colombian family with urofacial syndrome mapping to chromosome 10q24, Pang et al. (2010) analyzed multiple candidate genes and identified homozygosity for a nonsense mutation in HPSE2 (613469.0001). Analysis of 5 more Colombian UFS families revealed homozygosity for the same mutation in all patients. Screening of the HPSE2 gene in 2 UFS families from the United States revealed homozygosity for a 2-bp deletion in affected individuals (613469.0002), and in a French UFS family, 2 affected brothers were found to be compound heterozygous for the same 2-bp deletion and another 2-bp deletion (613469.0003).

In a consanguineous British Pakistani family with UFS mapping to 10q23-q24, Daly et al. (2010) performed copy number analysis and identified homozygosity for an approximately 11.25-kb intragenic deletion encompassing exons 8 and 9 of the HPSE2 gene that segregated with disease (613469.0004). PCR analysis and DNA sequencing across the breakpoints defined a complex rearrangement involving a 10.81-kb deletion and a 23-bp insertion at the breakpoints. Mutation screening of HPSE2 led to the identification of homozygous mutations in 5 unrelated UFS families from Spain, Ireland, and Turkey, previously reported by Garcia-Minaur et al. (2001), Derbent et al. (2009), and Aydogdu et al. (2010) (613469.0002; 613469.0005-613469.0008). Daly et al. (2010) noted that they did not find HPSE2 mutations in 2 previously published cases (Aydogdu et al., 2010) or in 6 other UFS families, 3 of which were consanguineous families that showed heterozygosity for polymorphic variants at the HPSE2 locus, suggesting the likelihood of genetic heterogeneity in UFS.