Autopsy Report of a 7-Year Old Patientwith the Mosaic Trisomy 13

George Imataka, Hideo Yamanouchi,
Junko Hirato, Mitsuoki Eguchi, Masaru
Kojima, Koichi Honma & Osamu
Arisaka
Cell Biochemistry and Biophysics
ISSN 1085-9195
Cell Biochem Biophys
DOI 10.1007/s12013-013-9567-y

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Cell Biochem Biophys
DOI 10.1007/s12013-013-9567-y

TRANSLATIONAL BIOMEDICAL RESEARCHAutopsy Report of a 7-Year Old Patient with the Mosaic
Trisomy 13
George Imataka • Hideo Yamanouchi •Junko Hirato • Mitsuoki Eguchi • Masaru Kojima •Koichi Honma • Osamu ArisakaÓ The Author(s) 2013. This article is published with open access at Springerlink.com

Abstract We present here a long survival case of apatient with the mosaic form of trisomy 13 who died ofaspiration pneumonia at the age of 7 years and 4 months.
The autopsy revealed olfactory aplasia and fenestration of
the septum pellucidum, and dilated lateral ventricles andatrophic hippocampus. Furthermore, there were numerous‘‘torpedos’’ (i.e., swollen fusiform Purkinje cell axons),
mostly in the granular layer underneath the Purkinje celllayer, and, occasionally, in the granular layer. Similar
neuropathological findings have been reported in elderly
cases of essential tremor, Parkinson’s disease, or Alzheimer’s disease. Precise mechanism for this axonal change isstill unclear. These pathological changes have never previously been reported in the literature on trisomy 13, andthe present patient is one of the oldest autopsied individuals
with the mosaic trisomy 13.

G. Imataka (&)  O. Arisaka
Department of Pediatrics, Dokkyo Medical University Schoolof Medicine, 880 Mibu, Shimotsuga, Tochigi 321-0293, Japane-mail: geo@dokkyomed.ac.jp
H. Yamanouchi
Department of Pediatrics, Saitama Medical University,Saitama, Japan
J. Hirato
Department of Human Pathology, Gunma University Graduate
School of Medicine, Gunma, JapanM. Eguchi
Department of Pediatrics, International University of Healthand Welfare Shioya Hospital, Tochigi, JapanM. Kojima  K. Honma
Department of Anatomic and Diagnostic Pathology, Dokkyo
Medical University School of Medicine, Tochigi, Japan

Keywords Trisomy 13  Patau syndrome Survival  Autopsy  Olfactory aplasia  TorpedosIntroduction
The trisomy 13 syndrome, also called Patau syndrome, wasfirst reported in 1960 [1]. It is a congenital anomaly syndrome caused by accessory chromosome 13 of the D1
group. Clinically, this syndrome is manifested by variable
deformities and their complications. Most patients with thissyndrome die soon after birth because of the severe congenital heart disease and brain deformity. The mortality
rate is approx. 50 % in the first month of life and 90 %during the first year of life [2]. Although a few cases oflonger survival have been reported [3, 4], there have been
no published reports to date on neuropathological findings
in long survival cases with trisomy 13. Here, we report anautopsy case of a 7-year-old boy with mosaic type of thetrisomy 13 syndrome. This autopsy in one of the longest
survival cases in the literature.

Patient’s History
This patient was born vaginally after 39 weeks of gestation
weighting 3,366 g. He was immediately transported to ourHospital because of neonatal aspiration and meconium
aspiration syndrome. The boy had systolic heart murmurs
and was further diagnosed with ventricular septal defecttype IV. He also had several minor anomalies, including
capillary hemangioma on forehead, frontal alopecia, narrow V-shaped palate, narrow fingernails, cryptorchidism,
inguinal hernia, and penis palmatus. Cytogenetic analysis
was carried out using a peripheral blood specimen, and the123

Cell Biochem Biophys

G-banding karyotype analysis revealed the presence oftrisomy 13. We did not conduct the chromosome analysis
of buccal mucosa or skin fibroblasts. Fluorescence in situ
hybridization (FISH) assay showed mosaic trisomy 13:
73.2 % of cultured cells had the karyotype 13 (47,
XY ? 13), while the remainder of the cells had normal
karyotype (Fig. 1). Convulsions developed in the infancy.
Electroencephalogram showed multifocal spikes; theconvulsions were well controlled by 0.05 mg/kg/day ofclonazepam. At the age of 3 years, repeated respiratory
infections were seen, so that the boy frequently neededmechanical respiratory support. Respiratory problems wereeventually controlled by tracheotomy, following which thepatient was able to stay at home. At the age of 5 years,
there were frequent urinary infections due to penis palmatus. These infections ceased after urethroplasty. At the ageof 7 years, the patient could roll over his body and enjoyedtouching the toys. Physical examination revealed poorly
developed and underweight child with respiratory failure.
Severe aspiration pneumonia developed at the age of
7 years and 4 months, leading to the patient’s demise.

Neurological Evaluation at the Age of 7 Years
From the age of 6 years, the patient developed aggravatedepileptic seizures accompanied by partial convulsions of
the left arm. Repeated electroencephalogram (EEG) spikes
in the centroparietal area of the right hemisphere wereobserved. Followed the diagnosis of focal epilepsy, thedose of clonazepam was increased up to 0.1 mg/kg/day
which led to cessation of seizures. At the age of 7 years,
the drug-induced sleep EEG showed no spikes. On theextremities’ examination, spastic paralysis of lower extremities

and increased deep-tendon reflex were observed. Furthermore, neurological examination showed brisk deep-tendon
reflexes and a rigid and spastic muscle tone. The examination of the cranial nervous system revealed declined
activities of the facial expression muscles, diminishedeyelash reflex, and attenuated vomiting reflex. The pupil
dilation response was slow bilaterally. The ophthalmoscopy revealed atrophic changes in bilateral optic nerves.
The brain MRI showed no brain malformation (Fig. 2a, b),
and the brain showed relatively good myelination. Both left
and right lateral ventricles were enlarged, and there werehypoplasia of transparent septum and thinning of thesplenium of the corpus callosum. The auditory brainstem
response to 100 dB revealed prolongation of bilateral I
wave latency at 2.9 and 3.0 ms for the left and right side,respectively (Fig. 3a). However, the central conduction
time and the I–V wave latencies were normal, with nodifference between the left and right side of the boy’s brain(3.8 and 3.7 ms, respectively). The amplitudes of the II, III,and IV waves were low. Components of the normal reaction
wave were seen on the visual evoked potential (Fig. 3b) andelectroretinogram. Prolongation was observed in the central
conduction time at 7.04 ms (?2.8 SD) upon short-latency
somatosensory evoked potential (Fig. 3c).

Blood Cell Morphology at the Age of 7 Years
Nuclear hypersegmentation and drumstick deformation
with club-shaped protrusions were frequently observed inperipheral blood neutrophils (Fig. 4a). Blood cells werefixed in 1 % osmium tetroxide, dehydrated with ethanol,and embedded in epoxy resin. Then, ultrathin (100 nm)
sections were prepared and double-stained with uranyl
acetate and lead citrate. These specimens were observed
using electron microscopy, which revealed small protrusions of neutrophil nuclei, nuclear pockets, and dendritic
deformation of the mitochondria (Fig. 4b).

Neuropathology

Fig. 1 Fluorescence in situ hybridization (FISH) reveals mosaic
trisomy 13, with 73.2 % of cells carrying normal karyotype and26.8 % trisomy 13123

Autopsy was performed soon after death. The boy was
93 cm tall and weighed 6 kg. The brain weight was notmeasured. Cerebral hemisphere showed symmetric atrophy
with widened sulci and narrow gyri. The olfactory bulb,
tract, and trigone, and anterior perforated substance wereabsent, and gyrus rectus showed shape deformation(Fig. 5a). The septum pellucidum was fenestrated, andcorpus callosum was thin (Fig. 5b).
Histopathologically, each layer of the cerebral cortex
was preserved, and polarity of pyramidal cells was intact.
The melanin granule was absent in pars compacta of theCell Biochem Biophys
Fig. 2 a Magnetic resonanceimaging (MRI), T1-weighted,
1.5T axial view (SE spin echo;
TR = 15 ms; TE = 450 ms).
MRI reveals dilatations oflateral ventricles and bifurcatedseptum pellucid. b The
splenium of the corpus callosumis thinFig. 3 a The auditory
brainstem response to 100 dB
reveals prolonged wave I
latency (2.9 and 3.0 ms in theleft and right sides,
respectively). b The visualevoked potential shows intact
wave components with delayed
latency. c The short-latency
somatosensory evoked potential
demonstrates prolonged central
conduction time (7.04 ms)

Fig. 4 a Hematoxylin–eosin
staining of peripheral bloodneutrophils reveals
hypersegmentation anddrumsticks of neutrophil nuclei(magnification 9100).
b Electron microscopy (JOEL,Tokyo, Japan; magnification
9100) reveals nuclear pockets
and dendritic deformation of
mitochondria

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Cell Biochem Biophys
Fig. 5 a The olfactory bulb,
tract, trigone, and anterior
perforated substance are absent,and gyrus rectus is abnormallyshaped. b Coronal section of theautopsied brain demonstrates
fenestration of the septum
pellucidum

Fig. 6 a Decreased melanin
granule is observed in pars
compacta of the substantia nigra(hematoxylin–eosin staining;9100). b The presence ofcharacteristic axonal swelling of
Purkinje cells (torpedoes)(neurofilament; 9100).
c Similar axonal swelling of
Purkinje cells is seen in themolecular layer (Bodian; 9200)

substantia nigra (Fig. 6a). A large number of torpedoes(swollen axons of Purkinje cells) were seen in the granularlayer below the Purkinje cell layer (Fig. 6b). Similar axonal swelling was seen even in the molecular layer, albeit
not as extensive (Fig. 6c). There were numerous spheroids
in the gray matter of the spinal cord and medulla.

Discussion
A commonly encountered brain anomaly in trisomy 13 isholoprosencephaly, which is a brain disorder characterized
by a failure of differentiation and a various degree ofcleavage of the prosencephalon [5]. This patient exhibited
olfactory aplasia and partial dysgenesis of the septum
pellucidum. However, there was no fusion of cerebral
hemispheres nor a partial or complete absence of the123

corpus callosum. Olfactory aplasia is sometimes associatedwith septo-optic dysplasia [6]. However, this diagnosis was
not applicable to our patient because of incomplete absenceof septum pellucidum. Furthermore, the autopsy revealed a
relatively well-preserved optic tract. Isolated olfactoryaplasia has never previously been reported in trisomy 13.
The mortality is generally associated with the severity ofdeformities in the central nervous system, heart, andrespiratory system. To the best of our knowledge, ourpatient is one of the longest survivors with trisomy 13
subjected to autopsy. The patient’s long survival was due tothe absence of complications associated with deformities ofmajor organs, such as the brain, the heart, or the lungs.
Another unique feature in our case was the presence ofnumerous torpedoes, i.e., swollen axons of Purkinje cells,
within the granular layer. The precise mechanism for thisaxonal change remains unknown. It has been reported inCell Biochem Biophys

several neuropathologic conditions with diffuse or focal
cerebellar changes, such as necrotic lesions, degenerativedisease involving the cerebellum, elderly cases of essential
tremor, Parkinson’s disease, Alzheimer’s disease, cerebellar injury, and aging [7–9]. However, this characteristicchange in the cerebellum has never previously beenreported in autopsy reports on trisomy 13.
Open Access This article is distributed under the terms of theCreative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the originalauthor(s) and the source are credited.

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