Congenital anomalies of kidney and urinary tract in siblings: An uncommon condition

Introduction

Congenital anomalies of kidney and urinary tract (CAKUT) occur in about 0.5% of all pregnancies and contribute to almost 50% of abdominal masses detected in infancy.[1] These include pelviureteric junction obstruction (PUJO), multicystic dysplastic kidneys, single kidneys, vesicoureteric reflux, duplex systems, and obstructive uropathies. Anomalies such as PUJO and multicystic dysplastic kidneys are mostly unilateral. End-stage renal disease due to CAKUT is a common childhood presentation. Although genetic defects have been identified for some structural anomalies occurring with syndromes, most CAKUT occur in isolation. It is rather unusual to see CAKUT in siblings. We present here two families having two siblings each afflicted with CAKUT, one with bilateral PUJO and the other with posterior urethral valves (PUV).

Case Reports

Discussion

Based on end-stage renal disease data from different registries, CAKUT contributes to CKD in 45-60% of the pediatric patients.[2] Non-syndromic CAKUT is more frequent. CAKUT includes a wide spectrum of anomalies such as renal hypoplasia, dysplasia, horse shoe kidney, ectopic kidney, PUJO, vesicoureteric reflux, megaureters, obstructive uropathy, and neurogenic bladder. The overall incidence of CAKUT in all pregnancies is around 0.5%, with a higher predisposition in male fetuses.[1] Familial occurrence of the condition is rather uncommon.

Various theories have been proposed for the occurrence of a wide anatomical spectrum of renal anomalies. These include a stress on the developing kidney due to partial obstruction of the outflow tract and ectopic budding of the ureters from the Wolffian ducts. Recently, it has been proposed that a primary defect in the interaction at the cellular level between the ureteric bud and metanephric mesoderm may result in CAKUT.[3] Although developmental errors in many areas can result in CAKUT, the most implicated processes are induction of metanephric kidney, establishment of urinary conduit, and maturation of pyeloureteral peristaltic mechanisms.[4] Anomalies in metanephric kidney induction may result in renal hypoplasia, renal agenesis, ectopic and supernumerary ureters and a range of other defects. Glial-derived neurotrophic factor (GDNF) is one of the most important proteins expressed in the metanephric mesenchyme. This along with another receptor GDNF-family receptor α1 is involved in induction of ureteric bud growth. Mutations of this gene result in renal agenesis or severe dysplasia. Vitamin A-dependant Ret gene is involved in ureteric growth and its abnormality may result in upper urinary tract obstruction. The pyeloureteral persistaltic mechanisms are primarily initiated by pacemaker cells that are likely to be specialized smooth muscle cells in the renal pelvis and ureters. Abnormality of these may result in PUJO and megaureters.[4]

A number of syndromes that involve multiple organ anomalies, including that of the kidney and urinary tract, have been identified with specific inheritance patterns. However, the genetics of isolated CAKUT are less well defined. PAX 2, a paired-box transcription factor gene, has been identified as the first specific gene associated with the occurrence of CAKUT, especially vesicoureteric reflux.[5] Abnormalities of another gene angiotensin2 receptor (Agtr2) have been recently shown to be associated with the occurrence of CAKUT.[6]

Most patients having pelviureteric junction abnormalities have a unilateral lesion. Occurrence of bilateral PUJO is rare. We came across only a single case report of siblings with pelviureteric junction abnormality.[7] The siblings in the present report had bilateral PUJO. Bilateral pyeloplasties stabilized the renal disease in both brothers.

Posterior urethral valves are the most common cause of lower urinary tract obstruction in boys. This condition is observed in 1 in 8,000–25,000 births. About one-third of all children born with PUV progress to end-stage renal disease. Ten cases of PUV in two siblings and 13 cases in twins have been identified in the literature till date, often with a variable phenotype.[8–10]

Genetic factors in PUV are poorly understood. Recessive inheritance in a subgroup of patients with PUV is supported by a higher incidence of the condition in populations with an elevated background rate of consanguinity.[11] Our patients were, however, born of a non-consanguineous marriage.

Screening of family members, especially siblings, is recommended for renal cystic diseases, vesicoureteric reflux, or a family history of renal disease. A sonography of the abdomen is often sufficient as a screening tool for identifying CAKUT. Antenatal screening is especially important if a previous child was born with CAKUT. A good level II scan in the second trimester can identify most renal and urinary tract abnormalities. Genetic counseling is recommended for all patients with familial cases of CAKUT or newly diagnosed forms of CAKUT that suggest the presence of genetic anomalies.[6] Conditions such as PUJO or PUV are less likely to recur. However, if more than one child in the family is afflicted, the others too should be screened.

To have siblings with CKD imposes a great burden of care on the family, especially in a resource-poor setting like ours. The ideal management in such a situation is aimed at preventing the progression of CKD by early surgical intervention, treatment of hypertension, and correction of anemia and acidosis. In view of the limited finances of both these families, any form of renal replacement therapy is not feasible in the near future.

To conclude, the occurrence of similar structural abnormalities in these siblings is probably a result of genetic and other modifying influences, rather than a mere coincidence.