Urofacial (Ochoa) syndrome with a founder pathogenic variant in the HPSE2 gene: a case report and mutation origin.

Urofacial syndrome or Ochoa syndrome (UFS or UFOS) is a rare disease characterized by inverted facial expression and bladder dysfunction that was described for the first time in Colombia. It is an autosomal recessive pathology with mutations in the HPSE2 and LRIG2 genes. However, 16% of patients do not have any mutations associated with the syndrome. Despite the importance of neurobiology in its pathophysiology, there are no neurological, neuropsychological, or psychological studies in these patients. A 30-year-old male from Medellín, Colombia, with a significant perinatal history, was diagnosed with grade 4 hydronephrosis on his first ultrasound test. At 4 months of age, symptoms such as hypomimia, lagophthalmos, and recurrent urinary tract infections started to manifest. Imaging studies revealed urinary tract dilatation, vesicoureteral reflux, and a double collector system on his left side, which led to the diagnosis of UFS. Multiple procedures, including vesicostomy, ureterostomy, and enterocystoplasty, were performed. At 20 years of age, he achieved urinary sphincter control. Genetic analysis revealed a founder pathogenic variant, c.1516C > T (p.Arg506Ter), in the HPSE2 gene, which produces a truncated protein that lacks 86 amino acids. This variant is classified as pathogenic according to the ClinVar database for UFS. The mutation age is approximately 260-360 years, and the two alleles share a 7.2-7.4 Mb IBD segment. Moreover, we detected European local ancestry in the IBD segment, which is consistent with a Spanish introduction. Neurological examination, neuropsychological assessment, and psychological testing revealed no abnormalities, except for high stress levels. Clinical analysis of this patient revealed distorted facial expression and detrusor-sphincter dyssynergia, which are typical of patients with UFS. Genetic analysis revealed a pathogenic variant in the HPSE2 gene of European origin and a mutation age of 260-360 years. From a neurological, neuropsychological, and psychological (emotional and personality) perspective, the patient showed no signs or symptoms of clinical interest.

Ochoa Syndrome - Neurogenic Bladder with an Inverted Smile.

Ochoa or urofacial syndrome is a rare autosomal recessive syndrome with around 150 cases reported in the medical literature comprising of neurogenic bladder and facial abnormalities, culminating in obstructive uropathy and chronic kidney disease. We report a 5-year-old boy presenting to us with Stage IV chronic kidney disease with bilateral hydroureteronephrosis secondary to chronic urinary incontinence. His peculiar facial expression with a grimace while smiling suggested the diagnosis of Ochoa syndrome. He was managed conservatively for neurogenic bladder and is under follow-up. We wish to highlight this unique syndrome and the simplicity in making this syndromic diagnosis, just by appreciating abnormal facial expressions.

Urofacial syndrome: Uncommon and unforeseen cause of lower urinary tract dysfunction in children.

Dr. Ochoa proposed a condition known as Urofacial syndrome (UFS) which is characterized by the abnormal facial expression while smiling along with dysfunctional lower urinary tract in 1987. This study investigated 7 years old boy who presented with recurrent urine retention, dysuria, and inversion facial expression. Radiological and genetic work-up diagnosed him with UFS.

Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family.

OBJECTIVES: Ochoa syndrome (UFS1; Urofacial syndrome-1) is a very rare autosomal recessive disorder caused by mutations in the HPSE2 gene that results bladder voiding dysfunction and somatic motor neuropathy affecting the VIIth cranial nerve. Niemann-Pick disease is a rare autosomal recessive lysosomal storage disorder with systemic involvement resulting from sphingomyelinase deficiency and generally occurs via mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1). CASE PRESENTATION: Here, we report a 6-year-old girl with symptoms such as urinary incontinence, recurrent urinary tract infections, peculiar facial expression, mainly when smiling, hypertelorism, constipation, incomplete closure of eyelids during sleep and splenomegaly. Homozygote mutations in two different genes responsible for two distinct syndromes were detected in the patient. Homozygous NM_000543.5:c.502G>A (p.Gly168Arg) mutation was found in the SMPD1 gene causing Niemann-Pick disease. In addition, some of the clinical features were due to a novel homozygous mutation identified in the HPSE2 gene, NM_021828.5:c.755delA (p.Lys252SerfsTer23). CONCLUSIONS: Here, we discuss about the importance of considering dual diagnosis in societies where consanguineous marriages are common. Accurate diagnosis of the patient is very important for the management of the diseases and prevention of complications.

Urofacial (ochoa) syndrome: A literature review.

The Urofacial or Ochoa Syndrome (UFS or UFOS) is characterized by an inverted facial expression (those affected seem crying while smiling) associated with lower urinary tract dysfunction without evident obstructive or neurological cause. It is associated with autosomal recessive inheritance mutations in the HPSE2 gene, located at 10q23-q24, and the LRGI2 gene, located in 1p13.2; however, in up to 16% of patients, no associated mutations have been found. Recent evidence suggests that these genes are critical to an adequate neurological development to the lower urinary tract and that the origin of the disease seems to be due to peripheral neuropathy. There is clinical variability among patients with UFS and not all present the classic two components, and it has even been genetically confirmed in patients with a prior diagnosis of Hinman Syndrome or other bladder dysfunctions. Also, the presence of nocturnal lagophthalmos in these patients was recently described. Early recognition and timely diagnosis are critical to preventing complications such as urinary tract infections or chronic kidney disease. Next, the history of Urofacial Syndrome, the advances in its pathophysiology, and its clinical characteristics is reviewed.

Congenital Disorders of the Human Urinary Tract: Recent Insights From Genetic and Molecular Studies.

The urinary tract comprises the renal pelvis, the ureter, the urinary bladder, and the urethra. The tract acts as a functional unit, first propelling urine from the kidney to the bladder, then storing it at low pressure inside the bladder which intermittently and completely voids urine through the urethra. Congenital diseases of these structures can lead to a range of diseases sometimes associated with fetal losses or kidney failure in childhood and later in life. In some of these disorders, parts of the urinary tract are severely malformed. In other cases, the organs appear grossly intact yet they have functional deficits that compromise health. Human studies are beginning to indicate monogenic causes for some of these diseases. Here, the implicated genes can encode smooth muscle, neural or urothelial molecules, or transcription factors that regulate their expression. Furthermore, certain animal models are informative about how such molecules control the development and functional differentiation of the urinary tract. In future, novel therapies, including those based on gene transfer and stem cell technologies, may be used to treat these diseases to complement conventional pharmacological and surgical clinical therapies.

Clinical and genetic characteristics for the Urofacial Syndrome (UFS).

The Urofacial (Ochoa) Syndrome (UFS) is a rare autosomal recessive disorder and over 100 patients have been reported thus far. UFS is characterized by the abnormal facial expression and dysfunctional voiding. The patients show a peculiar distortion of the facial expression (grimacing as if in pain or sadness when they tried to smile or laugh) along with urinary tract infection, enuresis, vesicoureteral reflux and hydronephrosis without any underlying neurological lesion and previous urinary obstruction. Some patients are also noted with nocturnal lagophthalmos. Until 2010, HPSE2, the gene encodes Heparanse 2 on chromosome 10, was thought to be the only culprit gene for this syndrome. However, another criminal gene, LRIG2, which encodes leucine-rich repeats and immunoglobulin-like domains 2, was also come into the light in 2012. Studies for dissecting the biological functions of HPSE2 and LRIG2 in urinary abnormalities are ongoing. In this minireview, we will update the discovery of novel clinical manifestations relevant to this syndrome and discuss with focus for the impact of HPSE2 on voiding dysfunction.