NORD gratefully acknowledges William G. Newman, MD, PhD, Manchester Centre for Genomic Medicine, University of Manchester and Manchester University NHS Foundation Trust, Manchester, UK, for assistance in the preparation of this report.
Summary
Urofacial syndrome (UFS is an extremely rare inherited disorder characterized by an unusual facial expression and disorder of the urinary tract (uropathy). When the bladder tries to empty, the outlet closes, meaning that the urine goes back towards the kidneys rather than out of the body. This problem can be present at birth (congenital). When affected infants smile, their facial musculature turns upside down or “inverts” so that they appear to be grimacing or crying. The urinary abnormality is due to a failure of nerve signals between the bladder and the spinal cord resulting in incomplete emptying of the bladder (neurogenic or neuropathic bladder). In addition, neurogenic bladder may result in involuntary discharge of urine (enuresis), urinary tract infections, and/or abnormal accumulation of urine in the kidneys (hydronephrosis). Additional abnormalities may include inflammation of the kidneys and pelvis (pyelonephritis), backflow of urine into the tubes that carry urine from the kidney to the bladder (vesicoureteral reflex), and constipation. Prompt diagnosis and treatment can reduce or potentially prevent severe, irreversible bladder and kidney damage. Intellect is not affected. Urofacial syndrome can occur due to disruption or changes (mutations) of the HPSE2 gene or the LRIG2 gene and is inherited in an autosomal recessive manner.
Introduction
Urofacial syndrome was first described in 1960s by Dr. Bernardo Ochoa, a urological surgeon and researcher from Colombia, South America. The disorder is also known as Ochoa syndrome and was originally believed to be a local disorder, unique to the region were it was first identified. Urofacial syndrome has since been identified in countries and ethnic groups worldwide.
As the term “urofacial” suggests, the disorder is characterized by urinary and facial problems. The initial finding that may be apparent in affected infants is an unusual “inverted” facial expression. When affected infants attempt to laugh or smile, their facial musculature “inverts” so that they appear to be grimacing or crying. The symptoms and severity of urofacial syndrome can vary greatly, even among members of the same family.
The urinary abnormality is an obstructive disease of the urinary tract that can be present at birth (congenital obstructive uropathy). This uropathy occurs due to failure of nerve signals between the bladder and spinal cord causing incomplete emptying (voiding) of the bladder (neurogenic or neuropathic bladder). At the lowest point of the bladder, there is a circular band of muscle fibers (urethral sphincter) that opens into the urethra, the tubular structure through which urine is expelled. When the bladder fills with urine, signals are normally sent to the spinal cord. Nerve signals are then sent back that cause the urethral sphincter to relax. The bladder then contracts and sends urine through the urethra. However, in affected individuals, there is a failure of such nerve signaling for unknown reasons, resulting in improper, incomplete emptying of the bladder (neurogenic bladder).
Neurogenic bladder may lead to the backflow (reflux) of urine into the tubes that normally bring urine to the bladder (ureters) from the kidneys; an abnormal swelling (distention) of and accumulation of urine in the ureters (hydroureter) and kidneys (hydronephrosis). In affected individuals, hydroureter and hydronephrosis may range from mild to severe. An early symptom of such abnormalities may include an inability to hold urine during the day and/or at night during sleep (diurnal and nocturnal enuresis).
Obstructive abnormalities of the urinary tract may result in urinary tract damage and repeated urinary tract infections. In some cases, such infections may cause no symptoms (asymptomatic). However, in other cases, a variety of symptoms may occur such as a frequent urge to urinate, the passage of an excessive amount of urine (polyuria), excessive thirst (polydipsia), a burning sensation when passing urine, painful or difficult urination (dysuria), loss of bladder control (incontinence), a general feeling of ill health (malaise), fever, pain in the lower abdomen and/or loins, and/or, in severe infections, the presence of blood (hematuria) and/or pus in the urine. A urinary tract infection can spread to the bloodstream, a serious complication known as urosepsis. Without appropriate treatment, repeated urinary tract infections and chronic damage to the kidney tract may ultimately lead to chronic renal failure. Renal failure occurs when the kidneys lose their ability to excrete waste products through the urine, to regulate the balance of salt and water in the body, and to perform their other vital functions. The exact proportion of affected individuals who eventually develop renal failure is unknown but early treatment can reduce the likelihood of this outcome. Some individuals with the disorder may also have high blood pressure (hypertension) due to kidney damage. This also requires active treatment to prevent further kidney damage.
Approximately two thirds of affected individuals may experience infrequent or incomplete passing of stools (constipation). Some children may develop encopresis, a condition in which the failure to have bowel movements causes stool to accumulate in the colon or rectum.
Some affected individuals are unable to fully close their eyelids when sleeping, a condition known as nocturnal lagophthalmos. This can cause the feeling of dry eyes upon awaking, a sensation that can be mild or severe. Lagophthalmos can cause various complications including inflammation of the cornea (keratitis), a scratched cornea (corneal abrasion), infection, and poor sleep.
Urofacial syndrome is caused by mutations in one of two different genes, the HPSE2 gene or the LRIG2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Some individuals with urofacial syndrome do not have mutations in either of the two known disease gene, suggesting that additional, as-yet-unidentified genes may also cause the disorder in certain cases.
Urofacial syndrome is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits two copies of the abnormal gene for the condition, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Urofacial syndrome affects both sexes equally. More than 150 cases have been reported in the medical literature. According to the literature, the majority of families are from Columbia although affected families have also been reported in the United States, the United Kingdom, Kuwait, Denmark, and Spain.
Because extremely rare disorders like urofacial syndrome often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of such disorders in the general population.
Some researchers suspect that many infants and children who experience abnormalities of the bladder, hydroureter, hydronephrosis, and associated symptoms may have urofacial syndrome. However, recent research has revealed that affected individuals with dysfunctional bladder without the characteristic facial findings may not be in the category of urofacial syndrome because their genetic patterns are typically different.
No formal diagnostic criteria have been established for urofacial syndrome. A diagnosis is suspected based upon identification of characteristic findings, a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. Physicians, particularly pediatricians, nephrologists, and urologists, should be aware of the association of urinary voiding abnormalities and the unique facial expression that characterizes this disorder.
At birth, the first feature that may be apparent in affected infants is the “inverted” facial expression. Due to the strong association of this feature and urological abnormalities, the presence of inverted facial expressions should lead to a prompt, thorough examination of the urinary tract. Such evaluation may lead to early diagnosis of urofacial syndrome and specific associated features (e.g., urinary tract infection), playing an essential role in ensuring appropriate preventive steps and/or prompt treatment.
During such urological evaluation, specialized imaging techniques may be used to examine the structure and assess the function of organs within the urinary tract (e.g. different portions of the kidneys, the bladder, the ureters). Such tests may include intravenous pyelography (IVP), during which a special contrast medium is injected and x-rays are then taken, and urodynamic evaluation, which examines the movement and flow of liquids through the urinary tract.
In addition to neuropathic bladder and obstructive abnormalities, such specialized imaging studies may also reveal structural abnormalities of the urinary tract. The bladder may have abnormal, anchoring bands and cords of connective tissue (trabeculation) and demonstrate overgrowth (hypertrophy) and abnormal hardening (sclerosis) of mucous membranes (mucosa), causing small sac-like protrusions (hernias) of tissue through the bladder’s muscular wall (diverticula). In addition, the bladder’s outer muscular layer (detrusor muscle) may demonstrate unusually increased reflex reactions (hyperreflexia) and abnormal, prolonged contractions (hypertonic contractures); the neck of the bladder may be abnormally enlarged (hypertrophic); and/or the urethra may have irregular spasms (spastic urethra) and have an abnormal diameter (caliber).
Urinary tract infections may be diagnosed by clinical evaluation, microscopic examination and bacteriological culture of urine specimens.
Molecular genetic testing can confirm a diagnosis of urofacial syndrome. Molecular genetic testing can detect mutations in the disease specific genes (i.e. HPSE2 or LRIG2) known to cause the disorder, but is available only as a diagnostic service at specialized laboratories.
Prenatal diagnosis is possible in families with a history of urofacial syndrome and in whom the specific disease-causing gene mutation is known.
Treatment
The treatment of urofacial syndrome is geared toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating disorders of the urinary tract (urologists), physicians who specialize in disorders of the kidneys (nephrologists), surgeons, dietitians, and/or other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is beneficial for affected individuals and families.
Prompt recognition and early treatment of urofacial syndrome is critical in reducing or preventing the potentially severe, irreversible bladder and kidney damage that can develop in severe cases.
Therapy for urinary tract infections usually includes antibiotics for the treatment and prevention of bacterial infections and pain relievers (e.g. analgesics). In some people, surgery may be conducted to eliminate urinary tract obstruction and reconstruct certain portions of the urinary tract (e.g. ureters, ureterovesicular junction). The surgical procedures performed depend upon the severity of the anatomical abnormalities and their associated symptoms.
Specific medications, anti-cholinergic and alpha-1-adrenergic blockers, have been used to treat individuals with urofacial syndrome. Constipation should be treated by standard guidelines as in the general population.
In affected children who experience chronic renal failure, treatment options may include certain procedures that regularly remove excess waste products from the blood (dialysis). Such procedures may include the removal of wastes by filtering the blood through a machine (hemodialysis) and/or by using a natural filtering membrane in the body’s abdomen (peritoneal dialysis). In some cases of severe renal failure, kidney transplantation may be considered.
Early intervention is important to ensure that affected children reach their potential. Special services that may be beneficial may include special social support and other medical and/or social services.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For more information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruiting Office:
Tollfree: (800) 411-1222
TTY: (866) 411- 1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., kidney abnormalities].)
JOURNAL ARTICLES
Bulum B, Ozcakar ZB, Duman D, et al. HPSE2 mutations in urofacial syndrome, non-neurogenic neurogenic bladder and lower urinary tract dysfunction. Nephron. 2015;130:54-58. http://www.ncbi.nlm.nih.gov/pubmed/25924634
Rondon AV, Leslie B, Netto JM, et al. The Ochoa urofacial syndrome: recognize the peculiar smile and avoid severe urological and renal complications. Einstein (Sao Paolo). 2015;[Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25946049
Mermerkaya M, Suer E Ozturk E, et al. Nocturnal lagophthalmos in children with urofacial syndrome (Ochoa): a novel sign. Eur J Pediatr. 2014;173:661-665. http://www.ncbi.nlm.nih.gov/pubmed/24248520
Woolf AS, Stuart HM, Roberts NA, et al. Urofacial syndrome: a genetic and congenital disease of aberrant urinary bladder innervation. Pediatric Nephrol. 2014;29:513-518. http://www.ncbi.nlm.nih.gov/pubmed/23832138
Stuart HM, Roberts NA, Burgu B, et al. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet. 2013;92:259-264. http://www.ncbi.nlm.nih.gov/pubmed/23313374
Daly SB, Urquhart JE, Hilton E, et al. Mutations in HPSE2 cause urofacial syndrome. Am J Hum Genet. 2010;86:963-969. http://www.ncbi.nlm.nih.gov/pubmed/20560210
Pang J, Zhang S, Yang P, et al. Loss-of-function mutations in HPSE2 cause the autosomal recessive urofacial syndrome. Am J Hum Genet. 2010;86:957-962. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032074/
Aydogdu O, Burgu B, Demirel F, et al. Ochoa syndrome: a spectrum of urofacial syndrome. Eur J Pediatr. 2010;169:431-435. http://www.ncbi.nlm.nih.gov/pubmed/19669792
Nicanor FA, Cook A, Pippi-Salle JL. Early diagnosis of the urofacial syndrome is essential to prevent irreversible renal failure. Int Braz J Urol. 2005;31:477-481. http://www.ncbi.nlm.nih.gov/pubmed/16255797
Ochoa B. Can a congenital dysfunctional bladder be diagnosed from a smile? The Ochoa syndrome updated. Pediatr Nephrol. 2004;19:6-12. http://www.ncbi.nlm.nih.gov/pubmed/14648341
Garcia-Minaur S, Oliver F, Yanez JM, et al. Three new European cases of urofacial (Ochoa) syndrome. Clin Dysmorphol. 2001;10;165-70. http://www.ncbi.nlm.nih.gov/pubmed/11446407
Chauve X, Missirian C, Malzac P, et al. Genetic homogeneity of the urofacial (Ochoa) syndrome confirmed in a new French family. 2000. Am J Med Genet. 2000;95:10-12. http://www.ncbi.nlm.nih.gov/pubmed/11074487
Wang CY, Shi JD, Huang YQ, et al. Construction of a physical and transcript map for a 1-Mb genomic region containing the urofacial (Ochoa) syndrome gene on 10q23-q24 and localization of the disease gene with two overlapping BAC clones (<360 db). Genomics. 1999;15:12-19. http://www.ncbi.nlm.nih.gov/pubmed/10458906
Wang CY, Hawkins-Lee B, Ochoa B, Walker RD, She JX. Homozygosity and linkage-disequilibrium mapping of the urofacial (Ochoa) syndrome gene to a 1-cm interval on chromosome 10q23-q24. Am J Med Genet. 1997;60:1461-67. http://www.ncbi.nlm.nih.gov/pubmed/9199567
Ochoa B, Gorlin RJ. Urofacial (Ochoa) syndrome. Am J Med Genet. 1987;27:661-67. http://www.ncbi.nlm.nih.gov/pubmed/3631137
Elejalde BR. Genetic and diagnostic considerations in three families with abnormalities of facial expression and congenital urinary obstruction: “the Ochoa syndrome.” Am J Med Genet. 1979;3:97-108. http://www.ncbi.nlm.nih.gov/pubmed/474623
INTERNET
Newman WG, Woolf AS, Stuart HM. Urofacial Syndrome. 2013 Aug 22. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK154138/ Accessed April 3, 2018.
Verloes A. Ochoa Syndrome. Orphanet Encyclopedia, October 2008. Available at: http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=2465&Disease_Disease_Search_diseaseGroup=Ochoa-syndrome&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group of diseases=Ochoa-syndrome&title=Ochoa-syndrome&search=Disease_Search_Simple Accessed April 3, 2018.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:236730; Last Update: 03/25/2017. Available at: http://omim.org/entry/236730 Accessed April 3, 2018.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:615112; Last Update:03/12/13. Available at: http://omim.org/entry/615112 Accessed April 3, 2018.
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