48, XXXY/49, XXXXY mosaic: new neuroradiological features in an ultra-rare syndrome
Milani et al. Italian Journal of Pediatrics
48, XXXY/49, XXXXY mosaic: new neuroradiological features in an ultra-rare syndrome
Donatella Milani 0 2
Francesca Bonarrigo 0 2
Sabrina Avignone 1
Fabio Triulzi 1
Susanna Esposito 0 2
0 Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Via Commenda 9, 20122 Milan , Italy
1 Neuroradiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
2 Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Via Commenda 9, 20122 Milan , Italy
Background: Sex chromosomal aneuploidies in males are rare diseases with an overwhelming involvement of endocrinological and auxological issues; less frequently, other anomalies are observed. Neuroradiological issues are often not taken into account in single patients, and neuroradiological examinations are rarely performed. Case presentation: Here, we report a boy with 48,XXXY/49,XXXXY mosaicism, phenotypically characterized by hypotonia, intellectual disability, ventricular septal defect, micropenis, and with mild hypertelorism, inverted nipples, a congenital hip dysplasia, and some neuroradiological features so far not described. The Magnetic Resonance Imaging showed white matter abnormalities and enlargement of lateral ventricles with never described dysmorphisms of cranio-cervical junction and posterior fossa. A cranio-cervical Computerized Tomography confirmed a dysmorphic aspect of the posterior fossa and occipital condyles, slight morphological asymmetry of C1 and slight lateralization to the right of the odontoid's apex. Conclusions: Considering the possible relevant clinical impact of these findings, the neuroradiological assessment seems potentially useful to the diagnostic approach of these patients.
Cranio-cervical junction; Klinefelter syndrome; Fraccaro syndrome; Sex chromosomal aneuploidies; X chromosome
Genetic conditions characterized by a variation in sex
chromosome’s number are defined as sex chromosomal
aneuploidies (SCAs). The most common of them is
Klinefelter syndrome (KS). About 80 % of male patients
with an X chromosome gain has the classical 47,XXY
karyotype, whereas 20 % has other SCAs (48,XXXY,
48,XXYY, 49,XXXXY), a chromosomal mosaicism, or
other structurally abnormal sex chromosomes .
KS has a prevalence of 1 in 500 males; its clinical
features include infertility, gynecomastia, eunuchoidism,
small testes and penis and hypergonadotropic
hypogonadism. 48,XXXY syndrome has an incidence of
1:50,000, whereas 49, XXXXY (also known as Fraccaro
syndrome) is the rarest one, with an incidence of
1:85.000–1:100.000 male births .
48, XXXY, 49, XXXXY and KS share some phenotypic
traits, but trisomy and tetrasomy of the X chromosome
show a different phenotype with more severe clinical
features [2, 3].
The height of patients with 48,XXXY syndrome as well
as those with KS is above the average, particularly after
puberty. This feature is not found in 49,XXXXY
syndrome where height is below the average; this condition
is often described as the most severe variant of the
spectrum. Clinical features include characteristic facial
appearance, intellectual disability, hypogonadism, severe
speech delay, multiple skeletal anomalies, and cardiac
defects [1, 3].
SCA patients have lower intellectual quotient (IQ),
related with the number of X chromosomes; every
additional X chromosome reduces IQ by about 15 points
. The social, cognitive, and neurological development
of patients with SCA are highly variable [1, 3, 4].
Patients with 48,XXXY have language difficulties, social
and emotional problems [1, 4]. Patients with 49,XXXXY
have lower IQs, nonverbal and verbal production
difficulties [1, 4]. Usually, they are shy but sociable, although
they also easily go wild with outbursts of anger if
frustrated [1, 3, 4].
Brain magnetic resonance imaging (MRI) studies on
KS have provided evidence that sex-chromosome
polysomy exerts specific effects on brain development .
Individuals with XXX and XXY can have smaller brain
volumes (microencephaly), enlarged lateral ventricles,
cortical atrophy, hypoplastic or thin corpus callosum,
and white matter abnormalities [4, 5]. Brain MRI in 48,
XXXY showed nonspecific white matter hyperintensities.
49,XXXXY is associated with more markedly decreased
brain volume and increased incidence of white matter
We describe a patient with a 48,XXXY/49,XXXXY
mosaicism having some unusual and undescribed
The patient is a 20-months-old boy born to
nonconsanguineous parents at 39 weeks of gestational age
by iterative caesarean section, which followed a normal
pregnancy. His birth weight was 2.650 Kg, birth length
46 cm, occipitofrontal circumference (OFC) 34.5 cm,
Apgar 10/10. At birth, he presented facial
dysmorphysms, inverted nipples, and ventricular septal defect
(VSD). The cerebral ultrasonography showed a slight
hemorrhage of the germinal zones. Furthermore, a
congenital hip dysplasia was diagnosed. He came to our
attention for developmental delay, congenital heart defect
and hypogenitalism. Weight was 10.2 kg (10th
percentile), length 81 cm (25th percentile) and OFC 48 cm
(25–50th percentile). He had mild hypertelorism,
flattened nasal bridge, slightly pronounced chin, inverted
right nipple, small penis, small hands and mild
generalized hypotonia. Due to his phenotype, our geneticist
(DM) recommended to perform a karyotype analysis; the
analysis showed a mosaic karyotype 49,XXXXY/
48,XXXY. Considering this cytogenetic result and
according to the literature, an X-ray examination of arms
was performed and this ruled out radioulnar synostosis.
Moreover, a brain MRI was performed. A moderate
ventriculomegaly with predominant expansion of the
posterior segments and slight asymmetry was found. Small
focal hyperintensities of the frontal, parietal and
posterior periventricular white matter were detected; they are
associated with a mild reduction of white matter. The
myelination was normal for his age. There were no
alterations of the cerebellar and brainstem signal. The MRI
showed an asymmetric dysmorphic appearance of the
posterior cranial fossa, small in size, with dysmorphism of
cranio-cervical junction (CVJ) and reduced visualization
of cerebrospinal fluid spaces (Fig. 1). A cranio-cervical
Computerized Tomography (CT) was performed to better
assess the anomalies of the skull base and it confirmed a
dysmorphic aspect of the posterior fossa and occipital
condyles, slight morphological asymmetry of C1, regular
morphology of C2 and slight lateralization to the right of
the odontoid’s apex (Fig. 2).
49,XXXXY is a very rare condition often classified as a
KS variant; however, various authors proposed that it
should be diagnosed as an independent clinical
syndrome . KS variants may present different features,
medical problems and complications. Our case includes
some of these (i.e., dysmorphisms and hip dysplasia) .
Gropman et al. described patients with 48,XXXY
syndrome with tics, intentional tremor and generalized
hypotonia . At present, only a mild generalized
hypotonia emerged in our patient.
Fig. 1 a and b Axial and coronal T2 images showing asymmetric and dysmorphic posterior fossa, right rotation and asymmetry of C1-C2 as well
as reduced visualization of cerebrospinal fluid spaces. c Axial T2 image showing ventriculomegaly and small focal hyperintensities of the frontal
and parietal white matter
Fig. 2 a Coronal CT multiplanar reconstruction showing asymmetric occipital condyles aspects. b Sagittal CT multiplanar reconstruction shows
clivus platybasic aspect. c 3D reconstruction (bone volume rendering) showing dysmorphic aspects of cranio-cervical junction
Brain abnormalities are frequently found in KS
variants; in particular, loss of brain volume,
ventriculomegaly, white matter hyperintensities (such as T2
hyperintensity signals ranging from extensive confluent
white matter alterations to punctate foci), decreased
width of the corpus callosum, and cortical atrophy are
reported [5, 7]. Therefore, the supernumerary X
chromosome seems to have a negative effect on white
matter and central nervous system (CNS) development
. Gropman et al. correlated these findings with the
neurodevelopemental performance, mainly in 49,XXXXY
As a matter of fact, the brain MRI performed on our
patient showed ventriculomegaly, white matter
hyperintensities, particularly of the frontal and parietal lobes,
and anomalies of posterior fossa and CVJ. Raven et al.
reported a Chiari type 1 malformation associated with
ventriculomegaly and a cervical syrinx in a patient with
49,XXXXY syndrome; this was found after performing a
brain MRI on the patient after his first episode of seizure
. Chiari malformation can be associated with
craniocervical junction anomaly, but in our patient, we found
an isolated CVJ dysmorphism, better highlighted by CT
that confirmed the asymmetric and dysmorphic aspect
of the posterior fossa. We found a platybasic and
asymmetric aspect of clivus with elongated right portion
towards omolateral occipital condyle that was
hypertrophic and prominent, whereas the left occipital
condyle was hypotrophic as the left clivus portion. C2 and
odontoid’s apex had normal morphology even if there
was a slight lateralization to the right of the apex.
To the best of our knowledge, our patient is the first
case of a CVJ malformation associated with 48,XXXY/
49,XXXXY syndrome. Some intriguing considerations
about a possible genotype-phenotype correlation can be
drawn. In particular, we suggest that the mosaicism found
in our patient can lead to a milder neuroradiological
phenotype compared to Raven’s patient. Mosaicism could
also have an effect on two different embryogenetic
components of CVJ (the central pillar and the surrounding
rings) leading to different and coexisting dysmorphic
aspects (platybasia and hyper-hypoplastic occipital
condyles). Therefore, it is important to underline that
skeletal abnormalities are not exclusively related to the
limbs, but also to the axial structures (such as the cervical
spine) and could give neurological signs. Considering all
the reported abnormalities and the possible relevant
clinical impact of some findings, the neuroradiological
assessment (MRI and CT) seems potentially useful in the
diagnostic approach to patients with 48,XXXY and
This case report has been approved by the Ethics
Committee of Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, Milan, Italy. Written informed
consent was obtained from the patient's parents
forpublication of this Case report and any accompanying
images. A copy of the written consent is available forreview
by the Editor-in-Chief of this journal.
CT: Computerized tomography; CNS: Central nervous system; CVJ:
Craniocervical junction; IQ: Intelligence quotient; KS: Klinefelter syndrome;
MRI: Magnetic resonance imaging; OFC: Occipitofrontal circumference;
SCA: Sex chromosomal aneuploidies; VSD: Ventricular septal defect.
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