diatrie 30 (2023) 240−246

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Review article

Cystic kidney diseases in children

J. De Groofa, A. Dachyb,c, L. Breysemd, D. Mekahlia,b,*
a
Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium
b
PKD Research Group, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
c
Department of Pediatrics, ULi
ege Academic Hospital, Li
ege, Belgium
d
Department of Pediatric Radiology, University Hospitals Leuven, Leuven, Belgium

A R T I C L E I N F O A B S T R A C T

Article History: Cystic kidney disease comprises a broad group of heterogeneous diseases, which differ greatly in age at onset,
Received 1 September 2022 disease manifestation, systemic involvement, disease progression, and long-term prognosis. As our under-
Revised 24 November 2022 standing of these diseases continues to evolve and new treatment strategies continue to emerge, correctly
Accepted 12 February 2023
differentiating and diagnosing these diseases becomes increasingly important. In this review, we aim to high-
Available online 14 April 2023
light the key features of the most relevant cystic kidney diseases, underscore important diagnostic character-
istics of each disease, and present specific management options if applicable.
Keywords:
© 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.
Kidney cyst
ARPDK
ADPKD
Nephronophthisis
Bardet−Biedl syndrome
tuberous sclerosis complex
HNF1-beta
Multicystic dysplastic kidney
Cystic dysplasia
Simple kidney cyst

1. Introduction
The incidence of cystic kidney diseases vary widely depending on
the underlying disease, ranging from 0.44 in 10,000 births for poly-
cystic kidney disease to 4.1 in 10,000 births for multicystic dysplastic
kidney (MCDK). Likewise, the clinical presentation is highly variable
with benign simple cysts at one end to chronic kidney disease (CKD)
at the other, and rarely even rapidly progressive disease leading to
kidney failure [1,2]. In the majority of cases there is a genetic base,
with a monogenic cause identified in 50−70% of children with two or
more cysts and/or increased echogenicity according to one study [3],
Abbreviations: ACE-i, angiotensin-converting enzyme inhibitors; ADPKD, autosomal
dominant polycystic kidney disease; AML, angiomyolipoma; ARB, angiotensin receptor
blocker; ARPKD, autosomal recessive polycystic kidney disease; CAKUT, congenital
anomalies of the kidney and urinary tract; CKD, chronic kidney disease; eGFR, esti-
mated glomerular filtration rate; HNF1 beta, hepatocyte nuclear factor-1-beta; MCDK,
multicystic dysplastic kidney; MODY, maturity onset diabetes of the young; mTOR,
mammalian target of rapamycin; mTORi, mammalian target of rapamycin inhibitor;
MVP, mitral valve prolapse; RCAD, renal cysts and diabetes syndrome; RCC, renal cell
carcinoma; UPJ, ureteropelvic junction; UVJ, ureterovesical junction; VEO-ADPKD, very
early onset autosomal dominant polycystic kidney disease
* Corresponding author at: Department of Pediatric Nephrology, University Hospi-
tals Leuven, Herestraat 49, B-3000 Leuven, Belgium.
E-mail address: djalila.mekahli@uzleuven.be (D. Mekahli).
and the diseases can be associated with a wide range of systemic
symptoms and extrarenal involvement [1,2].
Cystic kidney diseases can be classified in multiple ways and dif-
ferent systems have been proposed. For example, a distinction can be
made between cystic kidney diseases with a genetic base and spo-
radic cystic kidney diseases including MKDC and forms of cystic dys-
plasia and CAKUT [4]. Among the genetic kidney diseases, the
ciliopathies are the most common and include autosomal dominant
and autosomal recessive polycystic kidney disease (ADPKD and
ARPKD, respectively). Ciliopathies are characterized by the involve-
ment of the primary cilia, a microtubule-based, nonmotile cellular
structure, present throughout the body and involved in signal trans-
duction and regulation of planar cell polarity. Given the widespread
presence of cilia in different organs, genetic mutations interfering
with ciliary function can give rise to a multitude of manifestations,
most commonly involving the kidney, retina, liver, and brain [5].
In the developing and mature kidney, they play a role in regulating
cell proliferation and differentiation [6]. Because of misoriented,
increased proliferation, decreased apoptosis, and expression of a
secretory phenotype, cysts develop leading to replacement of the
normal renal parenchyma and disruption of renal homeostasis [5].
In this review, we aim to give an overview of the most relevant
cystic kidney diseases in childhood.

https://doi.org/10.1016/j.arcped.2023.02.005
0929-693X/© 2023 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.
J. De Groof, A. Dachy, L. Breysem et al.
2. Autosomal dominant polycystic kidney disease
ADPKD is the most common hereditary kidney disease with an
estimated prevalence ranging from 1 in 400 to 1 in 1000 live births.
It is also the fourth most common cause for kidney replacement
therapy worldwide, and accounts for 7−10% of patients with kidney
failure with a median age at onset of 60 years [7−9].
ADPKD is caused by mutations in the PKD1 (80−85%) and PKD2
genes (15%), coding for polycystin-1 and polycystin-2, respectively,
which are both components of the primary cilium. The disease is
characterized by the development of multiple kidney cysts in both
kidneys leading to progressive loss of kidney function. PKD1 muta-
tions are associated with a more rapid kidney disease progression
compared with PKD2 mutations [10]. More recently other genes have
been identified in a small percentage of patients (GANAB, DNAJB11,
ALG9) with generally milder disease manifestations in GANAB muta-
tions, while there is a need for further characterization in the latter
two [11].
ADPKD disease manifestations in children are often nonspecific
and include abdominal, flank, or back pain, which is reported in 16
−30% of cases [11]. Decreased urinary concentrating capacity − mani-
festing as polyuria, urinary frequency, and enuresis − is seen in up to
58% of patients. Gross hematuria occurs in 10−14% of patients before
the age of 16 years. Urinary tract infections can also occur. Nephroli-
thiasis and cyst infections are very rare in children [12].
Hypertension is increasingly recognized as an early, asymptom-
atic disease manifestation and occurs in about 20% of pediatric
patients [11]. One study using ambulatory blood pressure monitoring
found that almost 35% of ADPKD children displayed hypertension
and 18% of children had isolated nocturnal hypertension [13]. Hyper-
tension in ADPKD is multifactorial and besides cyst expansion caus-
ing ischemia and activation of the renin−angiotensin system, other
mechanisms have been described. Hypertension is associated with
increased renal cystic burden, increased total kidney volume (TKV),
faster decline in kidney function, and increased cardiovascular
morbidity and mortality. Classically, hypertension precedes kidney
function decline and thus represents a therapeutic target for early
intervention [11,12,14,15].
Mild proteinuria is seen in about 20% of pediatric patients with
ADPKD. It is an established risk factor for progression of CKD and rep-
resents another target for early intervention [11,16].
As a ciliopathy, ADPKD is associated with several extrarenal
manifestations including cysts in other organs such as the liver,
pancreas, heart, brain, and seminal vesicles. Liver cysts are rare in
children (<5%) and no severe hepatic manifestations have been
reported [12,16]. Mitral valve prolapse (MVP) has been reported in
up to 12% of children with ADPKD. However, in a recent retrospec-
tive cross-sectional analysis conducted in the United Kingdom,
102 echocardiography examinations were performed o children
with ADPKD (mean age, 10.3 years) and only one patient (0.98%)
was found to have true MVP, thus showing a lower prevalence
than previously reported [12,17]. These data need to be validated
by larger cohorts. Intracranial aneurysms, although an important
cause of early cardiovascular morbidity and mortality in adults,
are very rare in children. Therefore, routine screening is not rec-
ommended in children [12,16].
Since many patients remain asymptomatic until the age of onset
of kidney failure, the disease was historically considered to be an
“adult-onset” disease [16]. However, recent studies have shown that
a significant proportion of patients already develop symptoms during
childhood, including hypertension and proteinuria [13]. In addition, a
small proportion of children show very early onset ADPKD (VEO-
ADPKD) or unusually rapid disease progression. Combined with the
onset of novel therapeutic options, early recognition and manage-
ment of clinical symptoms in childhood are becoming increasingly
important [11].
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Archives de pediatrie 30 (2023) 240−246
The diagnosis of ADPKD is usually made through kidney ultra-
sound, performed either in the prenatal period or throughout life.
Prenatal manifestations of ADPKD include kidney enlargement and
hyperechoic kidneys with or without macroscopic cyst formation.
Prenatal radiographic presentation can mimic ARPKD or hepatocyte
nuclear factor-1-beta (HNF1-beta)-associated disease, although com-
pared with ARPKD, oligohydramnios is usually absent. Postnatal
ultrasound diagnosis is based on the presence of kidney cysts [18].
The presence of one or more cysts in children with a positive family
history is highly suggestive of ADPKD. However, in the absence of
kidney cysts, the diagnosis of ADPKD cannot be ruled out because
kidney cysts can develop until the age of 40 years [19].
In patients with a known family history of ADPKD, multiple
approaches for screening need to be discussed with the parents and
the mature child. Ultrasound is used most often, given that it is read-
ily available and noninvasive. Alternatively, genetic testing can be
offered, especially in families with a known mutation or for patients
with an unusual severe clinical course. A third option is to defer
screening and to monitor for disease manifestations (hypertension,
proteinuria), which can be done without uncovering the transmission
status [11].
In patients with incidentally discovered kidney cysts without a
family history of ADPKD, the first step is to screen parents (or grand-
parents if parents are under 40 years) for kidney cysts using ultra-
sound. If familial imaging is normal, further work-up for cystic
kidney diseases should be started [11].
Management of ADPKD in children is mainly based on dietary life-
style interventions (reduced salt intake, improvement of physical
activity, healthy body weight etc.) as well as control of hypertension
and proteinuria. Angiotensin-converting enzyme inhibitors (ACE-i)
or angiotensin receptor blockers (ARB) are the first-line therapy for
hypertension and/or proteinuria [16].
Other therapeutic options are currently under investigation in
children. The vasopressin antagonist (tolvaptan), which is currently
used in adults with rapid disease progression of ADPKD, is not yet
licensed for children. A large placebo-controlled trial to assess the tol-
erability and safety of tolvaptan in adolescents was recently termi-
nated and results are expected soon [7]. Mammalian target of
rapamycin (mTOR) inhibitors are not recommended as no benefit on
the estimated glomerular filtration rate (eGFR) could be demon-
strated in adult clinical trials, while it was associated with important
adverse effects. Likewise, somatostatin analogues are not recom-
mended. There is no consensus on the use of statins in combination
with ACE inhibitors as trial results are conflicting [16].
3. Autosomal recessive polycystic kidney disease
ARPKD is less common compared with ADPKD with an estimated
prevalence of 1 in 20,000 live births. Nevertheless, it remains an
important cause of kidney failure in the pediatric population as more
than 30% of patients will progress to kidney failure within the first
decade of life [1,20].
ARPKD is caused by mutations in the PKHD1 gene, encoding the
fibrocystin protein. It is expressed predominantly in the kidney, liver,
and pancreas. In the kidney, it is localized in the primary cilia, making
ARPKD part of the broader ciliopathy group of cystic kidney diseases
[20]. Mutation analysis of the PKHD1 gene can be helpful in predict-
ing the course of the disease, with, for example, a double truncating
mutation conferring a worse prognosis; however, more research is
needed to increase our understanding of the interaction of different
mutations [21]. In addition, a new gene, DZIP1L, was recently identi-
fied in a small subset of patients with often milder disease [22].
ARPKD usually manifests prenatally or in the neonatal period.
Typical findings include bilaterally enlarged kidneys with or without
oligohydramnios. In severe cases, oligohydramnios can lead to a Pot-
ter sequence with pulmonary hypoplasia. Kidney function at birth
J. De Groof, A. Dachy, L. Breysem et al.
varies widely and can sometimes even improve over the first months
of life [23]. The age at onset of kidney failure is highly variable too
and depends mostly on age at presentation, with patients who pres-
ent in the neonatal period developing kidney failure earlier in life.
Other kidney manifestations include hyponatremia, urinary tract
infections, renal calcifications, and systemic hypertension. Hyperten-
sion, in particular, can be severe, with a reported prevalence of 55
−75% and often already observed in the first months of life [20].
All patients with ARPKD have associated hepatobiliary disease
caused by a developmental ductal plate malformation. Intrahepatic
bile ducts become progressively dilated with possible cyst formation
(Caroli syndrome) and progressive portal tract fibrosis leads to portal
hypertension. Possible consequences are ascending cholangitis and
esophageal varices with risk of bleeding, both associated with signifi-
cant morbidity and mortality. No clear correlation between renal and
hepatic disease severity has been demonstrated [20].
The diagnosis is usually made through ultrasound. Typical ultra-
sound findings include bilaterally enlarged kidneys with heteroge-
neous parenchymal echogenicity, multiple small cysts (usually
smaller than in ADPKD), and loss of corticomedullary differentiation.
Although ultrasound is the most useful imaging tool, additional infor-
mation is often necessary to confirm the diagnosis (e.g., family his-
tory, genetic testing, etc.). The most important differential diagnoses
include VEO-ADPKD, HNF1-beta disease and other ciliopathies such
as nephronophthisis [18,20].
Neonatal prognosis and management usually depend on the
respiratory status, with a reported early mortality rate of 30−40%
related to pulmonary hypoplasia. With advances in neonatal support-
ive care, newer reports have shown better survival. After the neona-
tal period, 1-year survival rates of 92−95% have been reported for
patients who survive the first month of life [20,23,24].
First-line therapy for hypertension are ACE inhibitors or ARBs, and
often multiple agents are necessary [20]. If dialysis is necessary in the
neonatal or pediatric period, peritoneal dialysis is the mode of choice.
In patients with both severe kidney and hepatic involvement, com-
bined or sequential liver and kidney transplantation is possible, for
which ARPKD is one of the major pediatric indications [23].
Historically, unilateral or bilateral nephrectomy has been per-
formed in order to improve respiratory and/or nutritional difficulties
caused by compression by the enlarged kidneys. Improvements in
nutrition have indeed been reported after nephrectomy, although
the effects on respiratory function are less clear. These potential ben-
efits need to be weighed against the possible side effects. Important
disadvantages include expedited loss of kidney function and even
possible neurological sequelae secondary to arterial hypotension
after nephrectomy [20,23]. Currently, nephrectomy is not routinely
recommended and possible advantages and disadvantages need to
be carefully weighed, taking into account the kidney function decline
and the need for kidney replacement therapy early in life [24].
4. Nephronophthisis
Nephronophthisis is an autosomal recessive cystic kidney disease
and the most frequent genetic cause of kidney failure during the first
three decades of life, with a median age at onset of kidney failure of
13 years [25]. The incidence varies widely and is reported between 1
in 50,000 and 1 in 900,000 births with differences in incidence
around the world [26]. Clinically, three types are distinguished: an
infantile form with onset of kidney failure prior to 4 years of age as
well as a juvenile form and an adolescent form with median age at
onset of kidney failure of 13 years and 19 years, respectively [27].
Mutations in 26 genes have been identified, most of which localize to
the primary cilia. Yet in only one third of patients is a pathogenic
mutation found [5,26].
Mutations in NPHP1 are the most common and represent 20−25%
of identified cases [5]. It causes juvenile nephronophthisis, with
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Archives de pediatrie 30 (2023) 240−246
symptoms generally developing around 4−6 years of age. The first
signs are most commonly polyuria and polydipsia related to a
reduced urinary concentrating ability before the onset of decline in
GFR. Hematuria, proteinuria, and hypertension are absent or mild.
With progression of CKD, anemia, metabolic acidosis, and growth
retardation arise [28]. The diagnosis is suggested by renal ultrasound.
Kidneys are typically normal sized to small with bilaterally increased
echogenicity and loss of corticomedullary differentiation. At later
stages, small cysts can be present, typically at the corticomedullary
junction [18,28].
Infantile nephronophthisis, caused by mutations in NPHP2, is a
very rare cause of nephronophthisis. In contrast to the juvenile form,
severe hypertension is common. Ultrasound findings include
enlarged kidneys and cortical microcysts, sometimes already present
prenatally. Adolescent nephronophthisis is caused by mutations in
NPHP3 and is clinically similar to the juvenile-onset form with a later
onset of kidney failure [18,28]. In 10−20% of cases, nephronophthisis
is associated with extrarenal findings, including involvement of the
eyes, central nervous system, liver, or musculoskeletal system
[26,27]. Associated ophthalmologic manifestations are the most com-
mon. Retinitis pigmentosa, resembling Leber’s congenital amaurosis,
or late-onset retinal degeneration is present in about 10−15% of
patients (Senior−Loken syndrome). A less common form of ocular
involvement is seen in Cogan syndrome with oculomotor apraxia
(impaired horizontal gaze and nystagmus) [27].
Anomalies of the central nervous system are seen in Joubert syn-
drome, which is characterized by developmental delay, neonatal
breathing anomalies, muscular hypotonia, and ataxia. The most typi-
cal finding is demonstration of the “molar tooth sign” on magnetic
resonance imaging (MRI) of the brain, caused by cerebellar vermis
aplasia/hypoplasia and midbrain/hindbrain malformations [27].
Given this association, MRI of the brain is recommended in all
patients with nephronophthisis and developmental delay [18].
Liver involvement, characterized by liver fibrosis, can be found
isolated or in syndromic associations. Meckel−Gruber syndrome
(MGS), for example, is a lethal syndrome characterized by occipital
encephalocele, postaxial polydactyly, liver fibrosis, and cystic kidney
disease. Other syndromes include Joubert, Boichis, and Arima syn-
drome [27]. Screening abdominal ultrasound for liver fibrosis is thus
recommended in all patients [18].
Skeletal anomalies are also possible, the most common form being
Jeune syndrome, also known as asphyxiating thoracic dystrophy. Clini-
cal features include rib cage narrowing, sometimes severe enough to
cause respiratory failure, polydactyly, and brachydactyly [27].
Situs inversus can occur in patients with infantile nephronophthi-
sis, sometimes associated with ventricular septal defects or other
congenital heart defects [27].
Currently, no specific treatment exists for nephronophthisis.
Management includes supportive therapy and kidney replacement
therapy.
5. Bardet−Biedl syndrome
Bardet−Biedl syndrome (BBS) is a rare, autosomal recessive ciliop-
athy with a prevalence of around 1 in 100,000. A total of 21 BBS genes
have been identified, which account for 80% of cases. Mutations in
BBS1 are the most common and account for about 50% of cases. BBS
is primarily characterized by rod-cone dystrophy, polydactyly, obe-
sity, and genital anomalies with about 50% of patients developing
kidney anomalies [29]. Kidney manifestations include a wide range
of anomalies, including polycystic disease, hydronephrosis, atrophic
kidneys, dysplasia, loss of corticomedullary differentiation, or devel-
opmental anomalies (persistent fetal lobulation, horseshoe kidney,
ectopic kidneys, renal agenesis, renal duplicity). Prenatal ultrasound
often shows enlarged, hyperechoic kidneys without corticomedullary
differentiation [18,29]. About 8% of patients develop kidney failure in
J. De Groof, A. Dachy, L. Breysem et al.
early childhood with the majority needing renal replacement therapy
before the age of 5 years. Conversely, many patients with structural
kidney anomalies do not develop functional kidney disease. Treat-
ment is primarily supportive with aggressive management of diabe-
tes, hypertension, and metabolic syndrome to minimize an adverse
impact on organ systems already affected (eyes, kidneys) [29].
A phase 3 trial using setmelanotide, a potent melanocortin receptor
type 4 agonist for the management of obesity and hyperphagia in
BBS, has been recently completed and could become an additional
management option in the future [30].
6. Tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is a multisystem, autosomal
dominant syndrome characterized by hamartoma formation in multi-
ple tissues including the kidneys, brain, skin heart, and lungs. It has
an estimated incidence ranging from 1 in 6000 to 1 in 10,000, inde-
pendent of population, ethnicity, or sex. It is caused by loss-of-func-
tion mutations in the TSC1 or TSC2 genes, encoding for the proteins
hamartin and tuberin, respectively. Together they form a complex
that downregulates the mTOR pathway essential for cell prolifera-
tion. Mutations in TSC2 are more common, found in approximately
70% of patients and associated with a more severe phenotype com-
pared with TSC1 mutations, which are found in 15−20% of patients;
in 10−15% of patients no mutation is found. Even though TSC has a
dominant inheritance, 60−70% of mutations arise de novo. Further-
more, TSC shows variable expression with a highly variable disease
severity and spectrum of organ involvement even within families
[31,32].
Kidney lesions are among the leading cause of morbidity and mor-
tality in TSC [33]. The most common kidney manifestation of TSC are
angiomyolipomas (AML), characterized by abnormal growth of blood
vessels, smooth muscle cells, and fat cells. They start developing in
childhood and by adulthood; AMLs are reported in 50−80% of
patients [32,33]. Most are asymptomatic but can cause hematuria,
hypertension, and flank pain. The most common major complication
is spontaneous intralesional bleeding, which can be fatal. Risk factors
associated with spontaneous bleeding include the size of the lesion
(>3 cm), the speed of growth, and the presence of intralesional
aneurysms [32]. Approximately 5% of benign AMLs found are fat poor
and need to be differentiated from the more serious malignant epi-
thelioid AML and renal cell carcinoma (RCC), which have a more rapid
growth. Malignant tumors are reported in about 3% of patients and
although rare in children, they have been reported in this patient
group, even from a very young age [32,33].
Another major kidney manifestation are renal cysts, occurring in
30−45% of patients and varying from microcystic involvement to the
presence of multiple large cysts. A more severe, early-onset pheno-
type is seen with deletions of the adjacent TSC2 and PKD1 genes, con-
stituting the TSC2/PKD1 contiguous gene deletion syndrome,
reported to occur in 2−5% of patients [34].
A complete review of the extrarenal manifestations of TSC is
beyond the scope of this review but are briefly summarized here.
Neurological manifestations include characteristic brain lesions (cor-
tical tubers, subependymal nodules, and subependymal giant cell
astrocytomas) and patients have a high risk of developing epilepsy,
cognitive impairment, and developmental delay. Neurological mani-
festations are the most important determinant of morbidity and mor-
tality in early childhood [34]. Other manifestations include typical
skin lesions (angiofibromas, shagreen patches, focal hypopigmenta-
tion). Cardiac lesions (rhabdomyomas) can be detected in utero or in
early childhood in the majority of patients, can regress spontane-
ously, and are useful for early diagnosis. Lung involvement (lymphan-
gioleiomyomatosis) is seen in the majority of female patients [31].
International guidelines on diagnosis, surveillance, and manage-
ment have been recently reviewed [35]. The diagnosis can be either
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Archives de pediatrie 30 (2023) 240−246
genetic by identification of a pathogenic variant in either TSC1 or
TSC2 or based on a constellation of major and minor clinical findings.
Pursuing a genetic diagnosis before onset of clinical manifestations
can be beneficial to ensure adequate follow-up and treatment [35].
Follow-up of the kidney manifestations comprises regular assess-
ment of kidney function, screening for hypertension, and abdominal
imaging. MRI is the preferred imaging modality since fat-poor lesions
are easily missed on kidney ultrasound [18,35]. Multidisciplinary fol-
low-up is necessary for extrarenal manifestations.
Over the past years, mTOR inhibitors (mTORi) such as everolimus
and sirolimus have become the mainstay of treatment for large
(>3 cm) AMLs as they have been shown to reduce both tumor size
and vascularization [33]. Recently, analysis of data from the Tuberous
Sclerosis Registry to Increase Disease Awareness (TOSCA) database
confirmed the efficacy of mTOR inhibitors since no patients in the
study exhibited kidney hemorrhage after starting mTORis [36]. Addi-
tionally, mTORis have been shown to have beneficial effects on sube-
pendymal giant-cell astrocytoma and epilepsy burden [37].
For acutely hemorrhaging AMLs, selective embolization followed
by corticosteroids remains the preferred treatment. Nephrectomy is
to be avoided as this can contribute to progressive loss of kidney
function and development of kidney failure. For hypertension, ACE-I
are the first choice of treatment [35].
7. HNF1-beta-associated nephropathy
HNF1-beta-associated kidney disease is the most common mono-
genetic cause of kidney malformations, reported in 5−38% of patients
with congenital anomalies of the kidney and urinary tract (CAKUT)
[38]. HNF1-beta is a transcription factor, encoded by the HNF1-beta
gene and expressed in multiple organs, including the kidneys, uro-
genital tract, and pancreas, leading to a wide range of kidney and
extrarenal symptoms. Over 50 different mutations are described,
inherited in an autosomal dominant pattern, yet about 50% of muta-
tions arise de novo. In addition, the genotype−phenotype correlation
is poor and expression can be highly variable, even within the same
families [39,40].
Cystic kidney disease, including cystic dysplasia, is the predomi-
nant renal manifestation in pediatric and adult populations, seen in
up to 73% of patients. Other anatomical anomalies reported include
renal hypoplasia, horseshoe kidney, duplex kidney, hydronephrosis,
or kidney agenesis [39].
Kidney function can range from normal to kidney failure with
most typically a slowly progressive deterioration of the kidney func-
tion throughout life, with a faster decline noted in adulthood. Devel-
opment of kidney failure during childhood is rare; nevertheless, a
small subset of patients seem to have rapidly progressive loss of kid-
ney function and development of kidney failure early in life, almost
always related to severe, bilateral dysplasia [41]. One retrospective
study of 14 pediatric patients found progression to kidney failure in
six (43%) at a median age of 10.7 years with one patient manifesting
during the neonatal period [38].
Other kidney manifestations include hypomagnesemia secondary
to hypermagnesuria and hyperuricemia with possible early-onset
gout in severe cases [39].
Since HNF1-beta is expressed in a multitude of organs, including
the kidney, pancreas, and urogenital tract, mutations can result in a
variety of clinical manifestations. Most typically is the association
with maturity-onset diabetes of the young type 5 (MODY5), also
known as renal cysts and diabetes syndrome (RCAD). Other associated
features include pancreatic hypoplasia and exocrine pancreatic dys-
function. Urogenital tract malformations are also seen, most com-
monly in females as uterine or upper vaginal malformations.
Asymptomatic liver dysfunction, manifesting as elevated liver
enzymes, is another possible manifestation. Autism spectrum disor-
der has been reported more frequently in patients with HNF1-beta
J. De Groof, A. Dachy, L. Breysem et al.
mutations compared with the general population, but more research
in this area is necessary [39,42].
The diagnosis can be suggested based on ultrasound findings, but
genetic confirmation is necessary as ultrasound findings are nonspe-
cific. Prenatal ultrasound can be characterized by isolated bilateral
hyperechogenic kidneys [18].
Multiple screening tools have been developed to help decide
which patients to screen for HNF1-beta mutations with the goal of
reducing screening costs while not missing mutations. These are
based mainly on findings from kidney imaging and associated bio-
chemical anomalies [43,44].
There are currently no guidelines regarding the follow-up of
patients with a known HNF1-beta mutation and no consensus about
routine screening for possible associated anomalies. Transabdominal
ultrasound of the genital tract in girls is recommended [18]. Abdomi-
nal ultrasound for screening of pancreatic anomalies can be consid-
ered. Monitoring of uric acid levels in the prevention of gout may be
indicated in adolescent or adult patients as is follow-up for the devel-
opment of diabetes [40].
Fig. 1. Key findings of different cystic kidney diseases.
AML: angiomyolipoma; UT: urinary tract; MODY: maturity onset diabetes of the young; US: ultrasound; ARPKD: autosomal recessive polycystic kidney disease; ADPKD: autoso-
mal dominant polycystic kidney disease; MCDK: multicystic dysplastic kidney; HNF1B: hepatocyte nuclear factor 1-beta; TSC: tuberous sclerosis complex.
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Archives de pediatrie 30 (2023) 240−246
8. Multicystic dysplastic kidney
MCDK is the most prevalent cystic kidney disease, occurring in 1
in 4300 live births. It is the most common cystic disease diagnosed
antenatally with a 100% sensitivity rate of antenatal ultrasound for
diagnosing MCDK [1]. The condition is predominant in males and
characterized by multiple, noncommunicating kidney cysts without
intervening normal parenchyma [45]. By definition, there is no resid-
ual kidney function left. In bilateral cases, development of severe oli-
gohydramnios and Potter sequence lead to fetal demise. A substantial
proportion of patients with unilateral MCDK have associated anoma-
lies of the contralateral kidney, including vesicoureteral reflux, ure-
teropelvic junction (UPJ), and ureterovesical junction (UVJ) stenosis.
These anomalies need to be monitored given the risk of urinary tract
infection in a solitary kidney [46].
Naturally MCDKs tend to involute, either partially or completely
with the highest velocity of involution seen early in life. Additionally,
hypertension is rare and the malignancy risk is low and seems com-
parable to the general population. Conservative management is thus
J. De Groof, A. Dachy, L. Breysem et al.
the mainstay of treatment [46]. The contralateral kidney should be
monitored with serial ultrasound to ensure appropriate compensa-
tory hypertrophy. The frequency of monitoring depends on the
child’s age and the degree of compensatory hypertrophy with local
practices differing [18]. Patients with kidneys failing to show com-
pensatory hypertrophy are at increased risk for CKD and require
nephrological follow-up with monitoring of blood pressure and kid-
ney function [18,46].
9. Cystic dysplasia
Cystic dysplasia is defined by the presence of at least one kidney
cyst within a dysplastic kidney, typically being hyperechogenic and
smaller in size. Cystic dysplasia can be isolated, associated with other
anomalies of the urinary tract (e.g., posterior urethral valves), or asso-
ciated with other congenital anomalies such as VACTERL syndrome
[4]. It is important to differentiate it from MCDK because, contrary to
MCDK, in cystic dysplasia there is still functioning renal parenchyma.
Usually, the distinction can be made based on imaging findings [47].
10. Simple kidney cyst
Simple kidney cysts, although common in adulthood with
reported incidence rates of 20% by age 40 and 50% by age 50, are rare
in children and remain a diagnosis of exclusion. Incidentally discov-
ered simple renal cysts are reported in 0.22% of the pediatric popula-
tion and raise concern for progression to CKD or polycystic kidney
disease [48].
Incidentally discovered cysts are first classified according to the
modified Bosniak classification. Cysts are graded as simple or com-
plex cysts according to wall thickness, septations, presence of calcifi-
cation, and cyst content. Although rare in children, complex cysts can
be a manifestation of underlying malignancy and always require a
specific work-up first to rule out this possibility [18,49]. Another
important differential diagnosis includes calyceal diverticula, as
diverticula are associated with proper complications (the most
important being nephrolithiasis and febrile urinary tract infection)
and require a different management approach. When a calyceal cyst
is considered in the differential diagnosis and ultrasound is inconclu-
sive, MR urography can be used [50].
To date, there is no consensus on the optimal follow-up of inci-
dentally discovered simple kidney cysts in the pediatric population.
Rates of development of ADPKD have varied, with two retrospective
studies reporting a final diagnosis of ADPKD in 12.6% [51] and 16.7%
[52] of cases, and no malignancies were reported to occur in simple
cysts in both studies. Another study showed a prevalence of 22% of
CKD during follow-up of simple cysts without a definitive diagnosis
made, highlighting the need for follow-up [53]. In simple cysts with-
out associated features, conservative management is the mainstay of
treatment with surgery only indicated for large, compressive cysts
[54].
11. Conclusion
Childhood cystic kidney diseases comprise a highly heteroge-
neous group of disorders, with considerable clinical overlap, making
the diagnosis challenging. Ultrasound is a first-line diagnostic tool for
the differential diagnosis. Combined with clinical symptoms and
(next-generation) genetic testing, a diagnosis can most often be
established and can help with appropriate management (Fig. 1).
Declaration of Competing Interest
None.
245
Archives de pediatrie 30 (2023) 240−246
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