Gene 508 (2012) 117–120

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Gene
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Short Communication

Skeletal abnormalities of the upper limbs — Neonatal diagnosis of

49,XXXXY syndrome
André Kidszun a,⁎, Anne-Jule Fuchs a, Alexandra Russo a, Marius Bartsch a, Gabriele Frey-Mahn b,
Vera Beyer b, Ulrich Zechner b, Oliver Bartsch b, Eva Mildenberger a
a
Department of Neonatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
b
Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany

a r t i c l e i n f o a b s t r a c t

Article history: A case of neonatal diagnosis of 49,XXXXY syndrome is presented. Clinical identification was prompted by a
Accepted 30 July 2012 bilateral thickening of the radioulnar joints and X-ray imaging disclosing almost complete radioulnar
Available online 7 August 2012 synostosis. Conventional karyotyping was initiated and revealed a karyotype of 49,XXXXY. Previously
reported neonatal symptoms such as low birth weight, muscular hypotonia, or genital malformations
Keywords:
were absent in this case. Microsatellite analysis showed two different X chromosomes each present in
49,XXXXY syndrome
Radioulnar synostosis
two copies, supporting that the four X chromosomes had arisen from a nondisjunction in maternal meiosis
Newborn I followed by a second nondisjunction involving both X chromosomes in meiosis II. Multidisciplinary
Microsatellite analysis follow-up was organised to ensure timely recognition of associated complications. Early awareness of the
diagnosis may offer a potential benefit regarding outcome.
© 2012 Elsevier B.V. All rights reserved.

1. Introduction 2. Case report

49,XXXXY syndrome is a rare sex chromosome aneuploidy with an
incidence of about 1:85,000–1:100,000 male births (Kleczkowska et al.,
1988). It was first described in 1960 and is considered to be a distinct
phenotype that shares some characteristics with Klinefelter syndrome
(47,XXY) (Fraccaro et al., 1960; Visootsak and Graham, 2006). The classi-
cal phenotype is a triad comprising hypergonadotropic hypogonadism,
radioulnar synostosis, and neurodevelopmental impairment (Visootsak
and Graham, 2006). Frequently associated dysmorphic features include
a characteristic facial appearance with arched eyebrows and upslanting
palpebral fissures, cardiac malformations, hip dysplasia, or clinodactyly.
Neurological signs comprise muscular hypotonia, severe speech delay,
and mental retardation (mean IQ around 35) (Gropman et al., 2009;
Tartaglia et al., 2008, 2011; Visootsak and Graham, 2006). Recently, a
mean age at diagnosis of 4 months was reported, but with a wide range
from neonatal age to age 16 months (Gropman et al., 2009). However,
most reported individuals were beyond neonatal age and relatively few
data are available on the perinatal clinical presentation of 49,XXXXY syn-
drome. We report on a case of a neonatal diagnosis of 49,XXXXY syn-
drome based on abnormalities of the upper limbs.
Abbreviations: bp, base pairs(s); RFLP, restriction-fragment length polymorphism;
STR, short tandem repeat.
⁎ Corresponding author at: Neonatologie, Zentrum für Kinder- und Jugendmedizin,
Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1,
55131 Mainz, Germany. Tel.: +49 6131 17 5892; fax: +49 6131 17 3477.
E-mail address: andre.kidszun@googlemail.com (A. Kidszun).
A newborn male German infant presented with lethargy, tachypnea,
paleness and poor feeding in his first hours of life and therefore was ad-
mitted to our neonatal unit because of suspicion of neonatal infection. He
had been born at term after an uneventful pregnancy. His brother and
parents were healthy. His condition significantly improved within 24 h
and sepsis was ruled out. His birth weight was 3500 g (25th–50th per-
centile), length 50 cm (10th–25th percentile), and head circumference
35 cm (25th–50th percentile). Detailed physical examination showed
prominent proximal radioulnar joints on both arms, abnormally posi-
tioned hands with ulnar deviation, and short 5th fingers with mild
clinodactyly (Fig. 1). X-ray imaging revealed bilateral osseous thickening
of the proximal radius and ulna, and nearly complete radioulnar synosto-
sis (Fig. 2). No restrictions in joint mobility and no other skeletal
malformations were seen. He also had hypertelorism, narrow palpebral
fissures, dorsally rotated ears and a small, right-sided pre-auricular tag.
His genitalia were unremarkable. Echocardiography showed a small pat-
ent ductus arteriosus and otherwise normal cardiac morphology and
function. Cranial and abdominal ultrasound was normal. Based on these
findings conventional karyotyping was initiated and revealed a karyo-
type of 49,XXXXY (Fig. 3). The patient was discharged home in good
health and a multidisciplinary follow up was organised. At the age of
12 months, his height was normal for age (75 cm; 25th percentile), as
was occipitofrontal circumference when last seen at age 15 months
(46.8 cm, 25th percentile). His facial dysmorphy had become more pro-
nounced with a large round flat face, brachycephaly, broad low nasal
bridge, inner epicanthal folds, and alternating strabism (Fig. 4). He had

0378-1119/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.gene.2012.07.053
118 A. Kidszun et al. / Gene 508 (2012) 117–120
Neurodevelopmental delay
Severe speech delay
Cardiac malformations
Genitourinary
malformations
Hypergonadotropic
hypogonadism
Inguinal hernia
Low birth weight
Muscular hypotonia
Fig. 1. Schematic representation of frequent abnormalities in 49,XXXXY syndrome. Features detected in the present case are highlighted in black. Facial appearance, see Fig. 4.
impaired pronation–supination of the forearms and ulnar deviation of
the hands. He could sit and stand stably and had just begun to walk
first steps with two-handed support. Further recent achievements in-
cluded baby talk and understanding of first words.
3. Molecular studies
Molecular studies were performed using lymphocyte DNA of the pa-
tient. Parental DNA samples were not available for study. Microsatellite
genotyping analysis was performed using a tailed primer method and a
locus-specific forward primer with M13 universal tail, a non-tailed
locus-specific reverse primer, and a fluorescence-tagged primer specific
for the M13 universal tail (Boutin-Ganache et al., 2001). Microsatellite
PCR products were separated and visualised on a Beckman CEQ 8000
Genetic Analysis System. Quantitative analysis of the peak areas was
performed to estimate allele dosage ratios. Microsatellite markers
DXS6810, DXS6789, and DXS2390 provided informative results. Each
Fig. 2. Representative X-ray of the right arm confirms thickening of the proximal
radioulnar joint. The joint space is marginally visible.
Short stature
Craniofacial abnormalities
Radioulnar synostosis
5th finger clinodactyly
Scoliosis
Congenital hip dysplasia
Genu valgum
Club foot
marker displayed two peaks with similar peak area sizes, indicating
the presence of only two different alleles and equal dosages of both
alleles (Table 1).
4. Discussion
In this boy with 49,XXXXY syndrome, the main clinical symptoms
leading to the presumptive diagnosis have been bilateral upper limb ab-
normalities at newborn age. Data on newborns with 49,XXXXY syndrome
are still limited. The presence of multiple nonspecific congenital anoma-
lies such as low birth weight, muscular hypotonia, clinodactyly, patent
ductus arteriosus, scoliosis, or genital malformations has led to the diag-
nosis of 49,XXXXY syndrome in several newborns (Dissanayake et al.,
2010; Gropman et al., 2009; Hayek et al., 1971; Muis et al., 1982; Ságodi
et al., 1999). However, the onset of the most characteristic skeletal abnor-
mality, radioulnar synostosis, is still unknown. In general, it has been con-
sidered to develop at a later stage of the disease (Muis et al., 1982). In a
recent review of antenatal findings in fetuses with 49,XXXXY syndrome,
radioulnar synostosis was not detected in any of the 14 cases (Peitsidis
et al., 2009). In this patient the bilateral thickening of the radioulnar joints
was the most remarkable morphological abnormality. In contrast to pre-
vious reports, radioulnar synostosis was already present at birth. In the
absence of other characteristic symptoms such as low birth weight, mus-
cular hypotonia, or genital malformations, the bilateral thickening of the
radioulnar joints and radioulnar synostosis prompted the diagnosis of
49,XXXXY syndrome. Thus, this report adds to the complex clinical pre-
sentation of the 49,XXXXY syndrome in newborns.
Early diagnosis offers multidisciplinary follow up involving paediat-
ric sub-specialists as endocrinologists, cardiologists, and orthopaedics.
Moreover, parents can be counselled in detail and accompanied in the
further clinical course. A subset of the clinical characteristics of patients
with 48,XXXY and 49,XXXXY syndromes may be treated. For instance,
early recognition and treatment of hypergonadotropic hypogonadism
seem to be crucial for adequate growth and pubertal development of
patients with 49,XXXXY syndrome (Dötsch et al., 2000). Furthermore,
there might be a potential benefit of early intervention with regard to
neurodevelopment.
Microsatellite analysis indicated that our patient carries two different
alleles on his four X chromosomes, suggesting that his X chromosomes
 A. Kidszun et al. / Gene 508 (2012) 117–120 119

Fig. 3. Karyogramm showing 49,XXXXY karyotype.

are derived from only two different parental X chromosomes. Our data Conflicts of interest
also demonstrate that both alleles and hence chromosomes are equally
represented. These results confirm findings in previous studies of 49, The authors have no conflicts of interest to disclose.
XXXXY patients and their parents that used short tandem repeat (STR)
analysis or Southern blot analysis of conventional two-allele restriction Acknowledgments
fragment length polymorphisms (RFLPs) (Huang et al., 1991). These
studies concluded that the presence of the four X chromosomes in We would like to thank the family for their support of this study.
these patients is due to two consecutive nondisjunction events in mater-
nal meiosis. The first error occurred in maternal meiosis I and the second Appendix A. Supplementary data
nondisjunction involved both X chromosomes in meiosis II.
In summary, we report on a case of neonatal diagnosis of 49,XXXXY Supplementary data to this article can be found online at http://
syndrome based on bilateral upper limb abnormalities. dx.doi.org/10.1016/j.gene.2012.07.053.

Broad nasal bridge and hypertelorism

Arched eyebrows

Brachycephaly

Upslanting palpebral
fissures

Low-set and dorsally

rotated ears

Cleft palate or bifid uvula

Round flat face

Receding chin

Alternating strabism Inner epicanthal folds

Fig. 4. Schematic diagram of the typical facial appearance of 49,XXXXY syndrome in infancy. Features detected in the present case are highlighted in black.
120 A. Kidszun et al. / Gene 508 (2012) 117–120

Table 1 Dötsch, J., Foerster, W., Holl, R., Rascher, W., Kiess, W., 2000. Case of XXXXY syndrome.
Results of microsatellite genotyping in the patient. STR short tandem repeat. Horm. Res. 53, 154–156.
Fraccaro, M., Kaijser, K., Lindsten, J., 1960. A child with 49 chromosomes. Lancet 22,
STR Positiona Allele 1 Allele 2 899–902.
(size of peak area) (size of peak area) Gropman, A.L., Rogol, A., Fennoy, I., Sadeghin, T., Sinn, S., Jameson, R., Mitchell, F., Clabaugh,
J., Lutz-Armstrong, M., Samango-Sprouse, C.A., 2009. Clinical variability and novel
DXS9902 15,323,636 1 neurodevelopmental findings in 49, XXXXY syndrome. Am. J. Med. Genet. 152,
(175,000) 1523–1530.
DXS6810 42,918,691 1 2 Hayek, A., Riccardi, V., Atkins, L., Hendren, H., 1971. 49, XXXXY chromosomal anomaly
(140,000) (145,000) in a neonate. J. Med. Genet. 8, 220–221.
DXS7132 64,655,338 1 Huang, T.H., Greenberg, F., Ledbetter, D.H., 1991. Determination of the origin of nondis-
(125,000) junction in a 49, XXXXY male using hypervariable dinucleotide repeat sequences.
DXS6789 95,449,415 1 2 Hum. Genet. 86, 619–620.
(100,000) (90,000) Kleczkowska, A., Fryns, J.P., van den Berghe, H., 1988. X-chromosome polysomy in the
male. The Leuven experience 1966–1987. Hum. Genet. 80, 16–22.
DXS2390 140,061,921 1 2
Muis, N., Cats, B.P., Ippel, P.F., Beemer, F.A., 1982. A newborn infant with the xxxxy-
(175,000) (175,000)
syndrome. Tijdschr. Kindergeneeskd. 50, 112–116.
a Peitsidis, P., Manolakos, E., Peitsidou, A., Petersen, M.B., Tsoplou, P., Kadir, R., Agapitos, E.,
Position on the X chromosome in bp based on the NCBI 37.3 assembly of the
human genome [October 2011]. 2009. Pentasomy 49, XXXXY diagnosed in utero: case report and systematic review
of antenatal findings. Fetal Diagn. Ther. 26, 1–5.
Ságodi, L., Lukács, V., Lechner, E., 1999. A case of neonatal 49, XXXXY syndrome. Orv.
Hetil. 140, 1787–1790.
Tartaglia, N., Davis, S., Hench, A., Nimishakavi, S., Beauregard, R., Reynolds, A., Fenton,
L., Albrecht, L., Ross, J., Visootsak, J., Hansen, R., Hagerman, R., 2008. A new look at
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