Urofacial syndrome

Onset is congenital; some affected infants are identified prenatally by enlarged bladders on antenatal ultrasound, while others present in early childhood with dysfunctional voiding and urosepsis. The cardinal urological feature is detrusor-sphincter dyssynergia, in which the bladder fails to empty fully because its outflow tract does not relax during micturition. The characteristic facial feature, from which the eponym derives, is an inverted expression: the appearance of crying when attempting to smile or laugh, reflecting abnormal patterning of facial autonomic innervation. Recurrent urinary-tract infection, vesicoureteral reflux, and progressive hydronephrosis can culminate in chronic kidney disease and kidney failure when the bladder dysfunction is not recognised and managed early.

Due to insufficient data, no reliable statement on prevalence can currently be made. Approximately 150 cases have been reported in the medical literature. The majority of cases reported in the literature are from Columbia, although affected families have also been reported worldwide.

Urofacial syndrome is caused by biallelic germline pathogenic variants in HPSE2 or LRIG2. HPSE2, encoding heparanase-2, accounts for around 50% of genetically confirmed families. Biallelic LRIG2 variants, encoding leucine-rich repeats and immunoglobulin-like domains 2, underlie a smaller subset. Both proteins localie to pelvic ganglia innervating the bladder, and in murine knock-out models the bladder nerves are abnormally patterned, supporting a developmental peripheral neuropathy of the lower urinary tract.

Urofacial syndrome is inherited in an autosomal recessive pattern. Both parents of an affected child are typically heterozygous carriers, and each pregnancy carries a 25% recurrence risk. Heterozygous carriers are asymptomatic. Once the familial pathogenic variants have been identified, prenatal molecular testing is technically possible.

Clinical suspicion arises from the combination of dysfunctional voiding from infancy and the characteristic inverted facial expression on smiling and crying. Urodynamic assessment typically demonstrates detrusor-sphincter dyssynergia, and urinary-tract imaging shows bladder distension, vesicoureteral reflux, and hydronephrosis. Definitive diagnosis is established by molecular genetic testing.

• Establishing the diagnosis: confirmation of the underlying molecular cause ends the diagnostic odyssey, supports accurate prognosis, and underpins genetic counselling for the affected individual and family.
• Specific and individualised surveillance: a confirmed molecular diagnosis allows surveillance and clinical management to be tailored to the specific condition and provides the prerequisite for targeted medical care, decided upon by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variants have been identified, at-risk relatives can be offered targeted carrier or predictive testing through clinical genetic counselling.

• Newman WG, Woolf AS, Beaman GM, Roberts NA. Urofacial syndrome. 2013 Aug 22 [updated 2023 Sep 28]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:.
• Govindarajan V, Hanumanna AK, Kumari VK, Kariyappa M. Ochoa syndrome – neurogenic bladder with an inverted smile. Indian J Nephrol. 2022;32(4):384-6. doi:10.4103/ijn.ijn_235_21. PMID:; PMCID:PMC9364997.
• Beaman GM, Lopes FM, Hofmann A, Roesch W, Promm M, Bijlsma EK, et al. Expanding the HPSE2 genotypic spectrum in urofacial syndrome, a disease featuring a peripheral neuropathy of the urinary bladder. Front Genet. 2022;13:896125. doi:10.3389/fgene.2022.896125. PMID:; PMCID:PMC9259970.
• Grenier C, Lopes FM, Cueto-González AM, Rovira-Moreno E, Gander R, Jarvis BW, et al. Neurogenic defects occur in LRIG2-associated urinary bladder disease. Kidney Int Rep. 2023;8(7):1417-29. doi:10.1016/j.ekir.2023.04.017. PMID:; PMCID:PMC10334403.