Thompson & Thompson Genetics in Medicine, 8th Edition

Case 37. Polycystic Kidney Disease (PKD1 and PKD2 Mutations, MIM 173900 and MIM 613095)

Autosomal Dominant


• Variable expressivity

• Genetic heterogeneity

• Two-hit hypothesis

Major Phenotypic Features

• Age at onset: Childhood through adulthood

• Progressive renal failure

• Renal and hepatic cysts

• Intracranial saccular aneurysms

• Mitral valve prolapse

• Colonic diverticula

History and Physical Findings

Four months ago, P.J., a 35-year-old man with a history of mitral valve prolapse, developed intermittent flank pain. He eventually presented to his local emergency department with severe pain and hematuria. A renal ultrasound scan showed nephrolithiasis and polycystic kidneys consistent with polycystic kidney disease. The findings from his physical examination were normal except for a systolic murmur consistent with mitral valve prolapse, mild hypertension, and a slight elevation of serum creatinine concentration. His father and his sister had died of ruptured intracranial aneurysms, and P.J.'s son had died at 1 year of age from polycystic kidney disease. At the time of his son's death, the physicians had suggested that P.J. and his wife should be evaluated to see whether either of them had polycystic kidney disease; however, the parents elected not to pursue this evaluation because of guilt and grief about their son's death. P.J. was admitted for management of his nephrolithiasis. During this admission, the nephrologists told P.J. that he had autosomal dominant polycystic kidney disease.


Disease Etiology and Incidence

Autosomal dominant polycystic kidney disease (ADPKD1, MIM 173900) is genetically heterogeneous. Approximately 85% of patients have ADPKD1 caused by mutations in the PKD1 gene; most of the remainder have ADPKD2 (MIM 613095) due to mutations of PKD2. A few families have not shown linkage to either of these loci, suggesting that there is at least one additional, as yet unidentified locus.

ADPKD is one of the most common genetic disorders and has a prevalence of 1 in 300 to 1 in 1000 in all ethnic groups studied. In the United States, it accounts for 8% to 10% of end-stage renal disease.


PKD1 encodes polycystin 1, a transmembrane receptor–like protein of unknown function. PKD2 encodes polycystin 2, an integral membrane protein with homology to the voltage-activated sodium and calcium α1channels. Polycystin 1 and polycystin 2 interact as part of a heteromultimeric complex.

Cyst formation in ADPKD appears to follow a “two-hit” mechanism similar to that observed with tumor suppressor genes and neoplasia (see Chapter 15); that is, both alleles of either PDK1 or PDK2 must lose function for cysts to form. Polycystin-1 and -2 likely contribute to fluid-flow sensation by the primary cilium in renal epithelium within the same mechanotransduction pathway. The mechanism by which loss of either polycystin 1 or polycystin 2 function causes cyst formation has not been defined but includes mislocalization of cell surface proteins of developing renal tubular cells (see Chapter 14).

Phenotype and Natural History

ADPKD may manifest at any age, but symptoms or signs most frequently appear in the third or fourth decade. Patients present with urinary tract infections, hematuria, urinary tract obstruction (clots or nephrolithiasis), nocturia, hemorrhage into a renal cyst, or complaints of flank pain from the mass effect of the enlarged kidneys (Fig. C-37). Hypertension affects 20% to 30% of children and nearly 75% of adults with ADPKD. The hypertension is a secondary effect of intrarenal ischemia and activation of the renin-angiotensin system. Nearly half of patients have end-stage renal disease by 60 years of age. Hypertension, recurrent urinary tract infections, male sex, and early age of clinical onset are most predictive of early renal failure. Approximately 43% of patients presenting with ADPKD before or shortly after birth die of renal failure within the first year of life; end-stage renal disease, hypertension, or both develop in the survivors by 30 years of age.


FIGURE C-37 Cross section of a kidney from a patient with autosomal dominant polycystic kidney disease showing large cysts and widespread destruction of the normal renal parenchyma. See Sources & Acknowledgments.

ADPKD exhibits both interfamilial and intrafamilial variation in the age at onset and severity. Part of the interfamilial variation is secondary to locus heterogeneity because patients with ADPKD2 have milder disease than patients with ADPKD1. Intrafamilial variation appears to result from a combination of environment and genetic background because the variability is more marked between generations than among siblings.

In addition to renal cysts, patients with ADPKD develop hepatic, pancreatic, ovarian, and splenic cysts as well as intracranial aneurysms, mitral valve prolapse, and colonic diverticula. Hepatic cysts are common in both ADPKD1 and ADPKD2, whereas pancreatic cysts are generally observed with ADPKD1. Intracranial saccular aneurysms develop in 5% to 10% of patients with ADPKD; however, not all patients have an equal risk for development of aneurysms because they exhibit familial clustering. Patients with ADPKD have an increased risk for aortic and tricuspid valve insufficiency, and approximately 25% develop mitral valve prolapse. Colonic diverticula are the most common extrarenal abnormality; the diverticula associated with ADPKD are more likely to perforate than those observed in the general population.


In general, ADPKD is diagnosed by family history and renal ultrasound examination. The detection of renal cysts by ultrasound examination increases with age such that 80% to 90% of patients have detectable cysts by 20 years, and nearly 100% have them by 30 years. If necessary for prenatal diagnosis or identification of a related kidney donor, the diagnosis can be confirmed by mutation detection in most families.

The management and treatment of patients with ADPKD focus on slowing the progression of renal disease and minimizing its symptoms. Hypertension and urinary tract infections are treated aggressively to preserve renal function. Pain from the mass effect of the enlarged kidneys is managed by drainage and sclerosis of the cysts.

Inheritance Risk

Approximately 90% of patients have a family history of ADPKD; only 10% of cases result from de novo mutations of either PDK1 or PDK2. Parents with ADPKD have a 50% risk of having an affected child in each pregnancy. If the parents have had a child with onset of disease in utero, the risk for having another severely affected child is approximately 25%. In general, however, the severity of disease cannot be predicted because of variable expressivity. For families in whom the mutation is known, prenatal diagnostic testing is available via amniocentesis or CVS.

Siblings and parents of patients with ADPKD also have an increased risk for disease. Renal ultrasonography is the recommended method for the screening of family members.

Questions for Small Group Discussion

1. Compare the molecular mechanism of cyst development in ADPKD with the development of neurofibromas in neurofibromatosis type 1.

2. Many mendelian diseases have variable expressivity that might be accounted for by modifier loci. How would one identify such loci?

3. Why is ADPKD occasionally associated with tuberous sclerosis? How might this illustrate a contiguous gene deletion syndrome?

4. How can ADPKD be distinguished from autosomal recessive polycystic kidney disease?

5. Linkage analysis of families segregating ADPKD requires the participation of family members in addition to the patient. What should be done if individuals crucial to the study do not want to participate?


Chang MY, Ong AC. New treatments for autosomal dominant polycystic kidney disease. Br J Clin Pharmacol. 2013;76:524–535.

Eccles MR, Stayner CA. Polycystic kidney disease—where gene dosage counts. F1000Prime Rep. 2014;6:24.

Harris PC, Torres VE. Polycystic kidney disease, autosomal dominant. [Available from]