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European Journal of Medical Genetics 51 (2008) 573e579

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Short report
The changing phenotype in diploid/triploid mosaicism
may mimic genetic syndromes with aberrant genomic
imprinting: Follow up in a 14-year-old girl
Olaf Rittinger a,*, Gabriela Kronberger a, Andrea Pfeifenberger a,
Dieter Kotzot b, Christine Fauth b
a
Section Clinical Genetics, Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria
b
Division of Clinical Genetics, Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical
University Innsbruck, Schoepfstrasse 41, 6020 Innsbruck, Austria
Received 14 May 2008; accepted 13 July 2008
Available online 26 July 2008

Abstract

Diploid/triploid mosaicism is a rare chromosome aberration characterized by growth and mental

retardation, muscular hypotonia, clinodactyly, syndactyly of fingers and toes, asymmetry of the body and
the face, truncal obesity, and pigmentary anomalies of the skin. Many patients initially present with severe
growth retardation and develop truncal obesity later in life. Variable phenotype expression during
development and restriction of triploid cells to certain tissues explain why the diagnosis of diploid/triploid
mosaicism is often delayed. Here, we report on a moderately retarded 14-year-old girl with diploid/triploid
mosaicism due to inclusion of the second polar body, whose changing phenotype overlaps considerably
with different genetic disorders associated with aberrant genomic imprinting. The observation that triploid
cells, which in our patient show remarkably variable distribution in different tissues, may also be present
in easily accessible tissues such as urinary sediment or buccal smear may contribute to an earlier diagnosis
of this rare syndrome.
Ó 2008 Elsevier Masson SAS. All rights reserved.

Keywords: Diploid/triploid mosaicism; Maternal origin; Second polar body inclusion; Aberrant genomic imprinting

* Corresponding author. Tel.: þ43 662 4482 2605; fax: þ43 662 4482 2621.
E-mail address: o.rittinger@salk.at (O. Rittinger).

1769-7212/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmg.2008.07.004
574 O. Rittinger et al. / European Journal of Medical Genetics 51 (2008) 573e579

1. Introduction

Diploid/triploid mosaicism (mixoploidy) is a rare dysmorphic syndrome which has been

described in about 30 patients [4,8,12]. In contrast to patients with full triploidy, which
occurs in approximately 1% of all conceptuses and is almost always prone to early spon-
taneous abortion, patients with mixoploidy may survive the neonatal period and live up to
adulthood [2,9,12,19]. Characteristic clinical features are facial and body asymmetry, growth
delay, pigmentary dysplasia of the skin, limb anomalies like syndactyly, clinodactyly and
highly characteristic camptodactyly, muscular hypotonia, subtle dysmorphic facial features
resembling SilvereRussell syndrome (SRS) [2,12,15], and mental disability of variable
degree.

2. Clinical report

The patient was born at term to a 26-year-old mother and a non-consanguineous 27-year-old
father. Both parents were healthy. The family history was unremarkable. Birth was without
complications. Birth weight was 2250 g (SD 3.49), length was 46 cm (SD 3.13), and OFC
was 32 cm (SD 3.02). Dysmorphic features included a broad forehead, a prominent nasal tip,
a small chin, bilateral clinodactyly of fingers II and V and camptodactyly of the phalanges of
fingers IIeV, bilateral single palmar crease, soft tissue syndactyly of toes II/III of the right foot
and III/IV of the left foot, a bulbous tip of the 2nd toe, and bilateral calcaneovalgus deformity
(Fig. 1). Neither pigmentary anomalies of the skin, nor asymmetry of the face or limbs were
seen in the newborn. As dystrophy remained during the first 3 years SRS was suggested.
Psychomotor and speech development was retarded with unaided sitting possible with 15
months and free walking with 20 months. Single words were correctly spoken with 17 months
and at the age of 30 months the vocabulary comprised about 20 words. At the age of 18 months
the patient developed seizures (mainly myoclonic seizures) treated successfully with pheno-
barbital, valproic acid, and lamotrigen. At that age truncal obesity developed. An MRI of the
brain, a muscle biopsy, screening for metabolic disorders, and molecular studies for Pradere
Willi syndrome and maternal uniparental disomy 14 gave normal results. X-rays of the spine
and hands showed 11 rib pairs, lumbalisation of the first sacral vertebrum, a bilateral elongation
of metacarpales II and III, and ankylosis of the proximal interphalangeal joint V. Patchy or
streaky cutaneous hyperpigmentation was first seen at the age of about 10 years, mainly on the
dorsal lower forearms and buttocks. Spontaneous puberty started early with menarche at 11
years. At the age of 14 years, growth was markedly decreased (142.5 cm, SD 2.82). Weight
was increased with 49.0 kg (BMI-SD þ1.42) and OFC was 54 cm (SD 0.6). S-shaped
scoliosis became worse leading to a corset supply and, lastly, surgical orthopaedic treatment
(Fig. 2). Now, the patient is supported with special education and is able to answer simple
questions in short sentences with correct spelling.

3. Methods and results

Initial standard karyotyping of peripheral blood lymphocytes showed a normal 46,XX

karyotype in a total of 50 metaphases examined. PradereWilli syndrome (PWS) was ruled
out by methylation sensitive PCR [20]. In addition, maternal UPD14 and subtelomeric
chromosome rearrangements were excluded by microsatellite markers and FISH,
respectively.
 O. Rittinger et al. / European Journal of Medical Genetics 51 (2008) 573e579 575

Fig. 1. The facial phenotype of our patient at the age of 3, 8, and 13 years as well as increasing camptodactyly at the age
of 7 and 14 years and ankylosis of the proximal interphalangeal joint V (L).

Cytogenetic analysis of cultured skin fibroblasts finally revealed a triploid karyotype

(69,XXX) in 15 out of 18 metaphases analysed and a normal diploid karyotype (46,XX) in the
remaining three metaphases. Interphase FISH with two different centromeric probes (CEP11
and CEP17 probes, Q-biogeneÒ) on cultured fibroblasts resulted in 200 triploid cells (91.3%),
13 diploid cells (5.94%), and six tetraploid cells (2.74%). Because in control persons up to 6%
of cells may have a tetraploid karyotype [3], this finding was not considered to be of clinical
significance. Triploid cells were also found by interphase FISH in urinary sediment cells with
four different centromeric probes (CEP8 and CEP11, DXZ1/DYZ3 Cocktail probe, Q-bio-
geneÒ), but not in buccal smear cells (Table 1).
Microsatellite analysis was performed on DNA from peripheral blood of the patient and both
parents and on DNA from cultured fibroblasts according to standard protocols. In total, 19 di-
and tetranucleotide repeats from different chromosomes were analysed (D2S115, D2S116,
D2S1384, D2S2358, D7S500, D7S640, D7S692, D7S1804, D14S68, D17S2220, D17S2224,
D17S2226, D17S2227, D17S2230, D19S228, DXS1221, DXS1222, DXS8015, DXS8054). In
two of the 19 loci studied (D7S500 and D7S1804, chromosome bands 7q32e33 and 7q31,
respectively) two maternal alleles and one paternal allele were present in fibroblasts and two
markers (D17S2226 and D17S2227, chromosome band 7p11.2) showed reduction to homo-
zygosity. No additional paternal allele was found.
576 O. Rittinger et al. / European Journal of Medical Genetics 51 (2008) 573e579

Fig. 2. Truncal obesity at the age of 14 years. Note the slender distal limbs, severe scoliosis, and patchy pigmentation
(arrows).

4. Discussion

Clinical diagnosis of diploid/triploid mosaicism may be achieved according to subtle but

distinctive phenotypic features described in about 30 patients so far [2,8,12,15]. Several clinical
conditions share age-dependently symptoms in common with mixoploidy like SRS in the first
year of life and maternal uniparental disomy 14 and PWS after onset of truncal obesity.
Moreover, accurate diagnosis depends on the familiarity with respective symptoms, which may
predominate during different phases of development and mimic other genetic syndromes.

Table 1
Distribution of diploid and triploid cells in blood lymphocytes, skin fibroblasts, urinary sediment cells, and buccal smear
Ploidy Blood lymphocytes (n ¼ 50) Skin fibroblasts (n ¼ 37) Urinary sediment Buccal smear (n ¼ 17)
cells (n ¼ 34)
2n 50 16 15 17
3n 0 21 19 0
 O. Rittinger et al. / European Journal of Medical Genetics 51 (2008) 573e579 577

Pigmentary anomalies, a subtle sign in our patient, may indicate genetic mosaicism but may
also be a hallmark of hypomelanosis of Ito [5,6]. Furthermore, there is also considerable
overlap with the even rarer diploid/tetraploid mosaicism [3,7] (Table 2). Lambert et al. [14]
published two patients diagnosed with CameraeMarugoeCohen syndrome, a disorder char-
acterized by short stature, obesity, metal retardation, hypogonadism and contractures and
recently considered as being not a monogenic syndrome but undetected mixoploidy. One of
them presented with a quite unusual cup-like crooking of the fingers with abnormal transversal
palmar creases [13] and prompted us to investigate skin fibroblasts providing the final diag-
nosis. While in our patient low degree camptodactyly was already visible in the newborn,
pigmentary anomalies were observed only after several years.
The mechanism leading to symptoms like camptodactyly, hypotonia, and later on truncal
obesity is still unknown. One may speculate that these symptoms result from either an over-
expression of dosis-sensitive genes or an imbalance in gene expression caused by imprinted
genes. In triploid cells, these genes are active in one haploid set and inactive in the remaining
two haploids or vice versa, thereby leading to an imbalance of gene products. This might also
explain the similarity of diploid/triploid mosaicism with genetic imprinting disorders like SRS
or BeckwitheWiedemann syndrome (BWS), which was also found by other authors [14,15].
Another hint that there might be an overlap between diploid/triploid mosaicism and syndromes
with aberrant imprinting comes from a recently published report by Giurgea et al. [4]. The
authors report two children with congenital hyperinsulinism, which is a clinical feature of BWS
[18]. Microsatellite analysis of DNA from resected pancreatic tissue revealed paternal iso-
disomy for the whole haploid chromosome set in the child with features of BWS, while in the
child with isolated hyperinsulinism triploid cells with two paternal chromosome sets were
found in the pancreatic tissue.
Four major mechanisms of origin for diploid/triploid mosaicism have been identified [4,11]:
First, incorporation of a second sperm pronucleus into one blastomere (delayed dispermy),
second formation of a chimaera by fusion of a diploid embryo with a triploid embryo, third
postzygotic diploidization of triploids, and fourth and most frequently reported delayed
incorporation of the second polar body into one blastomere (delayed digyny) [1,8,12,16].
Reduction to homozygosity of markers D17S2226 and D17S2227 localized close to the
centromere of chromosome 17 and heterozygosity of two markers (D7S500, D7S1804)
mapping to more telomeric regions of chromosome 7 suggests the latter mechanism in our
patient as well.

Table 2
Comparison of clinical findings in diploid/triploid (2n/3n) and diploid/tetraploid (2n/4n) mosaicism and in our proband
[modified to 7]
Features 2n/3n 2n/4n Proband
Asymmetry 11/17 4/10 0
Pigment anomaly 5/13 3/9 þ
Truncal obesity 6/8 1/3 þ
Contractures 6/12 8/10 þ
Syndactyly (hands) 6/12 2/9 0
Syndactyly (feet) 6/12 4/8 þ
Mental retardation 10/14 9/9 þ
Micrognathia 5/12 7/10 þ
Heart defect 2/6 4/11 0
578 O. Rittinger et al. / European Journal of Medical Genetics 51 (2008) 573e579

Mixoploidy may be underdiagnosed, because in most patients triploid cells are restricted to
certain tissues. In 70% a triploid cell line is seen only in fibroblasts which might be due to
selection against the triplod cell line in the very early differentiation of the hematopoetic system
[9]. If ever, less than 5% of triploid cells are detectable in lymphocytes [2]. Another reason for
the rare diagnosis may be the clinical variability of the disease in different individuals, espe-
cially regarding mental retardation, which may be very mild as in a recently reported patient
[17] or severe, like in the patient reported by Fryns et al. [10] mirrowing a phenomenon
inherent to mosaicism. Therefore, investigation of other tissues such as skin, buccal smear, or
urinary sediment cells is indicated. Because skin biopsy is an invasive method and buccal
smear, according to our experience, appears not to be a tissue relevant for proper diagnosis,
investigation of urinary sediment cells is recommended.
In conclusion, successful diagnosis of mixoploidy requires experience with the age-
dependent phenotypic features. An unusual cup-like form of camptodactyly, delayed onset of
truncal obesity after a period of dystrophy, and pigmentary anomalies are hallmarks of genetic
mosaicism in general and may prompt clinicians to investigate easily accessible tissues like
buccal smear and especially urinary sediment cells to establish final diagnosis. This may
contribute to a more frequent diagnosis of diploid/triploid mosaicism and providing early and
accurate genetic counselling.

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