Clinical characteristics.

Urofacial syndrome (UFS; also known as Ochoa syndrome) is characterized by prenatal or childhood onset of urinary bladder voiding dysfunction, abnormal facial movement with expression (resulting from abnormal co-contraction of the corners of the mouth and eyes), and often bowel dysfunction (constipation and/or encopresis). Bladder voiding dysfunction can present before birth as megacystis. In infancy and later childhood, UFS can present with a poor urinary stream and dribbling incontinence; incomplete bladder emptying can lead to urinary infection with progressive kidney failure. Investigations after birth can show abnormal bladder contractility and vesicoureteral reflux of urine into the ureter and renal pelvis. Nocturnal lagophthalmos (incomplete closing of the eyes during sleep) has also been documented.

Diagnosis/testing.

The clinical diagnosis of UFS can be established in an individual with urinary tract dysfunction and characteristic facial movement with expression, or the molecular diagnosis can be established in an individual with characteristic features and biallelic pathogenic variants in either HPSE2 or LRIG2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Rapid and complete antibiotic therapy for acute urinary tract infections. Anticholinergic and alpha-1 adrenergic blocking medications can respectively lower raised pressure within the bladder and enhance voiding of urine. Drug treatment can be complemented by intermittent catheterization per urethra or through vesicostomy. Management of kidney disease per nephrology; management of severe kidney failure may warrant long-term dialysis and kidney transplantation. Lubricant eye drops during the day and eye ointment at night under the care of an ophthalmologist for nocturnal lagophthalmos; standard management for constipation and encopresis.

Surveillance: Ultrasonography to monitor for evidence of urinary tract dysfunction including incomplete bladder emptying and hydroureteronephrosis. Kidney excretory function should be monitored, initially by measuring plasma creatinine at intervals determined by urinary tract features at presentation and their subsequent progression. Ophthalmology examinations to assess for corneal involvement; assessment for bowel dysfunction annually or at each visit.

Agents/circumstances to avoid: Nephrotoxic substances.

Evaluation of relatives at risk: At-risk sibs: it is appropriate to examine sibs of an affected individual as soon as possible after birth to determine if facial and/or urinary tract manifestations of UFS are present to allow prompt evaluation of the urinary tract and renal function and initiation of necessary treatment. At-risk fetus: although no guidelines for prenatal management of UFS exist, it seems appropriate to perform ultrasound examination of pregnancies at risk (in the second and third trimesters) to determine if urinary tract involvement of UFS is present, as this may influence the timing and/or location of delivery (e.g., in a tertiary medical center that could manage renal/urinary complications immediately after birth).

Genetic counseling.

UFS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a UFS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the UFS-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

UFS should be suspected in individuals with the following clinical findings and family history.

Classic clinical findings

• Urinary bladder dysfunction (also termed non-neurogenic neurogenic voiding dysfunction, occult or subclinical neuropathic bladder) with detrusor overactivity and detrusor sphincter dyssynergia [Feldman & Bauer 2006]. Affected individuals are at risk for urinary incontinence, urosepsis, and progressive kidney failure [Ochoa 2004, Aydogdu et al 2010, Stuart et al 2013]. Urinary tract features have been present in nearly all reported individuals [Aydogdu et al 2010, Stuart et al 2013, Stuart et al 2015, Beaman et al 2022, Grenier et al 2023].
  Characteristic urinary tract abnormalities:
  • Prenatal ultrasonography in the second or third trimester can show an enlarged bladder (megacystis) and dilated upper urinary tracts (hydronephrosis).
  • Postnatal imaging by ultrasonography and micturating cystourethrography typically shows muscular thickening and trabeculation of the urinary bladder, but appearances may also be normal [Ochoa 1992, Ochoa 2004, Derbent et al 2009, Aydogdu et al 2010].
  • Hydroureteronephrosis associated with vesicoureteral reflux is common in UFS [Ochoa 1992, Ochoa 2004].
  • Micturating cystourethrography and direct visualization by cystoscopy reveals a patent urethra, critically distinguishing UFS from conditions such as posterior urethral valves, which are characterized by an anatomic obstruction within the lumen of the urethra [Ochoa 2004].
  Urodynamics is generally only available in specialist pediatric urology centers. If performed, typical findings are abnormally high hydrostatic pressure within the bladder that persists during cycles of incomplete voiding. This is associated with failure of the outflow tract to fully dilate during voiding, the so-called dyssynergic voiding [Ochoa 2004].
• A characteristic abnormality of facial movement with expression, resulting from abnormal co-contraction of the corners of the mouth and eyes, which is most obvious during smiling or laughing (see Figure 1) and often described as a "grimace" [Ochoa 2004, Aydogdu et al 2010, Ganesan & Thomas 2011]. Typical facial expressions have been present in nearly all affected individuals.

Figure 1.

A video of a young man with urofacial syndrome demonstrating his facial appearance on smiling Reproduced from Beaman et al [2022]

Other clinical findings

• Bowel dysfunction, including constipation (66%) and encopresis (33%) of affected individuals [Ochoa 2004]
• Nocturnal lagophthalmos (incomplete closing of the eyelids during sleep)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The clinical diagnosis of UFS can be established in a proband with urinary bladder dysfunction and characteristic abnormality of facial movement with expression described in Suggestive Findings, or the molecular diagnosis can be established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in either HPSE2 or LRIG2 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of biallelic HPSE2 or LRIG2 variants of uncertain significance (or of one known HPSE2 or LRIG2 pathogenic variant and one HPSE2 or LRIG2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (serial single gene testing, concurrent gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Urofacial syndrome (UFS) is characterized by urinary bladder voiding dysfunction, abnormal facial expression, and often bowel dysfunction. Significant inter- and intrafamilial phenotypic variability has been observed. To date, more than 150 individuals with UFS have been identified/reported. The following description of the phenotypic features associated with this condition is based on these reports.

Urinary tract dysfunction is the main reason for presenting to medical attention and the main cause of associated morbidity and mortality. Urinary tract dysfunction has been present in all but two of more than 150 clinically defined individuals [Aydogdu et al 2010, Stuart et al 2013, Stuart et al 2015]. Antenatal ultrasound examination (if performed) is frequently described as abnormal and is associated with megacystis, hydroureteronephrosis, and renal pelvis dilatation [Skálová et al 2006, Bacchetta & Cochat 2010, Daly et al 2010, Stuart et al 2013]. In one large series, hydroureteronephrosis was found in 29/50 (58%) affected individuals. Vesicoureteral reflux occurred in 32/50 (64%); reflux was bilateral in 18 (36%) [Ochoa 1992, Ochoa 2004].

The typical complications of urinary tract dysfunction include recurrent urinary sepsis and failure to achieve urinary continence [Ochoa 1992, Ochoa 2004]. More severe complications of urinary tract dysfunction, including urinary bladder rupture and sepsis, have been reported in some infants [Ochoa 1992, Skálová et al 2006].

Kidney disease. The associated renal parenchymal damage with early impairment of kidney function and progression to severe kidney failure causes substantial morbidity and mortality [Ochoa 2004, Skálová et al 2006, Sutay et al 2010, Mahmood et al 2012]. The proportion of individuals who develop this is unknown but likely to be significant in the context of severe and recurrent urosepsis, especially if not promptly and completely treated with antibiotics [Ochoa & Gorlin 1987, Ochoa 1992, Ochoa 2004, Aydogdu et al 2010].

Abnormal facial expression. The most prominent facial feature, abnormal co-contraction of the corners of the mouth and eyes, is most obvious during smiling or laughing [Ochoa 2004, Aydogdu et al 2010, Ganesan & Thomas 2011] and can be socially debilitating. Abnormal facial movement with crying has been observed as early as the neonatal period [Ochoa 1992, Skálová et al 2006]. Rarely, affected individuals may have the typical facial phenotype with no urinary bladder dysfunction or symptoms [Stuart et al 2013; Authors, personal communication].

Symmetric partial facial paresis in the distribution of the facial nerve has been noted; however, the proportion of individuals in whom weakness is a significant feature is unknown [Garcia-Minaur et al 2001; Authors, personal observation].

Nocturnal lagophthalmos (incomplete closing of the eyes during sleep) appears to be a common and significant finding that may lead to keratitis, corneal abrasion, infection, vascularization, and, in extreme cases, ocular perforation, endophthalmitis, and loss of the eye [Mermerkaya et al 2014].

Gastrointestinal tract dysfunction. Constipation is reported in about 66% of affected individuals; encopresis is present in 33% [Ochoa 2004]. Fecal retention in the neonatal period has been noted once [Nicanor et al 2005]. Rectal prolapse has also been reported once in association with severe constipation [Al Badr et al 2011].

Central nervous system function is normal. Affected individuals do not typically show any other features of neurologic dysfunction besides nocturnal lagophthalmos. Development and intellect are normal. Brain MRI and imaging of the truncal spinal cord are typically normal [Nicanor et al 2005, Derbent et al 2009, Aydogdu et al 2010, Al Badr et al 2011, Akl & Al Momany 2012].

Genotype-Phenotype Correlations

There is evidence that individuals with biallelic missense variants in LRIG2 have urinary tract-limited disease (i.e., lacking the characteristic facial expression) [Stuart et al 2013, Roberts et al 2019, Grenier et al 2023].

Prevalence

UFS is rare. Its prevalence is currently unknown but is likely to be higher in certain regions with known founder variants (e.g., Colombia) [Ochoa 2004, Pang et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with UFS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Nephrotoxic substances contraindicated in individuals with renal impairment should be avoided if possible.

Evaluation of Relatives at Risk

At-risk sibs of a proband. It is appropriate to clarify the genetic/clinical status of sibs of an affected individual as soon as possible after birth in order to identify those who would benefit from prompt evaluation of the urinary tract and renal function and early initiation of necessary treatment. Evaluations can include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Physical examination and urinary tract ultrasound examination to determine whether facial and/or urinary tract manifestations of UFS are present if the pathogenic variants in the family are not known.

At-risk fetus. Although no guidelines for prenatal management of UFS exist, it seems appropriate to perform ultrasound examination of pregnancies at risk (in the second and third trimesters) to determine if urinary tract involvement of UFS is present in the fetus, as it may influence the timing and/or location of delivery (e.g., in a tertiary medical center that could manage renal/urinary complications immediately after birth).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Studies of gene therapy to correct the urinary tract manifestations in mice with mutated HPSE2 have been published and indicate that this may be a future therapeutic option (see bioRxiv).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Urofacial syndrome (UFS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a UFS-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a UFS-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a UFS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Significant intrafamilial phenotypic variability has been observed [Ochoa 1992, Aydogdu et al 2010, Stuart et al 2013, Stuart et al 2015].
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless the proband's reproductive partner also has UFS or is a carrier of UFS, offspring of a proband with HPSE2-related or LRIG2-related UFS will be obligate heterozygotes for an HPSE2 or LRIG2 pathogenic variant, respectively (i.e., all offspring are carriers of a pathogenic variant inherited from their parent).

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a UFS-related pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the UFS-related pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals affected with UFS and the reproductive partners of individuals known to be carriers of UFS, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. An HPSE2 founder variant has been identified in individuals of Colombian ancestry (see Table 7).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the UFS-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Fetal ultrasonography. In families at risk of having an affected child, prenatal ultrasound of the urinary tract may show megacystis, hydroureteronephrosis, or renal pelvis dilatation in an affected pregnancy. These features are not specific for UFS.

Note: Ultrasound examination of a fetus at risk (in the second and third trimesters) to determine if UFS-related urinary tract involvement is present should be considered, as it may influence the timing and/or location of delivery (see Evaluations of Relatives at Risk).

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The molecular pathogenesis of urofacial syndrome (UFS) is not fully understood. However, there is increasing evidence that UFS represents an abnormality of peripheral neurodevelopment or function [Ganesan & Thomas 2011, Stuart et al 2013, Roberts et al 2014, Woolf et al 2014b, Stuart et al 2015, Roberts et al 2019].

Both HPSE2 and its encoded protein (inactive heparanase-2) and LRIG2 and its encoded protein (leucine-rich repeats and immunoglobulin-like domains protein 2, or LRIG2) are expressed and localize to the peripheral nervous system, including the developing nerves of the fetal bladder [McKenzie et al 2000, Guo et al 2004, Homma et al 2009, Daly et al 2010, Stuart et al 2013, Stuart et al 2015, Beaman et al 2022, Grenier et al 2023].

While the functions of heparanase-2 and LRIG2 are not fully understood, current knowledge suggests that they have a role in regulating growth factor signaling [Hedman & Henriksson 2007; Fux et al 2009; Levy-Adam et al 2010; Pang et al 2010; Cui et al 2011; Authors, personal communication].

Mechanism of disease causation. Unknown; predicted to be due to loss of function

Author Notes

William G Newman is a clinical geneticist with a research program that includes the identification of the causes of rare inherited disorders. He leads a national UK network on research for lower urinary tract disorders.

Adrian S Woolf is a clinician scientist and has run a kidney and lower urinary tract genetic clinic. His research interest is to find out why some children are born with abnormal urinary tracts.

Glenda M Beaman is a postdoctoral fellow researching the causes of lower urinary tract disorders.

Neil A Roberts is a scientist developing advanced therapies for lower urinary tract disorders including urofacial syndrome.

William G Newman (ku.ca.retsehcnam@namwen.mailliw) is actively involved in clinical research regarding individuals with urofacial syndrome. He would be happy to communicate with persons who have any questions regarding diagnosis of urofacial syndrome or other considerations.

William G Newman (ku.ca.retsehcnam@namwen.mailliw) is also interested in hearing from clinicians treating families affected by urofacial syndrome in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this disorder.

Author History

Glenda M Beaman, PhD (2023-present)

William G Newman, MA, PhD (2013-present)

Neil A Roberts, PhD (2023-present)

Helen M Stuart, MD; University of Manchester (2013-2018)

Adrian S Woolf, MA, MD (2013-present)

Acknowledgments

The authors' work on UFS has been funded by Kidney Research UK (Paed_RP/002/20190925, Paed_RP/005/20190925), Newlife (15-15/03 and 15-16/06), National Institute for Health Research (NIHR203308), the Medical Research Council (MR/L002744/1, MR/T016809/1, MR/Y008340/1) and the Wellcome Trust. We have been supported by ERIC, a UK charity dedicated to improving children's bowel and bladder health. We dedicate this review to our colleague Dr Edward McKenzie, who first cloned HPSE2 and worked with us to understand the importance of this protein to health.

Revision History

• 28 September 2023 (sw) Comprehensive update posted live
• 7 June 2018 (bp) Comprehensive update posted live
• 22 August 2013 (me) Review posted live
• 17 May 2013 (wgn) Original submission

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