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\begin{document}

\title{Prenatal diagnosis of cystinuria with a heterozygous pathogenic variant
in SLC7A9 gene associated with isolated hyperechogenic fetal kidneys: a
case report}



\author[1]{Osaretin Aigbogun}%
\author[1]{Noemie Vancoppenolle}%
\author[2]{Sandra Coppens}%
\author[2]{Martina Marangoni}%
\author[1]{Elodie Elsen}%
\author[1]{Marie Cassart}%
\author[1]{Caroline Gounongbe}%
\affil[1]{CHU Saint-Pierre}%
\affil[2]{Hopital Erasme}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\emph{TITLE PAGE:}

\emph{Prenatal diagnosis of cystinuria with a heterozygous pathogenic
variant in SLC7A9 gene associated with isolated hyperechogenic fetal
kidneys: a case report}

\selectlanguage{ngerman}\textbf{Osaretin Pamela Aigbogun\textsuperscript{1}, Noémie
Vancoppenolle\textsuperscript{1}, Sandra Coppens\textsuperscript{2},
Martina Marangoni\textsuperscript{2}, Elodie Elsen\textsuperscript{1},
Marie Cassart\textsuperscript{1,3}, Caroline
Gounongbe\textsuperscript{1}}

\emph{Authors:} Aigbogun Osaretin Pamela\textsuperscript{1}:
osaretin.aigbogun@gmail.com Noémie Vancoppenolle\textsuperscript{1}~:
noemie.vancoppenolle@gmail.com

\emph{Co Authors:} Sandra Coppens\textsuperscript{2~}:
sandra.coppens@hubruxelles.be Martina Marangoni\textsuperscript{2}:
martina.marangoni@erasme.ulb.ac.be Elodie Elsen\textsuperscript{1}:
elsenelodie@hotmail.com Marie Cassart\textsuperscript{1,3}:
marie.cassart@icloud.com Caroline Gounongbe\textsuperscript{1}:
caroline.gounongbe@stpierre-bru.be

\emph{Affiliation} \textsuperscript{1}Department of Fetal Medicine, CHU
Saint Pierre, Brussels, Belgium\emph{} \textsuperscript{2} ULB Center of
Human Genetics, Hôpital Universitaire de Bruxelles, Université Libre de
Bruxelles, Brussels, Belgium\textsuperscript{3} Department of Radiology
and Fetal Medicine, Iris Sud Hospitals, Brussels, Belgium

\emph{Correspondance} Osaretin Pamela Aigbogun

\emph{Funding information} No fund was allocated for this study.

\emph{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.

\emph{Data Availability statement} Data available on request from the
authors

\emph{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.

\emph{Key words} Cystinuria, nephropathies, prenatal diagnosis, genetic
counselling

\emph{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
\selectlanguage{greek}\emph{HNF1β}\selectlanguage{english}mutation {[}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 dominant\emph{SLC7A9}
-related cystinuria associated with isolated hyperechogenic kidneys. To
our knowledge, only prenatal cases with hyperechogenic colon have been
reported in this context {[}19-21{]}.

\emph{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).

\emph{Methods}

For this pregnancy, the discovery of bilateral normal sized
hyperechogenic kidneys led to diagnostic hypotheses of a metabolic
disease, a \selectlanguage{greek}\emph{HNF1β} \selectlanguage{english}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\textgreater{}A p.(Gly105Arg) variant in the \emph{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)

\emph{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.

\emph{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{]}. \selectlanguage{greek}\emph{HNF1β} \selectlanguage{english}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
the\emph{CYP24A1} or\emph{SLC34A1} 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\textgreater{}A p.(Gly105Arg) in the \emph{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 \emph{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 \emph{SLC3A1} and \emph{SLC7A9} genes are implicated in
autosomal dominant and recessive forms of cystinuria. Autosomal dominant
transmission is associated with incomplete penetrance. The proteins
encoded by \emph{SLC3A1} and \emph{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 \emph{SLC3A1} gene, while in postnatal cases,
both\emph{SLC3A1} and \emph{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.

\emph{Acknowlegdement:} The authors would like to thank the teams of
gynecologists and pediatricians who collaborated on this clinical case.

\emph{Authors contributions:} Aigbogun Osaretin Pamela and No\selectlanguage{ngerman}émie
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.

\emph{Conflicts of interest disclosure} None declared

\emph{ORCID}Osaretin Pamela Aigbogun
https://orcid.org/0009-0009-7415-1008

\emph{References:}

\begin{enumerate}
\tightlist
\item
  Emmanuelli V, Lahoche-Manucci A, Holder-Espinasse M, Devisme L, Vaast
  P, Dieux-Coeslier A, Dehennault M, Petit S, Besson R, Houfflin-Debarge
  V. Diagnostic anténatal des reins hyperéchogènes~: à propos de 17~cas
  {[}Prenatal diagnosis of hyperechogenic kidneys: A study of 17
  cases{]}. J Gynecol Obstet Biol Reprod (Paris). 2010 Dec;39(8):637-46.
\item
  Amat S, Czerkiewicz I, Benoist JF, Eurin D, Fontanges M, Muller F.
  Isolated hyperechoic fetal colon before 36 weeks' gestation reveals
  cystinuria. Ultrasound Obstet Gynecol. 2011 Nov;38(5):543-7.
\item
  De Paolis E, Scaglione GL, De Bonis M, Minucci A, Capoluongo E.
  CYP24A1 and SLC34A1 genetic defects associated with idiopathic
  infantile hypercalcemia: from genotype to phenotype. Clin Chem Lab
  Med. 2019 Oct 25;57(11):1650-1667.
\item
  Hureaux M, Molin A, Jay N, Saliou AH, Spaggiari E, Salomon R, Benachi
  A, Vargas-Poussou R, Heidet L. Prenatal hyperechogenic kidneys in
  three cases of infantile hypercalcemia associated with SLC34A1
  mutations. Pediatr Nephrol. 2018 Oct;33(10):1723-1729.
\item
  Yinon Y, Farine D, Yudin MH. No. 240-Cytomegalovirus Infection in
  Pregnancy. J Obstet Gynaecol Can. 2018 Feb;40(2):e134-e141.
\item
  Guttierez PB, \emph{Síndrome nefrótico en el primer año de vida} ,
  Anales de pediatria Continuada, Feb 2014 Vol. 12, 17-24
\item
  Gubler MC. Renal tubular dysgenesis. Pediatr Nephrol. 2014
  Jan;29(1):51-9.
\item
  Murugapoopathy V, Gupta IR. A Primer on Congenital Anomalies of the
  Kidneys and Urinary Tracts (CAKUT). Clin J Am Soc Nephrol. 2020 May
  7;15(5):723-731.
\item
  Fleischer A.C , Toy E.C., Lee W., Manning F.A. Romero
  R.\emph{Sonography in Obstetrics \& gynecology Principles and
  Practice} , Chapter 18: The fetal genitourinary system. 2011. Mac
  Graw-Hill Gb, 7\textsuperscript{th} edition.
\item
  Decramer S, Parant O, Beaufils S, Clauin S, Guillou C, Kessler S,
  Aziza J, Bandin F, Schanstra JP, Bellanné-Chantelot C. Anomalies of
  the TCF2 gene are the main cause of fetal bilateral hyperechogenic
  kidneys. J Am Soc Nephrol. 2007 Mar;18(3):923-33.
\item
  Pryde PG, Sedman AB, Nugent CE, Barr M Jr. Angiotensin-converting
  enzyme inhibitor fetopathy. J Am Soc Nephrol. 1993 Mar;3(9):1575-82.
\item
  Yulia A, Napolitano R, Aiman A, Desai D, Johal N, Whitten M, Ushakov
  F, Pandya PP, Winyard PJD. Perinatal and infant outcome of fetuses
  with prenatally diagnosed hyperechogenic kidneys. Ultrasound Obstet
  Gynecol. 2021 Jun;57(6):953-958..
\item
  Tsatsaris V, Gagnadoux MF, Aubry MC, Gubler MC, Dumez Y, Dommergues M.
  Prenatal diagnosis of bilateral isolated fetal hyperechogenic kidneys.
  Is it possible to predict long term outcome? BJOG. 2002
  Dec;109(12):1388-93.
\item
  Digby EL, Liauw J, Dionne J, Langlois S, Nikkel SM. Etiologies and
  outcomes of prenatally diagnosed hyperechogenic kidneys. Prenat Diagn.
  2021 Mar;41(4):465-477.
\item
  Mashiach R, Davidovits M, Eisenstein B, Kidron D, Kovo M, Shalev J,
  Merlob P, Vardimon D, Efrat Z, Meizner I. Fetal hyperechogenic kidney
  with normal amniotic fluid volume: a diagnostic dilemma. Prenat Diagn.
  2005 Jul;25(7):553-8.
\item
  Eggermann T, Venghaus A, Zerres K. Cystinuria: an inborn cause of
  urolithiasis. Orphanet J Rare Dis. 2012 Apr 5;7:19.
\item
  Dello Strologo L, Rizzoni G. Cystinuria. Acta Paediatr Suppl. 2006
  Jul;95(452):31-3.
\item
  Haymann JP., Livrozet M., Rode J., Doizi S., Traxer O., Frochot V., et
  al. La cystinurie et ses traitements\selectlanguage{english} : une approche
  physiopathologique. \emph{Prog En Urol.} Mars 2021
\item
  Brasseur-Daudruy M, Garel C, Brossard V, Broux F, Heckettsweiler B,
  Eurin D. Hyper-echogenic colon: a prenatal sign of cystinuria? Prenat
  Diagn. 2006 Dec;26(13):1254-5.
\item
  Buxmann H, Eggermann T, Lorenz D, Sewell AC, Bohles H, Schlosser RL,
  Merz E. Cystinuria in a girl presenting with a hyperechogenic colon
  detected by prenatal ultrasonography and a new SLC3A1 gene mutation
  (p.Phe278Ser). Ultraschall Med. 2014 Oct;35(5):473-4.
\item
  Tostivint I, Royer N, Nicolas M, Bourillon A, Czerkiewicz I, Becker
  PH, Muller F, Benoist JF. Spectrum of mutations in cystinuria patients
  presenting with prenatal hyperechoic colon. Clin Genet. 2017
  Dec;92(6):632-638.
\item
  Font-Llitjos M, Jimenez-Vidal M, Bisceglia L, Di Perna M, de Sanctis
  L, Rousaud F, Zelante L, Palacin M, Nunes V. New insights into
  cystinuria: 40 new mutations, genotype-phenotype correlation, and
  digenic inheritance causing partial phenotype. J Med Genet. 2005
  Jan;42(1):58-68.
\item
  GnomAD v4.0
  https://gnomad.broadinstitute.org/news/2023-11-gnomad-v4-0/ (issued
  November 1\textsuperscript{st} 2023)
\item
  Font MA, Feliubadalo L, Estivill X, Nunes V, Golomb E, Kreiss Y, Pras
  E, Bisceglia L, d'Adamo AP, Zelante L, Gasparini P, Bassi MT, George
  AL Jr, Manzoni M, Riboni M, Ballabio A, Borsani G, Reig N, Fernandez
  E, Zorzano A, Bertran J, Palacin M; International Cystinuria
  Consortium. Functional analysis of mutations in SLC7A9, and
  genotype-phenotype correlation in non-Type I cystinuria. Hum Mol
  Genet. 2001 Feb 15;10(4):305-16.
\item
  Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW,
  Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory
  Quality Assurance Committee. Standards and guidelines for the
  interpretation of sequence variants: a joint consensus recommendation
  of the American College of Medical Genetics and Genomics and the
  Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24.
\item
  Gunay-Aygun M. Liver and kidney disease in ciliopathies. Am J Med
  Genet C Semin Med Genet. 2009 Nov 15;151C(4):296-306.
\item
  Avni FE, Garel C, Cassart M, D'Haene N, Hall M, Riccabona M. Imaging
  and classification of congenital cystic renal diseases. AJR Am J
  Roentgenol. 2012 May;198(5):1004-13.
\item
  Chaumoitre K, Brun M, Cassart M, Maugey-Laulom B, Eurin D, Didier F,
  Avni EF. Differential diagnosis of fetal hyperechogenic cystic kidneys
  unrelated to renal tract anomalies: A multicenter study. Ultrasound
  Obstet Gynecol. 2006 Dec;28(7):911-7.
\item
  Gimpel C, Avni FE, Bergmann C, Cetiner M, Habbig S, Haffner D, Konig
  J, Konrad M, Liebau MC, Pape L, Rellensmann G, Titieni A, von
  Kaisenberg C, Weber S, Winyard PJD, Schaefer F. Perinatal Diagnosis,
  Management, and Follow-up of Cystic Renal Diseases: A Clinical
  Practice Recommendation With Systematic Literature Reviews. JAMA
  Pediatr. 2018 Jan 1;172(1):74-86.
\item
  Brun M, Maugey-Laulom B, Eurin D, Didier F, Avni EF. Prenatal
  sonographic patterns in autosomal dominant polycystic kidney disease:
  a multicenter study. Ultrasound Obstet Gynecol. 2004 Jul;24(1):55-61.
\item
  Pronicka E, Ciara E, Halat P, Janiec A, Wojcik M, Rowi\selectlanguage{polish}ń\selectlanguage{english}ska E, Rokicki
  D, P\selectlanguage{polish}ł\selectlanguage{english}udowski P, Wojciechowska E, Wierzbicka A, Ksi\selectlanguage{polish}ąż\selectlanguage{english}yk JB, Jacoszek A,
  Konrad M, Schlingmann KP, Litwin M. Biallelic mutations in CYP24A1 or
  SLC34A1 as a cause of infantile idiopathic hypercalcemia (IIH) with
  vitamin D hypersensitivity: molecular study of 11 historical IIH
  cases. J Appl Genet. 2017 Aug;58(3):349-353.
\item
  Shuster S, Keunen J, Shannon P, Watkins N, Chong K, Chitayat D.
  Prenatal detection of isolated bilateral hyperechogenic kidneys:
  Etiologies and outcomes. Prenat Diagn. 2019 Aug;39(9):693-700.
\item
  Sadiq S, Cil O. Cystinuria: An Overview of Diagnosis and Medical
  Management. Turk Arch Pediatr. 2022 Jul;57(4):377-384.
\item
  Servais A, Thomas K, Dello Strologo L, Sayer JA, Bekri S,
  Bertholet-Thomas A, Bultitude M, Capolongo G, Cerkauskiene R, Daudon
  M, Doizi S, Gillion V, Gr\selectlanguage{ngerman}àcia-Garcia S, Halbritter J, Heidet L, van
  den Heijkant M, Lemoine S, Knebelmann B, Emma F, Levtchenko E;
  Metabolic Nephropathy Workgroup of the European Reference Network for
  Rare Kidney Diseases (ERKNet) and eUROGEN. Cystinuria: clinical
  practice recommendation. Kidney Int. 2021 Jan;99(1):48-58.
\item
  Dello Strologo L, Pras E, Pontesilli C, Beccia E, Ricci-Barbini V, de
  Sanctis L, Ponzone A, Gallucci M, Bisceglia L, Zelante L,
  Jimenez-Vidal M, Font M, Zorzano A, Rousaud F, Nunes V, Gasparini P,
  Palacín M, Rizzoni G. Comparison between SLC3A1 and SLC7A9 cystinuria
  patients and carriers: a need for a new classification. J Am Soc
  Nephrol. 2002 Oct;13(10):2547-53.
\item
  Fuchs F, Rodriguez A, Mousty E, Morin D, Roubertie A, Wells CF,
  Prodhomme O, Benoist JF, Dreux S, Faure JM, Willems M. Postnatal
  outcome of children with antenatal colonic hyperechogenicity. Prenat
  Diagn. 2024 Jan;44(1):28-34.
\end{enumerate}

\textbf{Hosted file}

\verb`Prenatal diagnosis of cystinuria with a heterozygous pathogenic variant in SLC7A9 gene associated with isolated hyperechogenic fetal kidneys. IMAGES.docx`  available at \url{https://authorea.com/users/763437/articles/740792-prenatal-diagnosis-of-cystinuria-with-a-heterozygous-pathogenic-variant-in-slc7a9-gene-associated-with-isolated-hyperechogenic-fetal-kidneys-a-case-report}

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