Gene Map Locus: 16p13.31-p13.12
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Age at onset of renal failure is variable, even within families.
Shokeir (1978) described families with
typical adult cystic kidney disease in which single individuals died
early in life from polycystic renal disease.
Zerres et al. (1985) suggested that early
manifestation of APKD may aggregate in families because of genetic
modifier(s).
They diagnosed such a case in utero by ultrasound.
A brother and a cousin also had early manifestation.
Reeders (1986) described a phenomenal family
ascertained through a fetus found incidentally on ultrasonography
to have polycystic kidney disease.
Adults had more conventional PKD in an autosomal dominant pedigree
pattern.
This is a situation comparable to the ascertainment of familial tuberous
sclerosis by the finding of cardiac rhabdomyomata on prenatal ultrasonography
(see 191100).
Among 321 offspring of probands with polycystic kidney disease, Ravine et al. (1991) identified 68 (21%) who
had ultrasound evidence of polycystic kidney disease.
Of this previously undiagnosed group, 25 (37%) had one or more treatable
complications at the time of diagnosis, including 20 cases of hypertension,
7 cases of impaired renal function, and 4 cases of bacterial urinary
tract infection.
The findings underscored the importance of screening at-risk family
members.
In 13 large Spanish families, Coto et al. (1992)
found that all subjects over the age of 30 who were shown by linkage
to carry the mutation had renal cysts by ultrasonography, whereas
40% of carriers of the mutation younger than 30 did not have renal
cysts.
Hypertension was found to be more frequent in those with renal cysts.
Wirth et al. (1987) studied 6 kindreds
in which polycystic kidney disease had early onset with cystic enlargement
of the kidneys detected by prenatal sonography in some cases and with
death soon after birth in several.
Linkage analysis indicated that the gene locus mutant in these families
is the same as that in standard adult-onset cases, i.e., the locus
on chromosome 16p.
Dalgaard (1963) found liver cysts in 43%
of 173 autopsied cases in Denmark.
In a review of cases, largely from the literature, Poinso
et al. (1954) found that polycystic kidneys occurred in 53% of
224 cases of polycystic livers.
Dalgaard (1963) said he had found a regular
transition from polycystic liver degeneration to the solitary liver
cyst in association with polycystic kidney.
Ellis and Putschar (1968) presented the
case of a 42-year-old woman with polycystic kidneys and portal hypertension
for which splenorenal shunt was performed.
Liver biopsy showed 'disseminated microcystic biliary hamartomas,
with congenital fibrosis.' The mother died with hypertension, renal
disease, and stroke at age 64.
Two of her sisters died of renal disease.
Two sisters of the proband were said to have polycystic kidney disease.
Congenital hepatic fibrosis may occur with normal kidneys or with
a variety of renal malformations, most often ectatic renal tubules
resembling medullary sponge kidneys (see polycystic kidney, infantile,
type I, 263200).
Terada and Nakanuma (1988) demonstrated
nonobstructive diffuse dilatation of intrahepatic bile ducts in 3
autopsy cases of autosomal dominant adult polycystic disease.
Meyenburg complexes and liver cysts not communicating with the biliary
tract lumen were also seen.
Jordon et al. (1989) described the very
rare association of Caroli disease with adult-type polycystic kidney
disease.
Caroli disease is a rare form of fibropolycystic disease of the hepatobiliary
system characterized by segmental cystic dilatation of intrahepatic
ducts and associated with intrahepatic cholelithiasis, cholangitis,
and hepatic abscesses.
It is found more commonly with other forms of cystic renal disease
(see 263200).
Telenti et al. (1990) reviewed 5 cases
of infected hepatic cyst in polycystic kidney disease together with
9 reported cases.
Clinical and laboratory features and the use of scanning techniques
facilitated diagnosis.
The treatment of choice was a combination of percutaneous drainage
and antimicrobial therapy.
Scheff et al. (1980) pointed out the high
incidence of diverticulosis and diverticulitis in patients with chronic
renal failure from polycystic disease.
Colonic diverticula affect about 80% of patients with end-stage renal
disease (Scheff et al., 1980), and colonic
perforation is rather frequent in these patients.
Ditlefsen and Tonjum (1960) described a
family in which there were 15 verified and 2 suspected cases of polycystic
kidney disease.
Six of the patients suffered from cerebral hemorrhage.
In 1 of the 6, aneurysm of the middle cerebral artery was verified.
Intracranial 'berry' aneurysm is a rather frequently associated malformation.
Levey et al. (1983) used decision analysis
to assess whether patients with polycystic renal disease should have
routine cerebral arteriography for intracranial aneurysms and prophylactic
surgery if an aneurysm is detected.
They concluded 'no' because the benefit exceeds 1 year only if the
prevalence of aneurysm exceeds 30%, the surgical complication rate
is 1% or less, and the patient is under 25 years of age.
Newer noninvasive tests, such as digital-subtraction angiography,
may change this decision.
To determine the prevalence of intracranial aneurysms, Chapman
et al. (1992) studied 92 subjects with autosomal dominant polycystic
kidney disease who had no symptoms or signs of any neurologic disorder.
High-resolution computed tomography (CT) was performed in 60 subjects,
4-vessel cerebral angiography in 21, and both procedures in 11.
In 4 of the 88 subjects in whom the radiologic studies were successfully
completed, intracranial aneurysms were found, as compared with the
prevalence of 1% reported for an angiographic study of the general
population.
Multiple aneurysms were found in 3 of the 4 subjects.
Chapman et al. (1992) concluded that an
increased frequency of asymptomatic intracranial aneurysms occurs
with polycystic kidney disease, although the 95% confidence interval
for their finding (0.1 to 9%) included the possibility of no difference
from the prevalence of 1% reported in the general population.
They recommended high-resolution CT as a screening test.
Chapman and Hilson (1980) suggested a relationship
between polycystic kidneys and abdominal aortic aneurysm.
Of 31 patients on chronic dialysis for polycystic kidneys, 3 had aortic
aneurysm.
Torra et al. (1996) examined this question
in detail by means of a sonographic study of the abdominal aorta in
139 ADPKD patients and in 149 healthy family members.
In both groups, an increase in aortic diameter related to age and
sex was found, the aortic diameter being wider in older men than in
women.
In ADPKD patients, neither a wider aortic diameter nor a higher prevalence
of abdominal aortic aneurysms could be found in any age group.
They concluded that, although these patients are prone to develop
aortic aneurysms because of hypertension and possibly associated connective
tissue disorders, abdominal aortic aneurysm does not appear to be
a frequent feature.
Hossack et al. (1988) used echocardiography,
including Doppler analysis, to assess the prevalence of cardiac abnormalities
in 163 patients with autosomal dominant polycystic kidney disease,
130 unaffected family members, and 100 control subjects.
In these 3 groups the prevalence of mitral valve prolapse was 26,
14, and 2%, respectively.
A higher prevalence of mitral regurgitation, aortic regurgitation,
tricuspid regurgitation, and tricuspid valve prolapse was also found
in the patients with polycystic kidney disease.
Hossack et al. (1988) interpreted these
findings as reflecting the systemic nature of polycystic kidney disease
and supporting the hypothesis that the disorder results from a defect
in the extracellular matrix and that the cardiac abnormalities are
an expression of that defect.
Emery et al. (1967) observed the coincidence of myotonic dystrophy (160900) and polycystic kidneys in at least 3 members of a family.
Zerres et al. (1984) gave a comprehensive
review of all forms of cystic kidney disease.
They suggested that since the Potter type III is pathogenetically
and genetically heterogeneous, the term should not be used synonymously
for autosomal dominant polycystic kidney disease.
Zerres et al. (1985) pointed out that patients
on longterm renal hemodialysis develop cystic kidneys that can be
nearly impossible to distinguish from autosomal dominant cystic kidney
disease.
Gabow (1993) reviewed all aspects of the
genetics, pathogenesis, clinical manifestations, and diagnosis of
autosomal dominant polycystic kidney disease.
She indicated that approximately 50% of patients have hepatic cysts
and that these increase with age.
Hypertension affects more than 80% of patients with end-stage renal
disease.
Renal failure is estimated to affect 45% of patients by the age of
60.
In the 10 families with a PKD1 mutation (i.e., linked to markers on
chromosome 16) reported by Parfrey et al. (1990),
46% of the members less than 30 years old who had a 50% risk of inheriting
a mutation had renal cysts, as compared with 11% of such members in
the 2 families without linkage (P less than 0.001).
In the PKD1 families, all 67 diagnoses made by ultrasonography were
confirmed by determination of the genotype as inferred from linkage.
Of the 48 members less than 30 years old who inherited the PKD1 mutation,
40 had renal cysts.
All 27 members 30 years old or older who inherited the mutation had
renal cysts, suggesting that the probability of a false-negative diagnosis
did not exceed 0.13 in this age group.
The mean age at onset of end-stage renal disease among members of
the PKD1 families was 56.7 +/- 1.9 years, as compared with 69.4 +/-
1.7 years among members of the unlinked families (P = 0.0025).
Hypertension and renal impairment were less frequent and occurred
later in the families without the PKD1 mutation.
In a survey in France involving 889 affected subjects, Simon
(1995) found no difference in the cumulative survival to end-stage
renal disease between males and females.
By the age of 50 years, 22% of the patients had ESRD, by the age of
58, 42%, and by the age of 73, 72%.
They found that males under 65 years of age have a rate of progression
toward renal failure that is significantly more rapid than in females
of the same age group.
The risk linked to gender disappeared after 65 years of age.
Somlo et al. (1993) described a family
in which an overlap connective tissue disorder (OCTD) cosegregated
with the chromosome 16-linked form of APKD.
The connective tissue phenotype in this family included aortic root
dilation, aortic and vertebral artery aneurysms with dissection, and
aortic valve incompetence, as well as pectus abnormalities, pes planus,
joint laxity, arachnodactyly, scoliosis, dolichostenomelia, and high
arched palate.
Two markers flanking the PKD1 region were tightly linked to both APKD
and OCTD, whereas there was no evidence for linkage with either fibrillin
gene FBN1 on chromosome 15 or FBN2 on chromosome 5.
Perrone (1997) led a discussion of extrarenal
manifestations of ADPKD.
The increased frequency of diverticular disease was reviewed, including
the increased risk of colonic perforation after renal transplantation.
The mechanism of this, as well as other extrarenal complications,
is unclear.
Begleiter et al. (1977) noted that ultrasound
is a valuable addition to our armamentarium for study of cystic kidney
families.
Sahney et al. (1982) suggested that when
an adult with end-stage renal disease due to polycystic kidneys is
encountered without previous genetic counseling (as was usually the
case in their experience), any children over 16 years of age should
have intravenous pyelography with nephrotomography; those with negative
studies should be tested periodically with ultrasonography until age
25 years.
Diagnosis by ultrasonography not only in adults but also in the fetus
was demonstrated by Zerres et al. (1982).
Sahney et al. (1983) recommended ultrasonography
as the initial screening method in asymptomatic relatives, followed
by intravenous pyelography if the sonogram is abnormal but not diagnostic.
Sedman et al. (1987) performed ultrasonography
or excretory urography in 154 children aged 18 years or younger from
83 families with APKD.
They concluded that those children diagnosed under 1 year of age may
have a deterioration of renal function early in life; however, those
identified in childhood by screening may have a benign early course.
In their opinion, the finding of a single renal cyst in a child in
an APKD family should be considered suggestive of the disease.
Further, with history, physical examination, and ultrasonography,
APKD may be identifiable in as many as two-thirds of affected subjects
during childhood.
From a study of 371 at-risk persons in 17 kindreds in Newfoundland,
Bear et al. (1984) estimated the probability
of clinical diagnosis of APKD to be 0.011 by age 20, 0.041 by age
30, 0.115 by age 40, 0.299 by age 50, and 0.404 by age 60 years (expected
= 0.50).
Ultrasonography of 172 asymptomatic at-risk persons showed definite
APKD in 60.
The probability of ultrasonographic detection of asymptomatic APKD
was estimated as 0.222, 0.657, and 0.855 at ages 5, 15, and 25 years,
respectively.
On the basis of further analyses, Bear et al.
(1992) stated that in 2 families in which the disorder was not
coinherited with chromosome 16 markers, only 11% of members aged less
than 30 years had kidney cysts and the mean age of onset of end-stage
renal disease was later (68.7 years) than for persons with the chromosome
16 form of the disease (56.3 years).
In PKD1 families, the age of onset of ESRD was unrelated to the sex
of the affected person but was earlier in persons inheriting the disease
from their mother than in those inheriting it from the father: 50.5
versus 64.8 years (P = 0.004).
In PKD1 families, resemblance in age of onset of ESRD was less within
than between families, and risk of false negative ultrasonographic
diagnosis appeared to be restricted largely to families in which ESRD
occurred relatively late.
Dobin et al. (1993) reported the results
of classic segregation analysis on 159 families with PKD.
They found that penetrance at the early ages of onset had increased
during the previous decade, presumably because of improvements in
renal imaging and consequent earlier age of diagnosis.
In their study, the mean age of diagnosis was estimated to be 20 years,
with a standard deviation of 15.94.
Over 70% penetrance was estimated by age 30 years, over 95% by 50
years, and 99% by 55 years.
The segregation ratio was not significantly different from 0.50, but
its confidence limits were broad: 0.36 to 0.64.
Neither transmission probability nor penetrance was significantly
influenced by gender.
The mutation was estimated to be 6.9 x 10(-5), consistent with the
previously observed high mutation rate for PKD.
Dobin et al. (1993) suspected, however,
that the mutation rate was overestimated in their study because it
neglected low penetrance alleles and phenocopies.
Ravine et al. (1994) used DNA linkage among
subjects from 128 sibships within 18 PKD1 families to assess ultrasound
sensitivity.
Currently used criteria (bilateral cysts with at least 2 in one kidney)
provided good sensitivity (88.5% at age 15-29 years and 100% at 30
years and above), but performance could be improved by less stringent
criteria in subjects aged 15-29 years and more stringent criteria
in older family members in whom simple renal cysts are frequent.
The presence of at least 2 renal cysts (unilateral or bilateral) in
individuals at risk and younger than 30 years may be regarded as sufficient
to establish a diagnosis; among those aged 30-59 years, the presence
of at least 2 cysts in each kidney may be required, and among those
aged 60 years and above, at least 4 cysts in each kidney should be
required.
Trent and Wallace (1989) and Vinet
et al. (1989) demonstrated that the presence of deletion type
alpha(+)-thalassemia is a potential source of error in DNA linkage
studies for PKD1.
The Caucasian family studied by Vinet et al.
(1989) had the leftward type of deletion alpha(+)-thalassemia
which, except for 1 case in a Mediterranean population (Troungos
et al., 1984), had been described only in Asiatic populations
(Winichagoon et al., 1984).
Hannig et al. (1991) reported on experiences
with presymptomatic testing for APKD by DNA linkage analysis on potential
renal donors among relatives of patients.
They emphasized that thorough counseling before DNA analysis (including
discussion of accuracy and possible testing outcomes of presymptomatic
diagnosis of APKD, diagnosis of noncarrier status, false paternity,
and noninformative study) was essential for informed consent and to
preserve confidentiality within the family.
Confidentiality of potential donors found presymptomatically to be
affected (with a 94% or greater probability) was especially difficult
to maintain.
Since the use of living, related donors for renal transplants provides
significant advantages over cadaver donors, Hannig
et al. (1992) focused on the fact that presymptomatic testing
to determine the PKD status of potential donors is an important consideration
and DNA linkage analysis is potentially more accurate than renal ultrasound
for prospective donors less than 30 years of age.
Hannig et al. (1992) found that of 5,026
renal transplants done in 1988, 390 (7.8%) involved a PKD1 recipient.
Only 7% of these 390 transplants used a living, related donor compared
to the 20% rate reported for all renal transplants.
DNA linkage studies were not used by any of the centers surveyed and
only 29% reported provision of risk counseling.
Hannig et al. (1992) suggested that this
represented an unfortunate failure to take full advantage of DNA testing.
In 13 large Spanish families, Coto et al. (1992)
found that all subjects over the age of 30 who were shown by linkage
to carry the mutation had renal cysts by ultrasonography, whereas
40% of carriers of the mutation younger than 30 did not have renal
cysts.
Breuning et al. (1990) recommended that
prenatal diagnosis of PKD by chorionic villus sampling should be attempted
only after the linkage phase of the DNA markers has been established
by haplotyping the index family.
Furthermore, the families should be of sufficient size to rule out
the rare form of PKD not caused by a mutation on 16p.
A survey by Hodgkinson et al. (1990) seemed to indicate that there would be little demand for prenatal diagnosis of this disorder on the basis of linkage or any other method.
Although APKD is typically a late-onset disorder, ultrasonography
has permitted the detection of the disorder in the newborn or infant
in some instances and occasionally even prenatally (Pretorius
et al., 1987; Ceccherini et al., 1989).
Turco et al. (1993) described a case of
bilateral microcystic kidneys being detected by fetal ultrasonography
at 20 weeks' gestation.
Polycystic kidneys were demonstrated at birth.
The mother and at least 14 other members of the family had typical
APKD.
In addition to the renal involvement, the newborn had complex skeletal
manifestations including bilateral complete syndactyly of the hands
and feet, bilateral polydactyly of the feet, and bilateral agenesis
of the tibia.
Molecular studies indicated that the infant had inherited the disease-bearing
chromosome 16 haplotype from his mother.