Dunedin School of Medicine

Optic Nerve Colobomas with Renal Disease and/or Vesico-Ureteric Reflux (Renal - Coloboma Syndrome)

Renal - Coloboma Syndrome (RCS) consists of colobomas of the eye, vesico-ureteric reflux and abnormalities of the kidney. The syndrome is listed in the OMIM database (OMIM #120330).

RCS has also been called several other names, including papillo-renal syndrome (Bron et al., 1988), morning glory syndrome (Karcher 1979), coloboma-ureteral-renal syndrome (Schimmenti et al., 1995), optic nerve coloboma with renal disease (ONCR)(Narahara et al., 1997, Weaver et al., 1988).

Mutations in PAX2 are responsible for the disorder. PAX2 is a transcription factor expressed in the developing kidney, eye, central nervous system and ear.

Eye and Kidney Abnormalities, Vesico-ureteric Reflux, and Hearing Loss in RCS

  • Eye Abnormalities

    Approximately 50% of patients with RCS present with eyesight abnormalities of one or both eyes, sometimes with considerable variation between them. In a few RCS patients eyesight is limited in one or both eyes to only light and colour perception, the detection of hand movements, or the counting of fingers held at arm's length, but most patients have either milder or no detectable eyesight abnormalities. Microphthalmia, i.e. a smaller than normal eye, has also been reported in a small number of RCS patients. Other eyesight abnormalities which have been reported at frequencies up to 25% in RCS patients are myopia, amblyopia, esotropia, nystagmus, strabismus and cataracts. Whether quality of eyesight in patients with RCS tends to deteriorate more rapidly with age than normal people is not known.
    Eyesight abnormalities in patients with RCS are the result of defects of the retina and optic nerve, which can be detected by ophthalmologists in approximately 87% of patients with RCS. Optic nerve defects are the most frequently observed abnormality and may occur in one or both eyes. In general, the severity and nature of the optic nerve or retinal defects correlates with loss of quality of eyesight.

  • Kidney Abnormalities

    Abnormal kidneys with or without impaired function is the second most frequent feature characterizing RCS, occurring in approximately 70% of patients with RCS. Renal hypoplasia, or a variant of this called oligomeganephronia, (i.e. small kidney) is the most frequent kidney abnormality. A small kidney may be observed on one or both sides, and may be identified pre-natally or at birth. Kidney defects arising from the presence of vesico-ureteric reflux (reflux nephropathy) might also be observed in addition (see below). The smaller the kidneys, compared with normal, the more chance the patient may develop impaired kidney function or kidney failure. The kidney failure can begin at probably any stage of life, and tends to become worse with age, occurring in approximately one third of patients with RCS. Almost 10% of RCS patients had kidney failure at age 10, while that figure reached almost 20% by age 20. Approximately two-thirds of those patients who develop kidney failure will progress and eventually require kidney dialysis, or renal transplantation. With careful management and monitoring, the progression of kidney failure can be reduced.

    Up to thirty seven percent of patients with small kidneys in isolation have been diagnosed with RCS, based on the identification of a PAX2 mutation, or because they were subsequently found to have fundus abnormalities. Therefore, all patients with small kidneys in isolation should have an eye examination, and genetic testing to determine whether they have RCS.

Vesico-Ureteric Reflux

Vesico-ureteric reflux (VUR) in 17% of RCS patients is due to a malformation of the vesico-ureteral junction of the ureter with the bladder and involves the regurgitation of urine from the bladder into the ureter and back towards the kidney. In patients with RCS abnormal development of the ureter and of the shape and position of the ureteric orifice in the bladder wall occurs during fetal development. It is possible that the incidence of VUR in RCS patients is underestimated. VUR often resolves spontaneously (especially grades I and II) in early childhood, and because VUR itself is not painful or symptomatic, it may occur undetected and never be identified in a proportion of RCS patients. The initial presentation of VUR is often as a result of a urinary tract infection. Occasionally, the initial presentation is kidney failure and/or scar formation, called reflux nephropathy. The occurrence of VUR is detected by micturating cystourethrogram (MCU), while the extent of renal damage caused by VUR is determined using a dimethyl succinic acid (DMSA) scan.

It appears unlikely that VUR itself is a major cause of kidney failure in RCS patients, especially when the VUR is grade I or II. However, high grade VUR (VUR of grades III to IV) in RCS patients may contribute towards progression of kidney failure. Recent studies suggest that grade I or II reflux are unlikely to play a role in progressive kidney failure, whereas high-grade (III and IV) VUR may require surgical reimplantation of the ureters to correct the reflux, and therefore prevent the recurrence of urinary tract infections and related problems. It is debatable, however, whether surgical reimplantation of the ureters alters the rate of progression to kidney failure in patients who have unresolving grade III or IV reflux.

Hearing Loss

Approximately 3% of RCS patients present with hearing loss in the high frequency range. The exact anatomical nature of this deficit is unknown, but may be due to abnormal development of the neurogenic portion of the inner ear.