Prenatal diagnosis of tuberous sclerosis and analysis using magnetic resonance spectroscopy

Article (PDF Available)inUltrasound in Obstetrics and Gynecology 36(4):522-4 · October 2010with15 Reads
DOI: 10.1002/uog.7655 · Source: PubMed
Ultrasound Obstet Gynecol 2010; 36: 521524
Published online in Wiley Online Library (wileyonlinelibrary.com).
Letters to the Editor
Enlarged parietal foramina: findings on prenatal
ultrasound and magnetic resonance imaging
A 35-year-old G2P1L1 woman of European descent,
whose pregnancy had been initially uncomplicated, under-
went fetal ultrasound at 21 weeks of gestation. This
examination showed large bilateral choroid plexus cysts
extending into the anterior horns and two focal occip-
ital protrusions. She was referred for suspicion of
fetal encephalocele (Figure 1) and reported a significant
family history of posterior calvarial defects (Figure 2).
She herself had two calvarial defects, each measuring
30 × 30 mm, at the posterior part of the parietal bones.
Fetal magnetic resonance imaging (MRI) at 22 weeks
of gestation demonstrated bilateral calvarial foramina
measuring 18.919.6 mm with cerebrospinal fluid-filled
protrusions not involving brain tissue. The remainder
of the fetal anatomy was normal. A male infant was
delivered at 39 weeks of gestation. The neonate had
an anterior fontanelle measuring 35 × 35 mm and a
posterior fontanelle measuring 5 × 5 mm. There were
bilateral parietal foramina joined across the midline,
located between the anterior fontanelle and the posterior
fontanelle. There was also a separation of 2 mm along
the lambdoid, sagittal and coronal sutures. The infant’s
growth and development were normal at 17-month
follow-up.
DNA analysis on the mother identified an R244W
(c.730C > T) mutation in the ALX4 gene. The mutation
was found to be located in helix II of the crucial DNA-
binding homeodomain. This is a novel mutation and we
believe it is the cause of the familial enlarged parietal
foramina.
Enlarged parietal foramina consist of symmetrical,
paired openings in the parietal bones, located close to
Figure 2 Family pedigree chart demonstrating the autosomal-
dominant mode of inheritance of enlarged parietal foramina
showing males (
), females ( ) and the fetus in our case ( ).
Shading indicates individuals known to have had parietal foramina.
the intersection of the sagittal and lambdoid sutures.
They are caused by insufficient ossification around the
parietal notch, which is normally completed by 20 weeks
of gestation
1
. The openings decrease in size with age, and
significant intrafamilial heterogeneity has been reported.
They are generally benign but have been reported
to be associated with abnormal venous anatomy and
seizures
2,3
.
The key to the diagnosis of enlarged parietal foramina
in our case was careful documentation of family history
(five generations were affected) and examination of
affected family members (the mother and her elder
daughter). The bilaterality of the protrusions, as seen on
the fetal ultrasound scan, also points to this diagnosis
as encephalocele and meningocele are almost always
in the midline, or in some exceptional circumstances,
unilateral. A few prenatally detected cases of enlarged
Figure 1 (a) Axial ultrasound image through the level of the thalamus in a 21-week fetus, showing normal anatomy and head shape at this
level. (b) Oblique axial ultrasound through the convexity showing bilateral enlarged parietal foramina (arrows). (c) Sagittal magnetic
resonance image showing parietal calvarial foramina measuring 18.919.6 mm with a 6.7-mm cerebrospinal fluid-filled protrusion (arrow).
There was no brain tissue protruding and the rest of the brain appeared structurally normal.
Copyright
2010 ISUOG. Published by John Wiley & Sons, Ltd. L E TT ER S T O TH E E D I TO R
522 Letters to the Editor
parietal foramina have been reported
4–6
.Inthecase
described by Salamanca et al.
6
, family history could be
traced back three generations along the paternal side,
indicating the importance of including the father in the
evaluation. Recognition of this condition is important
as it alleviates anxiety associated with ‘suspected
encephalocele’ and allows minimization of head trauma
at delivery. Fetal MRI can be offered to confirm the
diagnosis and rule out alternative diagnoses and possible
associated intracranial venous anomaly and cortical
dysplasia
3,7
.
Enlarged parietal foramina is an autosomal-dominant
condition, and two genes – MSX2 and ALX4 – have
been reported to be associated with the condition.
DNA sequencing detected heterozygous mutations in
up to 80% of the cases, especially in those with a
positive family history
8,9
, and both genes have a sim-
ilar prevalence and clinical features
9
. Genetic testing
can confirm the prenatal diagnosis, especially if the
familial mutation is known. It is important to include
fluorescence in situ hybridization (FISH) and/or mul-
tiplex ligation-dependent probe amplification (MLPA)
in the investigation, especially for the ALX4 gene,
to rule out 11p11.2 microdeletion or PotockiShaffer
syndrome
10,11
, characterized by enlarged parietal foram-
ina, multiple exostosis (caused by deletion of the
EXT2 gene) and mental retardation. This has great
impact on genetic counseling as the prognosis is very
different.
H. Y. B. Chung†‡, T. Uster-Friedberg†§, S. Pentaz¶,
S. Blaser**, K. Murphy§ and D. Chitayat*†§
Department of Obstetrics and Gynecology,
The Prenatal Diagnosis and Medical Genetics Program,
The Ontario Power Generation Building, 700 University
Avenue, Room 3292, M5G 1Z5, §Department of
Obstetrics and Gynecology, Mount Sinai Hospital,
University of Toronto, Department of Medical
Imaging, Mount Sinai Hospital and University Health
Network, University of Toronto and Division of
Clinical and Metabolic Genetics, Department of
Pediatrics and **Division of Neuroradiology,
Department of Pediatrics, Hospital for Sick Children,
University of Toronto, Toronto, Ontario, Canada
*Correspondence.
(e-mail: dchitayat@mtsinai.on.ca)
DOI: 10.1002/uog.7731
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JMedGenet2010; 152A: 565572.
Prenatal diagnosis of tuberous sclerosis and
analysis using magnetic resonance spectroscopy
We report a case of a primigravida diagnosed with seven
fetal cardiac rhabdomyomas on a routine ultrasound
examination at 34 weeks (Videoclip S1, online). Under
the likely diagnosis of tuberous sclerosis (TS), fetal
neurosonography was performed but failed to detect signs
of brain involvement. Fetal brain magnetic resonance
imaging (MRI) was performed at 36 weeks using a 3.0-
T unit (Magnetom Trio Tim syngo, Siemens, Erlangen,
Germany). Half-Fourier acquisition single-shot turbo
spin-echo (HASTE) images were acquired in three planes
and revealed at least eight focal hypointense nodules in
the frontal and parietal cortex and in the periventricular
regions (Figure 1). Magnetic resonance spectroscopy
(MRS) was performed on the frontal tubers using
a voxel of 40 × 20 × 20 mm and repetition time/echo
time (TR/TE) of 2000/30 ms (Figure 2). Spectroscopic
data were analyzed in a user-independent manner using
the linear combination model (LC Model) method for
analysis of the spectra of metabolites. The spectroscopic
results showed low levels of N-acetylaspartate (NAA)
(1.523 mmol/L). The parents were counseled based
on the diagnosis of TS. The pregnancy resulted in
the spontaneous vaginal delivery, at 37 weeks, of a
male infant weighing 3040 g. The neonate had a
favorable immediate perinatal outcome, but suffered
several seizures during the first 6 months of postnatal
life.
TS is an autosomal-dominant condition characterized
by the formation of benign hamartomas in multiple organ
systems
1,2
. Historically, TS was most often diagnosed
in adolescence or adulthood and its diagnosis during
the fetal and neonatal period is considered challenging
Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 521524.
Letters to the Editor 523
Figure 1 Fetal magnetic resonance image showing an axial section
of the brain at the level of the thalami. Tubers in the frontal cortex
and in the periventricular area (arrows) were detected.
Figure 2 Fetal magnetic resonance spectroscopy of the frontal
cortex showing a number of different metabolic peaks. Cho,
choline; Cr, creatine; Ins, inositol; NAA,
N-acetylaspartate.
as a result of its unpredictable phenotypic expression
2
,
making a definitive diagnosis highly dependent on imaging
techniques
2
. Moreover, the diagnosis of the condition
during this period is important as it is associated with a
high incidence of perinatal morbidity and mortality
1
.
It has been reported that brain lesions are the most
prevalent sign of TS in the neonatal period, with
this finding observed in 47% of cases, followed by
cardiac rhabdomyomas (33%)
1
. Cortical tubers and
subependymal nodules are the two main types of central
nervous system lesions that occur in fetal and neonatal
TS
1,2
; the former are located throughout the white
matter whilst the latter are found on the edges of
the ventricular system
1
. The correct identification and
measurement of these lesions is key because there is
an association between the number and size of the
tubers and impaired neurodevelopmental outcome
1–6
.
Fetal ultrasound is not a very sensitive technique for
this purpose
4
, but MRI is capable of achieving a more
precise diagnosis of TS
3
.Inourcase,wealsousedMRS
in order to provide further information on the nature of
the fetal brain tumors. MRS is able to quantify the levels
of different metabolites within a tissue, such as NAA,
which is considered a neuronal marker
7
. If we compare
the metabolic spectra from this case with fetal brain
reference values, it is noteworthy that the NAA levels in
our case were significantly lower (1.52 mmol/L vs. means
of 5.03 mmol/L
8
and 4.82 mmol/L
9
). This is in line with
in vitro and in vivo MRS studies on adults and infants
with TS, which have also identified a significant reduction
in NAA
7,10
.
To conclude, and based on this experience, fetal
MRI offers a higher sensitivity for brain tubers.
Moreover, it seems that the known postnatal metabolic
profile of TS brain tubers is already identifiable
during prenatal life. Consequently, MRS might be
a useful tool for assessing fetal brain lesions based
on their metabolic spectrum. The utility of MRS
to predict impaired neurodevelopment merits further
consideration.
M. Sanz-Cortes*, J. M. Martinez, M. Bennasar,
B. Puerto and E. Gratacos
Maternal-Fetal Medicine Department, Institut Clinic de
Ginecologia, Obstetricia i Neonatologia (ICGON),
Fetal and Perinatal Research Medcine Group, Institut
d’Investigacions Biom
`
ediques August Pi i Sunyer
(IDIBAPS), University of Barcelona and Centro de
Investigaci
´
on Biom
´
edica en Red de Enfermedades Raras
(CIBERER), ISCII, Barcelona, Spain
*Correspondence.
(e-mail: msanz1@clinic.ub.es)
DOI: 10.1002/uog.7655
References
1. Isaacs H. Perinatal (fetal and neonatal) tuberous sclerosis: A
review. Am J Perinatol 2009; 26: 755760.
2. Datta AN, Hahn CD, Sahin M. Clinical presentation and
diagnosis of tuberous sclerosis complex in infancy. J Child
Neurol 2008; 23: 268273.
3. Levine D, Barnes P, Korf B, Edelman R. Tuberous sclerosis in
the fetus: Second-trimester diagnosis of subependymal tubers
with ultrafast MR Imaging. AJR Am J Roentgenol 2000; 175:
10671069.
4. M
¨
uhler MR, Rake A, Schwabe M, Schmidt S, Kivelitz D,
Chaoui R, Hamm B. Value of fetal cerebral MRI in sonograph-
ically proven cardiac rhabdomyoma. Pediatr Radiol 2007; 37:
467474.
5. Chao AS, Chao A, Wang TH, Chang YC, Chang YL, Hsieh CC,
Lien R, Su WJ. Outcome of antenatally diagnosed cardiac rhab-
domyoma: Case series and metaanalysis. Ultrasound Obstet
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7. Mukonoweshuro W, Wilkinson ID, Griffiths PD. Proton MR
Spectroscopy of cortical tubers in adults with tuberous sclerosis
complex. Am J Neuroradiol 2001; 22: 19201925.
Copyright
2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 521524.
524 Letters to the Editor
8. Kok RD, van den Bergh AJ, Heerschap A, Nijland R, van den
Berg PP. Metabolic information from the human fetal brain
obtained with proton magnetic resonance spectroscopy. Am J
Obstet Gynecol 2001; 185: 10111015.
9. Kreis R, Ernst T, Ross BD. Development of the human brain:
in vivo quantification of metabolite and water content with
proton magnetic resonance spectroscopy. Magn Reson Med
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10. Li LM, Cendes F, Bastos AC, Andermann F, Dubeau F, Arnold
DL. Neuronal metabolic dysfunction in patients with cortical
developmental malformations. A proton magnetic resonance
spectroscopic imaging study. Neurology 1998; 50: 755779.
SUPPORTING INFORMATION ON THE INTERNET
The following supporting information may be found in the online version of this article:
Videoclip S1 Ultrasound imaging of the fetal heart at 34 weeks. Multiple tubers were found in both ventricles.
Copyright 2010 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2010; 36: 521524.
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