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 (
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
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
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
. 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
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.
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
described by Salamanca et al.
, 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
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
, and both genes have a sim-
ilar prevalence and clinical features
. 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
, 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
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
DOI: 10.1002/uog.7731
1. Currarino G. Normal variants and congenital anomalies in the
region of the obelion. Am J Roentgenol 1976; 127: 487494.
2. Pang D, Lin A. Symptomatic large parietal foramina. Neuro-
surgery 1982; 11: 3337.
3. Reddy AT, Hedlund GL, Percy AK. Enlarged parietal foramina:
association with cerebral venous cortical anomalies. Neurology
2000; 54: 11751178.
4. Fernandez G, Hertzberg BS. Prenatal sonographic detection of
giant parietal foramina. J Ultrasound Med 1992; 11: 155157.
5. Fink AM, Maixner W. Enlarged parietal formina: MR imaging
features in the fetus and neonate. Am J Neuroradiol 2006; 27:
6. Salamanca A, Gonzalez-Gomez F, Padilla MC, Motos MA,
Zorrilla F, Sabatel RM. Prenatal sonographic appearance
of formina parietalia permagna. Prenat Diagn 1994; 14:
7. Valente M, Valentine KD, Sugayama SSM, Kim CA. Malfor-
mation of cortical and vascular development in one family
with parietal foramina determined by an ALX4 homeobox gene
mutation. AJNR Am J Neuroradiol 2004; 25: 18361839.
8. Wilkie AOM, Mavrogiannis LA. Enlarged Parietal Foram-
ina/Cranium Bifidum.In:GeneReviews [http://www.ncbi.nlm.
=gene&part=msx2], Pagon RA,
Bird TC, Dolan CR, Stephens K (eds). University of Washing-
ton: Seattle, WA, 2004; Mar 30 [updated 2010 Mar 30].
9. Mavrogiannis LA, Taylor IB, Davies SJ, Ramos FJ, Olivares JL,
Wilkie AOM. Enlarged parietal foramina caused by mutations
in the homeobox genes ALX4 and MSX2: from genotype to
phenotype. Eur J Hum Genet 2006; 14: 151158.
10. Wu YQ, Badano JL, McCaskill C, Vogel H, Potocki L,
Shaffer LG. Haploinsufficiency of ALX4 as a potential cause
of parietal foramina in the 11p11.2 contiguous gene-deletion
syndrome. Am J Hum Genet 2000; 67: 13271332.
11. Swarr DT, Bloom D, Lewis RA, Elenberg E, Friedman EM,
Glotzbach C, Wissman SD, Shaffer LG, Potocki L. Potocki-
Shaffer syndrome: comprehensive clinical assessment, review
of the literature, and proposals for medical management. Am
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
TS is an autosomal-dominant condition characterized
by the formation of benign hamartomas in multiple organ
. 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,
as a result of its unpredictable phenotypic expression
making a definitive diagnosis highly dependent on imaging
. Moreover, the diagnosis of the condition
during this period is important as it is associated with a
high incidence of perinatal morbidity and mortality
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%)
. Cortical tubers and
subependymal nodules are the two main types of central
nervous system lesions that occur in fetal and neonatal
; the former are located throughout the white
matter whilst the latter are found on the edges of
the ventricular system
. 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
Fetal ultrasound is not a very sensitive technique for
this purpose
, but MRI is capable of achieving a more
precise diagnosis of TS
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
. 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
and 4.82 mmol/L
). 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
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
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
on Biom
edica en Red de Enfermedades Raras
(CIBERER), ISCII, Barcelona, Spain
DOI: 10.1002/uog.7655
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:
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:
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
Gynecol 2008; 31: 289295.
6. Milunsky A, Ito M, Maher TA, Flynn M, Milunsky JM. Prena-
tal molecular diagnosis of tuberous sclerosis complex. Am J
Obstet Gynecol 2009; 200: 321.
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.
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
1993; 30: 424437.
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.
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.
  • [Show abstract] [Hide abstract] ABSTRACT: Abnormal placentation is responsible for most failures in pregnancy; however, an understanding of placental functions remains largely concealed from noninvasive, in vivo investigations. Magnetic resonance imaging (MRI) is safe in pregnancy for magnetic fields of up to 3 Tesla and is being used increasingly to improve the accuracy of prenatal imaging. Functional MRI (fMRI) of the placenta has not yet been validated in a clinical setting, and most data are derived from animal studies. FMRI could be used to further explore placental functions that are related to vascularization, oxygenation, and metabolism in human pregnancies by the use of various enhancement processes. Dynamic contrast-enhanced MRI is best able to quantify placental perfusion, permeability, and blood volume fractions. However, the transplacental passage of Gadolinium-based contrast agents represents a significant safety concern for this procedure in humans. There are alternative contrast agents that may be safer in pregnancy or that do not cross the placenta. Arterial spin labeling MRI relies on magnetically labeled water to quantify the blood flows within the placenta. A disadvantage of this technique is a poorer signal-to-noise ratio. Based on arterial spin labeling, placental perfusion in normal pregnancy is 176 ± 91 mL × min-1 × 100 g-1 and decreases in cases with intrauterine growth restriction. Blood oxygen level-dependent and oxygen-enhanced MRIs do not assess perfusion but measure the response of the placenta to changes in oxygen levels with the use of hemoglobin as an endogenous contrast agent. Diffusion-weighted imaging and intravoxel incoherent motion MRI do not require exogenous contrast agents, instead they use the movement of water molecules within tissues. The apparent diffusion coefficient and perfusion fraction are significantly lower in placentas of growth-restricted fetuses when compared with normal pregnancies. Magnetic resonance spectroscopy has the ability to extract information regarding metabolites from the placenta noninvasively and in vivo. There are marked differences in all 3 metabolites N-acetyl aspartate/choline levels, inositol/choline ratio between small, and adequately grown fetuses. Current research is focused on the ability of each fMRI technique to make a timely diagnosis of abnormal placentation that would allow for appropriate planning of follow-up examinations and optimal scheduling of delivery. These research programs will benefit from the use of well-defined sequences, standardized imaging protocols, and robust computational methods.
    Article · Oct 2015
  • undefined · undefined
  • undefined · undefined

  • undefined · undefined
  • undefined · undefined
  • undefined · undefined