Urinary tract malformations account for half of all children with kidney failure, and some have defined monogenic causes. One such disorder is urofacial, or Ochoa, syndrome (UFS), an autosomal recessive disease featuring a dyssynergic bladder with detrusor smooth muscle contracting against an undilated outflow tract. Incomplete voiding predisposes to urosepsis and kidney failure. Half of individuals with UFS carry biallelic variants in HPSE2, whereas some carry variants in LRIG2 (leucine rich repeats and immunoglobulin like domains 2). We report one new kindred where the index case presented with fetal hydronephrosis and postnatally had urosepsis and functional bladder outlet obstruction. He had the grimace that, together with urinary tract disease, characterizes UFS. While HPSE2 sequencing was normal, he carried a homozygous, predicted pathogenic, stop variant (c.1939C>T; p.Arg647*) in LRIG2. Hypothesizing that neurogenic defects underlie LRIG2-associated bladder dysfunction, we studied Lrig2 homozygous mutant mice. Juveniles had enlarged bladders and ex vivo physiology experiments showed neurogenic defects in outflow tract relaxation. Mutants also displayed abnormal detrusor contractility. Moreover, there were nuanced differences in physiological defects between the sexes. The current case emphasizes that urinary tract disease in UFS begins before birth. Putting this family in the context of all reported urinary tract disease-associated LRIG2 variants, the urinary and facial phenotype of UFS occurs with biallelic putative loss of function variants, but missense variants lead to bladder-limited disease without the grimace. Finally, our murine observations support the hypothesis that UFS is a genetic autonomic neuropathy of the bladder affecting outflow tract and bladder body function.

The authors have declared no competing interest.

This study was funded by Medical Research Council (project grant MR/L002744/1 to ASW and WGN; project grant MR/T016809/1 to ASW, NAR, and FML; and Doctoral Training Programme to BWJ); Kidney Research United Kingdom (project grant Paed_RP/002/20190925 to WGN, GMB, and ASW; and Paed_RP/005/20190925 to NAR and ASW); Newlife Foundation (project grants 15-15/03 and 15-16/06 to WGN and ASW); the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007 to WGN); and Kidneys for Life (start-up grant 2018 to NAR). We thank the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA (EU Framework Partnership ID: 3HP-HP-FPA ERN-01-2016/739516) for their support.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Approval for patient studies was given by the Vall d'Hebron Hospital Ethics Committee, Vall d'Hebron Barcelona Hospital Campus, Autonomous University of Barcelona, Barcelona, Spain

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present work are contained in the manuscript