Osaretin Pamela Aigbogun1, Noémie
Vancoppenolle1, Sandra Coppens2,
Martina Marangoni2, Elodie Elsen1,
Marie Cassart1,3, Caroline
Gounongbe1
Authors: Aigbogun Osaretin Pamela1:
osaretin.aigbogun@gmail.com
Noémie Vancoppenolle1 :
noemie.vancoppenolle@gmail.com
Co Authors: Sandra Coppens2 :
sandra.coppens@hubruxelles.be
Martina Marangoni2:
martina.marangoni@erasme.ulb.ac.be
Elodie Elsen1:
elsenelodie@hotmail.com
Marie Cassart1,3: marie.cassart@icloud.com
Caroline Gounongbe1:
caroline.gounongbe@stpierre-bru.be
Affiliation 1Department of Fetal Medicine, CHU Saint Pierre,
Brussels, Belgium 2 ULB Center of Human Genetics, Hôpital
Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels,
Belgium3 Department of Radiology and Fetal Medicine, Iris Sud
Hospitals, Brussels, Belgium
Correspondance Osaretin Pamela Aigbogun
Funding information No fund was allocated for this study.
Ethics The patient and her family gave their written consent for this
publication. This study has been approved by the ethics committee of CHU
Saint Pierre.
Data Availability statement Data available on request from the authors
Key clinical message Cystinuria is suspected antenatally by a hyperechogenic fetal colonic
content. We report the first prenatal case of autosomal dominant
SLC7A9-related cystinuria associated with isolated hyperechogenic
kidneys as the only prenatal sonographic sign.
Key words Cystinuria, nephropathies, prenatal diagnosis, genetic counselling
Introduction:
Urinary tract anomalies represent approximately 20% of the fetal
malformations [1]. Hyperechogenic kidneys are defined as a renal
parenchyma more echogenic than the adjacent liver or spleen. It is
encountered in 1.6 out of 1000 prenatal sonographic examinations
[2].
Hyperechogenic fetal kidneys have several etiologies such as metabolic
diseases (like idiopathic infantile hypercalcemia) [3,4], congenital
viral infection [4,5], renal tubular dysgenesis, congenital
nephrotic syndromes [4,6,7]. Fetal hyperechogenic kidneys can also
be associated with congenital anomalies of the kidney and the urinary
tract (CAKUT) [8], autosomal dominant and recessive polycystic
kidney disease (ADPKD and ARPKD) and genetic anomalies as HNF1βmutation [9-11].
The etiology and prognosis of hyperechogenic kidneys remain challenging
[12-15]. However, the presence of oligohydramnios is an associated
poor prognostic factor [1,12-14].
Cystinuria is a hereditary tubulopathy characterized by insufficient
reabsorption of dibasic amino acids (COLA: cystine, ornithine, lysine,
arginine); associated with increased urinary excretion of COLA and
possible lithiasis formation in early childhood and adolescence which
leads to progressive deterioration of renal function in 80% of patients
[16-18].
We report an atypical prenatal case of autosomal dominantSLC7A9 -related cystinuria associated with isolated hyperechogenic
kidneys. To our knowledge, only prenatal cases with hyperechogenic colon
have been reported in this context [19-21].
Case history:
A 36-year-old Caucasian woman was referred at approximately 22 weeks of
gestation for isolated hyperechogenic kidneys. The fetus was eutrophic
for gestational age (Figure 1).
An early ultrasound screening at 12 weeks and 5 days was reported
normal. The non-invasive prenatal testing, known as NIPT, was offered as
part of the first trimester screening for Down syndrome, trisomy 13 and
18 and was normal for a female fetus.
The patient did not present any health problem, her body mass index was
within the normal range, and she didn’t develop gestational diabetes.
She did not use tobacco, alcohol, or drugs. The patient was not
immunized against toxoplasmosis or cytomegalovirus (CMV).
The patient had two previous uneventful singleton pregnancies, with the
same partner. The couple is not related. The first two children are two
boys, one born by cesarean section for breech presentation, the second
born by normal delivery. The first boy is in good health. The second
still benefits from neurological follow-up for a suspicion of hereditary
spastic paraplegia inherited from the father (walking on toes).
Methods
For this pregnancy, the discovery of bilateral normal sized
hyperechogenic kidneys led to diagnostic hypotheses of a metabolic
disease, a HNF1β mutation or an infectious nephropathy (CMV).
The fetal medicine department team proposed an amniocentesis to the
couple, for prenatal genetic and microbiological analyses, which was
carried out at 22 weeks and 6 days, after parental consent. The CMV
screening was unfortunately not performed in the amniotic fluid.
However, the maternal serologies were negative and at birth, the CMV
serology of the umbilical cord blood sampling was also negative. The
quantitative fluorescence polymerase chain reaction for chromosomes 13,
18, 21, X and Y and the array comparative genomic hybridization excluded
chromosomal abnormalities and confirmed a female fetus.
Trio clinical exome sequencing (fetal and parental DNA samples)
identified the presence, at the heterozygous state, of the
c.313G>A p.(Gly105Arg) variant in the SLC7A9 gene,
inherited from the mother. This variant has been reported several times
in the literature in families with autosomal dominant cystinuria with
variable expressivity [22]. It is present in population databases at
a frequency of 0,05% at the heterozygous state [23]. Functional
testing demonstrated that this variant leads to an almost complete loss
of transport activity [24]. According to the American College of
Medical Genetics and Genomics guidelines, this variant has been
classified as pathogenic [25].
Besides the genetic screening, the couple underwent a renal ultrasound
which turned out to be normal. A maternal urine analysis demonstrated an
excessive excretion of COLA corresponding to a diagnosis of cystinuria.
The mother never had urolithiasis, while the maternal grandfather had
several episodes of urolithiasis. He declined genetic testing.
At 32 weeks 6 days, a cortico-medullary differentiation (CMD) appeared
associated with hyperechogenicity of the apex of the pyramids which were
hypothesized to correspond to intratubular deposits.
A monthly fetal ultrasound monitoring until 36 weeks of gestation was
proposed and accepted by the couple. At 35 weeks 6 days the kidneys were
still hyperechogenic, undifferentiated, and growing normally with a
bipolar diameter of 30 mm. During the follow-up, the bladder and the
amount of amniotic fluid remained within normal values. No other
morphological abnormality was identified, including the fetal colon.
(Figure 2)
Conclusions and Results
The pregnancy continued uneventfully. The patient was admitted for
spontaneous labor at 39 weeks and 6 days of gestation and had a
non-assisted vaginal delivery of a live female infant of 3190g with a
body length of 48cm. Apgar was 9/10/10, arterial pH was 7.23, base
excess was -3.9 mEq/L and lactate was 3.5 mmol/L.
The neonatal clinical examination was normal. Renal ultrasound performed
at 3 days of age demonstrated the presence of hyperechogenic areas at
the apex of the pyramids.
At one month of age, a renal ultrasound showed a significantly increased
medullar hyperechogenicity (Figure 3). Liquid chromatography tandem mass
spectrometry confirmed an increased urinary excretion of COLA consistent
with the diagnosis of cystinuria. However, the newborn presented a good
clinical course with no evidence of urinary complaints.
A follow-up with a nephropediatrician and a pediatric radiologist was
organized. The child was monitored by renal ultrasound every 3 months
during the first year of life, and every 6 months during the second year
of life. The last ultrasound scan performed at 2 years of age showed
kidneys with good bilateral renal trophicity but persistent reversed
cortico medullar differentiation. Until now, the child has been
asymptomatic with a normal renal function.
Discussion:
On prenatal ultrasound, the renal pattern should present a CMD from the
18th week of pregnancy, with an echogenic cortex and hypoechoic medulla.
It is important to note that this cortical echogenicity diminishes
progressively throughout pregnancy [4,17,26,27]. The diagnosis of
hyperechogenic kidneys can be made after 18 weeks of pregnancy, when the
cortical echogenicity of the kidneys is higher than that of the spleen
and liver [28]. This diagnosis must be followed by a careful
sonographic examination of the whole fetus to exclude signs of metabolic
diseases or associated anomalies like CAKUT. The prenatal work-up
includes detection of congenital infections and genetic testing.
Additional magnetic resonance imaging is not required for renal
parenchymal anomalies [29].
In our case, aneuploidies such as trisomies 21, 13 and 18, that may
present with hyperechogenic kidneys associated with cerebral, cardiac
and genital malformations [18,28], had already been excluded by
NIPT.
A polymerase chain reaction (PCR) on the amniotic fluid could have been
carried out to exclude a CMV infection possibly responsible of
hyperechogenic kidneys. Although this is not the most common sign
[5]. The most frequently encountered prenatal signs are intrauterine
growth restriction, cerebral ventriculomegaly, microcephaly,
intracranial calcifications, foetal hydrops, oligohydramnios or
polyhydramnios, hyperechogenic bowel and hepatic calcifications [8].
However, none of these signs have been observed in our case and the
umbilical cord blood sampling at birth confirmed the absence of
congenital CMV infection.
ARPKD and ADPKD have also been ruled out from our differential diagnosis
as they are hepatorenal diseases characterized by enlarged and
hyperechogenic kidneys. ARKPD is associated with oligohydramnios and
kidneys without CMD and ADPKD is associated with kidneys with an
increased CMD [12,30]. HNF1β mutation, which is the most
common cause of hyperechogenic kidneys, was excluded by genetic testing
[9,10].
Infantile hypercalcemia is a metabolic disease, also associated with
hyperechogenic kidneys. It is caused by autosomal recessive variants in
theCYP24A1 orSLC34A1 genes, and leads to the development of nephrocalcinosis
[3,4,31]. Genetic testing enabled us to rule out these etiologies.
As stated above, genetic testing is a key element in diagnostic
investigations of hyperechogenic kidneys and in prognostic assessment
[32]. In our case, it showed the presence of the variant
c.313G>A p.(Gly105Arg) in the SLC7A9 gene, in
heterozygous state, that the fetus and the mother both carry. Given the
family history and the genetic results, the diagnosis of autosomal
dominant SLC7A9 -related cystinuria has been retained. A urine
analysis of the newborn and the mother confirmed an excessive excretion
of cystine and dibasic amnio acids, although both subjects are
asymptomatic to this date. Individuals with cystinuria can present with
cystine urolithiasis, which manifests from childhood or adolescence,
with a potential deterioration in renal function [2]. This
tubulopathy is characterized by a defect in tubular reabsorption,
leading to abundant urinary excretion of COLA-type dibasic amino acids,
such as cystine, ornithine, arginine and especially lysine. The
prevalence of this pathology is 1/7000 and the average age of first
kidney stone is 13 [33]. The reason why urolithiasis begins
postnatally in childhood is that the pH of fetal urine is +/- 7,
preventing cystine stones formation. During childhood, the pH decreases,
giving rise to the clinical manifestations of urolithiasis [1,2].
Diagnosis is based on microscopic examination of a stone, the
observation of cystine crystals in morning urine or the high
concentration of COLA in 24-hour urine and/or the ratio of COLA to
creatinine [34].
Mutations in the SLC3A1 and SLC7A9 genes are implicated in
autosomal dominant and recessive forms of cystinuria. Autosomal dominant
transmission is associated with incomplete penetrance. The proteins
encoded by SLC3A1 and SLC7A9 associates to form the
rBAT/b(0,+) amino acid transporter that is required for the reabsorption
of cystine and dibasic amino acids in the proximal renal tubule and in
the small intestine. [22,34,35]
In many cases, the diagnosis of cystinuria is made postnatally following
recurrent urolithiasis in childhood. However, a hyperechogenic colon
(HEC) can be detected antenatally in a subset of patients before 36
weeks of gestation, with a high positive predictive value
[19-21,34]. Cystine crystals are excreted with fetal urine in the
amniotic fluid and are swallowed by the fetus. The defective
reabsorption of cystine in the small intestine leads to an accumulation
of cystine in the colon, that appears hyperechogenic [21]. However,
the reason why the hyperechogenic colon sign is only present in some
fetuses with cystinuria remains unknown. In cases of HEC, most mutations
are located in the SLC3A1 gene, while in postnatal cases, bothSLC3A1 and SLC7A9 can be mutated [21,36].
Cystinuria is an incurable disease, and recurrent cystine stones cause
significant morbidity, with a high risk of renal failure. Management is
based on dietary measures aimed at reducing cystine-saturated urine to
avoid stones. This requires a low amino acids diet such as methionine
and is largely consistent with a vegan diet. It is also important to
maintain a high fluid intake, with the aim of alkalinizing the urine (pH
7.5-8). As a last resort, urine alkalinization drugs as potassium
citrate and sodium bicarbonate may be proposed, with the aim of
dissociating the disulfide bridges of cystine molecules, which
influences stone dissolution [3]. In case of renal calculi,
treatment is mainly symptomatic, with the use of analgesics. If
treatment fails, ureteroscopy or extracorporeal shock wave lithotripsy
may be considered.
The differential diagnosis of hyperechogenic kidneys is wide which
render antenatal counselling challenging as clinical presentation range
from asymptomatic to early end-stage renal insufficiency. We report the
first prenatal case in which isolated hyperechogenic kidneys are the
only sonographic sign of congenital cystinuria: a diagnosis that should
therefore be considered in such a context. Hyperechogenic colonic
content is classically described as the leading feature of such a
condition [16,17]. Additional cases and data are still required to
better understand this atypical prenatal presentation.
Acknowlegdement: The authors would like to thank the teams of gynecologists and
pediatricians who collaborated on this clinical case.
Authors contributions: Aigbogun Osaretin Pamela and Noémie Vancoppenolle wrote the article
and equally contributed to this work. Sandra Coppens and Martina
Marangoni analyzed the genetics data. Elodie Elsen, Marie Cassart and
Caroline Gounongbe coordinated the final version of the manuscript.
Conflicts of interest disclosure None declared
ORCIDOsaretin Pamela Aigbogun https://orcid.org/0009-0009-7415-1008