During the last 40 years over 100 patients have been reported with a dysfunctional lower urinary tract associated with a peculiar distortion of the facial expression. This most unusual disorder was initially considered a local observation. Time, however, has proven otherwise, since patients with this syndrome have now been reported from various countries throughout the world. This association of lower urinary tract and bowel dysfunction with an abnormal facial expression was named the urofacial (Ochoa) syndrome. Genetic studies have demonstrated that this condition is inherited as an autosomal recessive trait, and a potential gene has been mapped to chromosome 10q23-q24. There is also enough evidence to suggest that patients with this syndrome as well as those with subclinical neurological bladder, occult neuropathic bladder, non-neurogenic neurogenic bladder or Hinman syndrome, dysfunctional voiding, or dysfunctional elimination may be affected by the same congenital disorder of neurological origin.
Previously, we localized the defective gene for the urofacial syndrome (UFS) to a region on chromosome 10q24 by homozygosity mapping. We now report evidence that Heparanse 2 (HPSE2) is the culprit gene for the syndrome. Mutations with a loss of function in the Heparanase 2 (HPSE2) gene were identified in all UFS patients originating from Colombia, the United States, and France. HPSE2 encodes a 592 aa protein that contains a domain showing sequence homology to the glycosyl hydrolase motif in the heparanase (HPSE) gene, but its exact biological function has not yet been characterized. Complete loss of HPSE2 function in UFS patients suggests that HPSE2 may be important for the synergic action of muscles implicated in facial expression and urine voiding.
Between 1965 and 1986 we saw 36 children with enuresis and urinary tract infection in association with "inversion" of facial expression when laughing. Urologic work-up of these patients disclosed characteristic findings of mild neuropathic bladder in all cases, with severe urinary tract damage in most of them. The clear association of distortion in facial expression and neuropathic bladder with resultant damage to the genitourinary tract should prompt urological evaluation of individuals with "inversion" of facial expression. About two thirds of the patients also had moderate to severe constipation. We suggest the term urofacial syndrome for this disorder. The occurrence of the disorder in multiple sibs, normal parents, increased parental consanguinity, and equal sex ratio indicate autosomal recessive inheritance.
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