Urofacial syndrome (ORPHA:2704)
A rare syndromic urinary tract malformation characterized by the association of severe voiding dysfunction and inversion of facial expression when the child smiles or cries.
Epidemiology
The prevalence of the syndrome is not known; more than 150 cases, mostly children, have been reported. The majority of cases reported in the literature are from Columbia, although affected families have also been reported worldwide.
Clinical description
Patients present with incontinence, urinary tract infections and hydro-uretero-nephrosis with progressive renal impairment. Voiding dysfunction is the result of an obstructive uropathy. About two-thirds of the patients have moderate to severe constipation. Cryptorchidism has also been reported. The peculiar facial dysmorphism is related to an unusual inversion of facial expression that occurs when the child smiles or cries. Nocturnal lagophthalmos has recently been described.
Etiology
The disorder is due to recessive mutations in either HPSE2 (10q23-q24) encoding inactive heparanase-2, or LRIG2 (1p13.2) encoding leucine-rich repeats and immunoglobulin-like domains protein 2; however, in up to 16% of patients, no associated mutations have been found.
Diagnostic methods
No formal diagnostic criteria have been published. Diagnosis may be suspected following recognition of the peculiar facial expression during infancy. Ultrasonography, renal scan, voiding cystourethrogram and urodynamics can be used to evaluate the lower urinary tract dysfunction. A genetic diagnosis can be made through different tests including assessment of a single-gene testing (HPSE or LRIG2 gene), exome or genome sequencing.
Differential diagnosis
Differential diagnoses include Hinman-Allen syndrome (a rare voiding disorder of the bladder of neuropsychological origin), neuropathic bladder (e.g., due to a neurologic lesion such as spina bifida), vescicoureteric reflux, and urethral obstruction.
Antenatal diagnosis
The disorder can be suspected prenatally on ultrasound findings of megabladder, hydroureter, and/or hydronephrosis. However, not all patients will have prenatal manifestations as the onset of symptoms can occur in infancy or even adulthood. Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive and genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. The penetrance of the disease is complete, but the clinical expression is variable even in individuals of the same family.
Management and treatment
Treatment is symptomatic and involves bladder re-education, antibiotic prophylaxis, anticholinergic therapy and alpha-blockers. Intermittent catheterization may be needed. Constipation should be treated. Early diagnosis and treatment are essential in order to prevent upper urinary tract deterioration and renal failure.
Prognosis
Patients live a normal lifespan. Prognosis depends on the severity of the renal disease and precocity of treatment but is generally good, particularly if appropriate treatment is provided and established early.

                            Last update: 
                            June 2022


                            - Expert reviewer(s): 
                            Dr Camilla MEOSSI  - Dr Donatella MILANI | ITHACA* -  Dario MINOLI | EUROGEN*


                                * European Reference Network