Clinical characteristics.

Urofacial syndrome (UFS) is characterized by prenatal or infantile 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 increases the risk for urinary incontinence, megacystis, vesicoureteric reflux, hydroureteronephrosis, urosepsis, and progressive renal impairment. In rare instances, an individual who has (a) a molecularly confirmed diagnosis and/or (b) an affected relative meeting clinical diagnostic criteria manifests only the characteristic facial features or only the urinary bladder voiding dysfunction (not both). Nocturnal lagophthalmos (incomplete closing of the eyes during sleep) appears to be a common and significant finding.

Diagnosis/testing.

The diagnosis of UFS is based on investigations of the urinary tract that reveal characteristic urinary tract abnormalities and physical examination that reveals characteristic facial movement with expression. UFS is a heterogeneous condition resulting from biallelic pathogenic variants in either HPSE2 or LRIG2. In some instances no pathogenic change has been identified. Note that the majority of individuals with UFS reported to date have not had molecular confirmation of their diagnosis.

Management.

Treatment of manifestations: Rapid and complete treatment of urinary tract infections and routine treatment of urosepsis. For urinary incontinence and bladder dysfunction: use of anticholinergic and α₁-adrenergic blockers; intermittent catheterization or vesicostomy; surgical management of hydroureteronephrosis and bladder augmentation should be considered. Management of chronic kidney disease and end-stage renal disease relies on the standard optimal options.

Surveillance: Monitor for evidence of urinary tract features including vesicoureteric reflux and hydroureteronephrosis. Renal function should be monitored at intervals determined by urinary tract features at presentation and their subsequent progression.

Agents/circumstances to avoid: Nephrotoxic substances.

Evaluation of relatives at risk: 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 prompt initiation of necessary treatment.

Pregnancy management: Although no guidelines for prenatal management of UFS exist, it seems appropriate to perform ultrasound examination of pregnancies at risk 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. At conception, each sib of an affected individual has 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. If the pathogenic variants in the family are known, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Urofacial syndrome (UFS) should be suspected in individuals with the following clinical findings.

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 renal impairment [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].
  Characteristic urinary tract abnormalities:
  • Postnatal imaging of the bladder typically shows muscular thickening and trabeculation, but may also be normal [Ochoa 1992, Ochoa 2004, Derbent et al 2009, Aydogdu et al 2010].
  • Hydroureteronephrosis is common [Ochoa 1992, Ochoa 2004].
  • Micturating cystourethrogram may reveal vesicoureteric reflux [Ochoa 2004]; intra-urethral anatomic lesions are not observed.
  Cystoscopy, if performed, reveals no urethral lesions.
• 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 and often described as a "grimace" [Ochoa 2004, Aydogdu et al 2010, Ganesan & Thomas 2011]. Typical facial expressions have been present in all but one individual (who was diagnosed due to classic features in a relative) [Aydogdu et al 2010].

Other clinical findings

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

Establishing the Diagnosis

The diagnosis of UFS is established in a proband by either of the following:

• The presence of the two main clinical features involving the urinary bladder and face described in Suggestive Findings [Ochoa 2004]
• Identification of biallelic pathogenic variants in either HPSE2 or LRIG2 (Table 1)
  Note that the majority of individuals with UFS reported to date have not had molecular confirmation of their diagnosis.

Molecular genetic testing approaches can include gene-targeted testing (serial single-gene testing) and comprehensive genomic testing (exome or genome sequencing).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of UFS has not been considered due to the overlap of the urinary tract features of UFS with other disorders of the lower urinary tract and lack of recognition of the characteristic facial expression are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The main features of urofacial syndrome (UFS) are congenital urinary bladder voiding dysfunction and an abnormality of facial movement with expression that can be observed from birth. Bowel dysfunction is common. In rare instances, an individual who has: (a) a molecularly confirmed diagnosis; and/or (b) an affected relative meeting clinical diagnostic criteria manifests only the characteristic facial features or only the urinary bladder voiding dysfunction (not both).

Significant inter- and intrafamilial phenotypic variability has been observed [Ochoa 1992, Aydogdu et al 2010, Stuart et al 2013, Stuart et al 2015].

Urinary tract features are the main reason for presenting to medical attention and the main cause of associated morbidity and mortality.

UFS is not associated with growth or developmental abnormality other than that attributable to chronic renal disease. Intellect is normal.

Urinary tract. Urinary tract features have 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].

Severe neonatal and infant presentations with urinary tract complications including urinary bladder rupture and sepsis have been reported [Ochoa 1992, Skálová et al 2006].

More typical presentations of urinary tract features include recurrent urinary sepsis and failure to achieve urinary continence [Ochoa 1992, Ochoa 2004].

In the Ochoa cohort hydroureteronephrosis was found in 29/50 (58%) of affected individuals [Ochoa 1992, Ochoa 2004], a finding consistent with the range of urinary tract abnormalities in other case reports [Chauve et al 2000, Garcia-Minaur et al 2001, Al-Qahtani 2003, Nicanor et al 2005, Skálová et al 2006, Derbent et al 2009, Aydogdu et al 2010, Daly et al 2010, Stamatiou & Karakos 2010, Sutay et al 2010, Al Badr et al 2011, Akl & Al Momany 2012, Mahmood et al 2012, Stuart et al 2013, Stuart et al 2015].

Ochoa [2004] identified vesicoureteric reflux in 32/50 (64%); reflux was bilateral in 18 (36%).

The associated renal parenchymal damage with early impairment of renal function and progression to end-stage renal disease 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 renal impairment is unknown but likely to be significant [Ochoa & Gorlin 1987, Ochoa 1992, Ochoa 2004, Aydogdu et al 2010].

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.

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; Author, personal observation].

Abnormal facial movement with crying has been observed as early as the neonatal period [Ochoa 1992, Skálová et al 2006].

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].

Typical facial expressions have been present in all but one affected individual (who was diagnosed due to classic features in a relative) [Aydogdu et al 2010].

Rarely, affected individuals may have a facial phenotype with no urinary bladder dysfunction or symptoms [Stuart et al 2013; Author, personal communication].

Gastrointestinal tract. 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].

MRI of the central nervous system (CNS) – performed because the urinary tract features mimic those associated with CNS dysfunction – is typically normal [Nicanor et al 2005, Derbent et al 2009, Aydogdu et al 2010, Al Badr et al 2011, Akl & Al Momany 2012].

UFS most likely results from an abnormality of peripheral rather than central nervous system development [Roberts et al 2014], although affected individuals do not typically show any other features of neurologic dysfunction.

Note: Although early descriptions of UFS reported individuals with central nervous system abnormalities including spina bifida occulta, occipital meningocele, and hydrocephalus due to stenosis of the aqueduct of Sylvius, the subsequent failure to identify these findings indicates that they were most likely chance associations [Elejalde 1979, Teebi & Hassoon 1991].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been reported.

Prevalence

UFS is rare. Its prevalence is currently unknown but is likely to be higher in certain populations – for example, in Colombia as the result of a founder variant and associated consanguinity [Ochoa 2004, Pang et al 2010].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with urofacial syndrome (UFS), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Urinalysis and urine culture for occult or chronic infection
• Assessment of renal function: serum creatinine concentration and/or estimated glomerular filtration rate
• Urinary tract ultrasound examination
• Micturating cystourethrogram
• Uroflowmetry or urodynamic testing
• Blood pressure measurement
• Assessment of renal parenchymal damage: as indicated by the individual's presentation, dimercaptosuccinic acid (DMSA) isotope scan to visualize functional kidney parenchyma [Ochoa 2004, Aydogdu et al 2010, Stuart et al 2013]
• Assessment of bowel emptying
• Ophthalmologic examination for evidence of nocturnal lagophthalmos
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Urinary tract. No evidence-based guidelines exist for treatment of the urinary tract abnormalities of UFS.

Urinary tract infections warrant rapid and complete treatment. Urosepsis should be treated as per the general population with antibiotic use directed by culture; antibiotic prophylaxis may also be considered.

Anticholinergic and α₁-adrenergic blockers have been used in the medical management of urinary incontinence and bladder dysfunction [Aydogdu et al 2010, Stuart et al 2013].

Intermittent catheterization or vesicostomy to reduce residual urine volumes and achieve continence with a reduced risk of infections have been used.

Surgical management of hydroureteronephrosis and bladder augmentation to slow progression of renal impairment have been used; their efficacy is not known [Ochoa 2004, Stuart et al 2013].

Early recognition of renal impairment should prompt initiation of intensive management to prevent or slow progression. Renal impairment and hypertension are managed as per clinical status. Successful renal transplantation has been reported [Ochoa 2004].

Bowel. Constipation is managed as for the general population.

Nocturnal lagophthalmos requires lubricant drops during the day and ointments at night to protect the cornea from exposure keratopathy (typically under the care of an ophthalmologist) [Mermerkaya et al 2014].

Surveillance

Monitor:

• For evidence of urinary tract features including vesicoureteric reflux and hydroureteronephrosis;
• Renal function at intervals determined by urinary tract features at presentation and their subsequent progression;
• For evidence of significant corneal involvement in individuals with nocturnal lagophthalmos.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

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;
• Examination to determine whether facial and/or urinary tract manifestations of UFS are present if the pathogenic variants in the family are not known.

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

Pregnancy Management

Although no guidelines for prenatal management of UFS exist, it seems appropriate to perform ultrasound examination of pregnancies at risk to determine if urinary tract involvement of UFS is present, 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).

Therapies Under Investigation

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 obligate heterozygotes (i.e., carriers of one UFS-related pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with HPSE2-related or LRIG2-related UFS are 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, clarification of carrier status, 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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.

Molecular Pathogenesis

The molecular pathogenesis of urofacial syndrome (UFS) is not currently understood. It had previously been speculated that the features of UFS could result from a central nervous system abnormality [Ochoa 2004]. However, it is now considered more likely 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].

Both HPSE2 and its encoded protein (heparanase 2) and LRIG2 and its encoded protein (the leucine-rich repeats and immunoglobulin-like domains 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].

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; Author, personal communication].

Literature Cited

• Akl KF, Al Momany HM. Urofacial syndrome. Saudi J Kidney Dis Transpl. 2012;23:346–8. [PubMed: 22382233]
• Al Badr W, Al Bader S, Otto E, Hildebrandt F, Ackley T, Peng W, Xu J, Li J, Owens KM, Bloom D, Innis JW. Exome capture and massively parallel sequencing identifies a novel HPSE2 mutation in a Saudi Arabian child with Ochoa (urofacial) syndrome. J Pediatr Urol. 2011;7:569–73. [PMC free article: PMC3157539] [PubMed: 21450525]
• Al-Qahtani FN. Ochoa syndrome: new features. Saudi J Kidney Dis Transpl. 2003;14:61–4. [PubMed: 17657091]
• Aydogdu O, Burgu B, Demirel F, Soygur T, Ozcakar ZB, Yalcinkaya F, Tekgul S. Ochoa syndrome: a spectrum of urofacial syndrome. Eur J Pediatr. 2010;169:431–5. [PubMed: 19669792]
• Bacchetta J, Cochat P. Severe voiding dysfunction: ask the child to smile. Kidney Int. 2010;78:225–6. [PubMed: 20588289]
• Chauve X, Missirian C, Malzac P, Girardot L, Guys JM, Louis C, Philip N, Voelckel MA. Genetic homogeneity of the urofacial (Ochoa) syndrome confirmed in a new French family. Am J Med Genet. 2000;95:10–2. [PubMed: 11074487]
• Cui H, Shao C, Liu Q, Yu W, Fang J, Yu W, Ali A, Ding K. Heparanase enhances nerve-growth-factor-induced PC12 cell neuritogenesis via the p38 MAPK pathway. Biochem J. 2011;440:273–82. [PubMed: 21831044]
• Daly SB, Urquhart JE, Hilton E, McKenzie EA, Kammerer RA, Lewis M, Kerr B, Stuart H, Donnai D, Long DA, Burgu B, Aydogdu O, Derbent M, Garcia-Minaur S, Reardon W, Gener B, Shalev S, Smith R, Woolf AS, Black GC, Newman WG. Mutations in HPSE2 cause urofacial syndrome. Am J Hum Genet. 2010;86:963–9. [PMC free article: PMC3032078] [PubMed: 20560210]
• Derbent M, Melek E, Arman A, Uçkan S, Baskin E. Urofacial (Ochoa) syndrome: can a facial gestalt represent severe voiding dysfunction? Ren Fail. 2009;31:589–92. [PubMed: 19839856]
• Elejalde BR. Genetic and diagnostic considerations in three families with abnormalities of facial expression and congenital urinary obstruction: "The Ochoa syndrome. Am J Med Genet. 1979;3:97–108. [PubMed: 474623]
• Fadda A, Butt F, Tomei S, Deola S, Lo B, Robay A, Al-Shakaki A, Al-Hajri N, Crystal R, Kambouris M, Wang E, Marincola FM, Fakhro KA, Cugno C. Two hits in one: whole genome sequencing unveils LIG4 syndrome and urofacial syndrome in a case report of a child with complex phenotype. BMC Med Genet. 2016;17:84. [PMC free article: PMC5114772] [PubMed: 27855655]
• Feldman AS, Bauer SB. Diagnosis and management of dysfunctional voiding. Curr Opin Pediatr. 2006;18:139–47. [PubMed: 16601493]
• Fux L, Ilan N, Sanderson RD, Vlodavsky I. Heparanase: busy at the cell surface. Trends Biochem Sci. 2009;34:511–9. [PMC free article: PMC2755511] [PubMed: 19733083]
• Ganesan I, Thomas T. More than meets the smile: facial muscle expression in children with Ochoa syndrome. Med J Malaysia. 2011;66:507–9. [PubMed: 22390114]
• Garcia-Minaur S, Oliver F, Yanez JM, Soriano JR, Quinn F, Reardon W. Three new European cases of urofacial (Ochoa) syndrome. Clin Dysmorphol. 2001;10:165–70. [PubMed: 11446407]
• Gauthier J, Ouled Amar Bencheikh B, Hamdan FF, Harrison SM, Baker LA, Couture F, Thiffault I, Ouazzani R, Samuels ME, Mitchell GA, Rouleau GA, Michaud JL, Soucy JF. A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome. Eur J Hum Genet. 2015;23:1266–8. [PMC free article: PMC4538215] [PubMed: 25407000]
• Guo D, Holmlund C, Henriksson R, Hedman H. The LRIG gene family has three vertebrate paralogs widely expressed in human and mouse tissues and a homolog in Ascidiacea. Genomics. 2004;84:157–65. [PubMed: 15203213]
• Halim D, Brosens E, Muller F, Wangler MF, Beaudet AL, Lupski JR, Akdemir ZHC, Doukas M, Stoop HJ, de Graaf BM, Brouwer RWW, van Ijcken WFJ, Oury JF, Rosenblatt J, Burns AJ, Tibboel D, Hofstra RMW, Alves MM. Loss-of-function variants in MYLK cause recessive megacystis microcolon intestinal hypoperistalsis syndrome. Am J Hum Genet. 2017a;101:123–9. [PMC free article: PMC5501771] [PubMed: 28602422]
• Halim D, Wilson MP, Oliver D, Brosens E, Verheij JB, Han Y, Nanda V, Lyu Q, Doukas M, Stoop H, Brouwer RW, van IJcken WF, Slivano OJ, Burns AJ, Christie CK, de Mesy Bentley KL, Brooks AS, Tibboel D, Xu S, Jin ZG, Djuwantono T, Yan W, Alves MM, Hofstra RM, Miano JM. Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice. Proc Natl Acad Sci U S A. 2017b;114:E2739–E2747. [PMC free article: PMC5380076] [PubMed: 28292896]
• Hedman H, Henriksson R. LRIG inhibitors of growth factor signalling - double-edged swords in human cancer? Eur J Cancer. 2007;43:676–82. [PubMed: 17239582]
• Holmlund C, Nilsson J, Guo D, Starefeldt A, Golovleva I, Henriksson R, Hedman H. Characterization and tissue-specific expression of human LRIG2. Gene. 2004;332:35–43. [PubMed: 15145052]
• Homma S, Shimada T, Hikake T, Yaginuma H. Expression pattern of LRR and Ig domain-containing protein (LRRIG protein) in the early mouse embryo. Gene Expr Patterns. 2009;9:1–26. [PubMed: 18848646]
• Levy-Adam F, Feld S, Cohen-Kaplan V, Shteingauz A, Gross M, Arvatz G, Naroditsky I, Ilan N, Doweck I, Vlodavsky I. Heparanase 2 interacts with heparan sulfate with high affinity and inhibits heparanase activity. J Biol Chem. 2010;285:28010–9. [PMC free article: PMC2934666] [PubMed: 20576607]
• Mahmood S, Beetz C, Tahir MM, Imran M, Mumtaz R, Bassmann I, Jahic A, Malik M, Nürnberg G, Hassan SA, Rana S, Nürnberg P, Hübner CA. First HPSE2 missense mutation in urofacial syndrome. Clin Genet. 2012;81:88–92. [PubMed: 21332471]
• McKenzie E, Tyson K, Stamps A, Smith P, Turner P, Barry R, Hircock M, Patel S, Barry E, Stubberfield C, Terrett J, Page M. Cloning and expression profiling of Hpa2, a novel mammalian heparanase family member. Biochem Biophys Res Commun. 2000;276:1170–7. [PubMed: 11027606]
• Mermerkaya M, Süer E, Öztürk E, Gülpınar Ö, Gökçe Mİ, Yalçındağ FN, Soygür T, Burgu B. Nocturnal lagophthalmos in children with urofacial syndrome (Ochoa): a novel sign. Eur J Pediatr. 2014;173:661–65. [PubMed: 24248520]
• Moreno CA, Sobreira N, Pugh E, Zhang P, Steel G, Torres FR, Cavalcanti DP. Homozygous deletion in MYL9 expands the molecular basis of megacystis–microcolon–intestinal hypoperistalsis syndrome. Eur J Hum Genet. 2018;26:669–75. [PMC free article: PMC5945668] [PubMed: 29453416]
• Nicanor FA, Cook A, Pippi-Salle JL. Early diagnosis of the urofacial syndrome is essential to prevent irreversible renal failure. Int Braz J Urol. 2005;31:477–81. [PubMed: 16255797]
• Nilsson J, Vallbo C, Guo D, Golovleva I, Hallberg B, Henriksson R, Hedman H. Cloning, characterization, and expression of human LIG1. Biochem Biophys Res Commun. 2001;284:1155–61. [PubMed: 11414704]
• Ochoa B, Gorlin RJ. Urofacial (Ochoa) syndrome. Am J Med Genet. 1987;27:661–7. [PubMed: 3631137]
• Ochoa B. Can a congenital dysfunctional bladder be diagnosed from a smile? The Ochoa syndrome updated. Pediatr Nephrol. 2004;19:6–12. [PubMed: 14648341]
• Ochoa B. The urofacial (Ochoa) syndrome revisited. J Urol. 1992;148:580–3. [PubMed: 1640526]
• Pang J, Zhang S, Yang P, Hawkins-Lee B, Zhong J, Zhang Y, Ochoa B, Agundez JA, Voelckel MA, Fisher RB, Gu W, Xiong WC, Mei L, She JX, Wang CY. Loss-of-function mutations in HPSE2 cause the autosomal recessive urofacial syndrome. Am J Hum Genet. 2010;86:957–62. [PMC free article: PMC3032074] [PubMed: 20560209]
• Richer J, Milewicz DM, Gow R, de Nanassy J, Maharajh G, Miller E, Oppenheimer L, Weiler G, O'Connor M. R179H mutation in ACTA2 expanding the phenotype to include prune-belly sequence and skin manifestations. Am J Med Genet A. 2012;158A:664–8. [PubMed: 22302747]
• Roberts NA, Woolf AS, Stuart HM, Thuret R, McKenzie EA, Newman WG, Hilton EN. Heparanase 2, mutated in urofacial syndrome, mediates peripheral neural development in Xenopus. Hum Mol Genet. 2014;23:4302–14. [PMC free article: PMC4103677] [PubMed: 24691552]
• Skálová S, Rejtar I, Novák I, Jüttnerová V. The urofacial (Ochoa) syndrome--first case in the central European population. Prague Med Rep. 2006;107:125–9. [PubMed: 16752812]
• Stamatiou KN, Karakos CD. Urofacial syndrome: A subset of neurogenic bladder dysfunction syndromes? Indian J Urol. 2010;26:582–4. [PMC free article: PMC3034072] [PubMed: 21369396]
• Stuart HM, Roberts NA, Burgu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson JE, Mermerkaya M, Silay MS, Lewis MA, Olondriz MB, Gener B, Beetz C, Varga RE, Gülpınar O, Süer E, Soygür T, Ozçakar ZB, Yalçınkaya F, Kavaz A, Bulum B, Gücük A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet. 2013;92:259–64. [PMC free article: PMC3567269] [PubMed: 23313374]
• Stuart HM, Roberts NA, Hilton EN, McKenzie EA, Daly SB, Hadfield KD, Rahal JS, Gardiner NJ, Tanley SW, Lewis MA, Sites E, Angle B, Alves C, Lourenço T, Rodrigues M, Calado A, Amado M, Guerreiro N, Serras I, Beetz C, Varga RE, Silay MS, Darlow JM, Dobson MG, Barton DE, Hunziker M, Puri P, Feather SA, Goodship JA, Goodship TH, Lambert HJ, Cordell HJ, Saggar A, Kinali M, Lorenz C, Moeller K, Schaefer F, Bayazit AK, Weber S, Newman WG, Woolf AS, et al. Urinary tract effects of HPSE2 mutations. J Am Soc Nephrol. 2015;26:797–804. [PMC free article: PMC4378092] [PubMed: 25145936]
• Sutay NR, Kulkarni R, Arya MK. Ochoa or Urofacial syndrome. Indian Pediatr. 2010;47:445–6. [PubMed: 20519791]
• Teebi AS, Hassoon MM. Urofacial syndrome associated with hydrocephalus due to aqueductal stenosis. Am J Med Genet. 1991;40:199–200. [PubMed: 1897575]
• Vivante A, Hwang DY, Kohl S, Chen J, Shril S, Schulz J, van der Ven A, Daouk G, Soliman NA, Kumar AS, Senguttuvan P, Kehinde EO, Tasic V, Hildebrandt F. Exome sequencing discerns syndromes in patients from consanguineous families with congenital anomalies of the kidneys and urinary tract. J Am Soc Nephrol. 2017;28:69–75. [PMC free article: PMC5198271] [PubMed: 27151922]
• Weber S, Thiele H, Mir S, Toliat MR, Sozeri B, Reutter H, Draaken M, Ludwig M, Altmüller J, Frommolt P, Stuart HM, Ranjzad P, Hanley NA, Jennings R, Newman WG, Wilcox DT, Schlingmann K-P, Beetz R, Hoyer PF, Konrad M, Schaefer F, Nürnberg P, Woolf AS. Muscarinic acetylcholine receptor M3 (CHRM3) mutation causes urinary bladder disease and a prune-belly like syndrome. Am J Hum Genet. 2011;89:668–74. [PMC free article: PMC3213389] [PubMed: 22077972]
• Woolf AS, Stuart HM, Newman WG. Genetics of human congenital urinary bladder disease. Pediatr Nephrol. 2014a;29:353–60. [PubMed: 23584850]
• Woolf AS, Stuart HM, Roberts NA, McKenzie EA, Hilton EN, Newman WG. Urofacial syndrome: a genetic and congenital disease of aberrant urinary bladder innervation. Pediatr Nephrol. 2014b;29:513–8. [PubMed: 23832138]

Author Notes

Bill Newman is a clinical geneticist with a research program that includes the identification of the causes of rare inherited disorders and subsequent development of targeted treatments.

Adrian S Woolf is a clinician scientist and nephrologist. His research interest is to find out why some children are born with abnormal renal tracts.

Author History

William G Newman, MD, PhD (2013-present)
Helen M Stuart, MD; University of Manchester and Central Manchester University Hospitals NHS Foundation Trust (2013-2018)
Adrian S Woolf, MD (2013-present)

Acknowledgments

The authors' work on UFS has been funded by Kidney Research UK, Newlife, the Medical Research Council, and the Wellcome Trust.

Revision History

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