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DiGeorge syndrome with discordant phenotype in monozygotic twins

Authors:
Georg Hillebrand at Itzehoe Hospital
Georg Hillebrand
R Siebert
R Siebert
R Siebert
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E Simeoni
E Simeoni
E Simeoni
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René Santer at University Medical Center Hamburg - Eppendorf
René Santer
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Abstract

Editor—In a recent issue of this journal, Goodship et al 1 reported monozygotic twins with a deletion in chromosome region 22q11 and a discordant phenotype. They concluded that phenotypic variability in this syndrome cannot be explained on the basis of genotypic differences alone. Here we report another case of monozygotic twins with an identical deletion in 22q11 but with discordant manifestation of heart disease. The Turkish twins who were born 4 weeks preterm presented with typical symptoms of DiGeorge syndrome. Both boys had characteristic dysmorphic features, including short palpebral fissures, square nasal tip, small mouth, and prominent forehead. Both had hypoplasia of the thymus with markedly decreased levels of CD3 positive lymphocytes (50 and 39% of the total, respectively). Hypocalcaemia owing to low levels of parathyroid hormone (0.76 and 0.7 pmol/l, respectively) was found in both infants, leading to hypocalcaemic seizures in twin 1. Now, at 12 months of age, both infants show significant developmental delay. They are both rather quiet and display a general lack of activity. The second twin's coordination and motor skills …
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Electronic letter
J Med Genet 2000;37 (http://jmedgenet.com/cgi/content/full/37/9/e23)
DiGeorge syndrome with discordant
phenotype in monozygotic twins
EDITOR—In a recent issue of this journal, Goodship et al1
reported monozygotic twins with a deletion in chromosome
region 22q11 and a discordant phenotype. They concluded
that phenotypic variability in this syndrome cannot be
explained on the basis of genotypic diVerences alone.
Here we report another case of monozygotic twins with
an identical deletion in 22q11 but with discordant
manifestation of heart disease. The Turkish twins who were
born 4 weeks preterm presented with typical symptoms of
DiGeorge syndrome. Both boys had characteristic dysmor-
phic features, including short palpebral fissures, square
nasal tip, small mouth, and prominent forehead. Both had
hypoplasia of the thymus with markedly decreased levels of
CD3 positive lymphocytes (50 and 39% of the total,
respectively). Hypocalcaemia owing to low levels of
parathyroid hormone (0.76 and 0.7 pmol/l, respectively)
was found in both infants, leading to hypocalcaemic
seizures in twin 1. Now, at 12 months of age, both infants
show significant developmental delay. They are both rather
quiet and display a general lack of activity. The second
twin’s coordination and motor skills are at a 6-8 month
level and twin 1 is doing slightly better. Neither of them can
stand alone or has started walking yet.
In contrast to the previously mentioned manifestations,
the cardiac defects of the two children were significantly
diVerent. Twin 1 only had a small atrial septal defect with
spontaneous closure at 9 months of age, whereas the other
twin had complex heart disease consisting of an atrial sep-
tal defect, a large ventricular septal defect, a patent ductus
arteriosus, and an interrupted aortic arch distal to the ori-
gin of the left carotid artery (type 1b) necessitating cardiac
surgery on the second day of life.
Zygosity studies were carried out by typing for red cell
antigens (ABO, rhesus, MNSs, Kell) and plasma proteins
(haptoglobin, plasminogen, á1-antitrypsin, group specific
component, complement c3, transferrin, properdin factor
B) and erythrocyte enzymes (phosphoglucomutase, eryth-
rocyte acid phosphatase). Additionally, Southern blot
analysis of restricted DNA fragments (RFLP) with single
locus probes for hypervariable DNA polymorphisms MS1,
MS31, MS43a, MS205, YNH24, and G3 was performed
as well as PCR analysis of short tandem repeat systems
(VWA, TH01, FES). All tests showed an identical
genotype in both twins; thus the probability that they are
not monozygotic can be calculated to be <4.8 ×10-7. Cyto-
genetic analysis of 20 G banded metaphases of each twin
showed a male karyotype without numerical or gross
structural aberrations in either patient. However, fluores-
cence in situ hybridisation (FISH) with a probe for locus
D22S75 (Oncor, Heidelberg, Germany) and the more dis-
tally located probe TUPLE1 (Vysis, Bergisch-Gladbach,
Germany) detected a microdeletion in the region 22q11.2
in both twins. Thus,both twins have a karyotype 46,XY.ish
del(22)(q11.2 q11.2)(D22S75−, TUPLE−). There was
no evidence for a deletion or any other alteration of the
chromosomal region 22q11 nor for other structural or
numerical chromosomal changes in either parent by both
cytogenetic and FISH analysis.
This case draws attention to the possibility that non-
genetic factors contribute to the phenotype of patients with
microdeletion in 22q11. In this respect, it is interesting that
Ryan et al2also discussed such mechanisms when reporting
on a European collaborative study of 556 patients with dele-
tions in 22q11. Among them, there were 12 families with
more than one sib aVected. Comparison of sibs of the same
family showed a significant degree of variation of symptoms,
particularly in heart abnormalities. In their report, Goodship
et al1discussed the possibility of non-genetic influences that
could result in diVerent manifestation of defects. Monozy-
gosity on its own has been shown to account for a higher
incidence of a wide spectrum of heart malformations; how-
ever, the defect seen in our patient is quite characteristic for
DiGeorge syndrome and hence should be discussed in rela-
tion to the microdeletion. Goodship et al1hypothesised that
a deletion in 22q11 only predisposed twins to malforma-
tions, while the twinning process itself with factors such as
growth disadvantage, disturbance of laterality, and possible
placental vascular anastomoses with twin-twin transfusion
provides an additive eVect which then results in manifesta-
tion of the defect in only one of the twins.
The relevance of non-genetic factors as discussed above
is diYcult to evaluate, but they may certainly play a role.
Another possible reason for discordance in phenotype
could be an additional acquired change of genetic
information in only one twin. This could aVect the region
of 22q11, for example by point mutations, a small deletion
resulting in loss of hemizygosity, or alterations of imprint-
ing, but could also aVect other chromosomal regions. Such
a second, somatic mutation would have to occur locally,for
example in embryonic tissue involved in organogenesis of
the heart. Even within 22q11, several genes have been sug-
gested as possible candidates for DiGeorge syndrome. This
will probably make proving this hypothesis a diYcult task.
In summary, we report a second pair of monozygotic
twins with a microdeletion in 22q11 with significantly dis-
cordant manifestation of heart disease. This observation
provides further evidence that the variability of clinical
symptoms in patients with microdeletions in 22q11 cannot
be explained by the deletion itself nor by an eVect resulting
simply from interaction with other genes. It underlines that
exogenous factors that either do or do not aVect other
genes contribute to the manifestation of clinical symptoms
in 22q11 microdeletion syndromes.
G HILLEBRAND*
R SIEBERT†
E SIMEONI‡
R SANTER*
*Department of Paediatrics, University of Kiel, Schwanenweg 20, 24105
Kiel, Germany
†Department of Human Genetics, University of Kiel, Schwanenweg 24,
24105 Kiel, Ger many
‡Department of Forensic Medicine, University of Kiel, Schwanenweg 20,
24105 Kiel, Ger many
Correspondence to: Dr Hillebrand, Ghillebrand@pediatrics.uni-kiel.de
1 Goodship J, Cross I, Scambler P, Burn J. Monozygotic twins with chromo-
some 22q11 deletion and discordant phenotype J Med Genet 1995;32:746-
8.
2 Ryan AK, Goodship JA, Wilson, DI, Philip N, Levy A, Seidel H, SchuVen-
hauer S, Oechsler H, Belohradsky B, Prieur M, Aurias A, Raymond FL,
Clayton-Smith J, Hatchwell E, McKeown C, Beemer FA, Dallapiccola B,
Novelli G, Hurst JA, Ignatius J, Green JA, Winter RM, Brueton L,
Brøndum-Nielsen L, Stewart F, Van Essen T, Patton M, Paterson J,
Scambler PJ. Spectrum of clinical features associated with interstitial chro-
mosome 22q11 deletions: a European collaborative study. J Med Genet
1997;34:798-804.
Electronic letter 1of1
www.jmedgenet.com
on 1 November 2018 by guest. Protected by copyright.http://jmg.bmj.com/J Med Genet: first published as 10.1136/jmg.37.9.e23 on 1 September 2000. Downloaded from
... Powyższy wynik świadczy o tym, że w grupie pacjentów z wrodzoną wadą serca, również dorosłych, celowe może być wykonanie badania genetycznego w kierunku opisywanego zespołu. Częstość zachorowań nie jest zależna od płci (7) . INTRODUCTION 2 2q11.2 ...
... This result implicates that genetic tests for this syndrome might be justified also in patients, including adults, with congenital cardiac defects. The incidence is not related to gender (7) . ...
22q11.2 microdeletion syndrome as a multidisciplinary problem
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22q11.2 microdeletion syndrome, known also under the name of DiGeorge syndrome, is the most frequent deletion in the human chromosome. Its prevalence is estimated at about 1:9,700 newborns, but this is probably an underestimation. In over 90% of cases, the disease is caused by de novo microdeletion in the long arm of chromosome 22, and more rarely by microdeletion of the short arm of this chromosome or by a gene TBX1 point mutation. The consequences of these genotypic disorders are developmental anomalies of the third and fourth pharyngeal arches during the foetal life, which leads to abnormal development of the thymus, parathyroid glands and major cardiac vessels. The characteristic triad of symptoms includes a cardiac defect, hypocalcaemic tetany (hypoparathyroidism) and immunodeficiency. The syndrome may also manifest as facial dysmorphia, palate defects, gastrointestinal abnormalities, urogenital malformations, autoimmune diseases and psychiatric disorders. Standard tests to diagnose this syndrome are molecular studies, such as fluorescence in situ hybridization, array comparative genomic hybridization and a type of polymerase chain reaction: multiplex ligationdependent probe amplification. The therapy of DiGeorge syndrome may include: calcium supplementation, surgical correction of cardiac and palate defects, treatment of immunodeficiency by injections of immunoglobulins, stem cell transplantation or, in rare cases, thymus transplantation. The management of DiGeorge syndrome requires a multidisciplinary approach. Early diagnosis and treatment significantly improve patient’s chances for normal functioning in adult life.
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... Several reports have mentioned phenotypic discordance between the monozygotic twins with 22q11.2 microdeletion6789101112. No definite mechanism has been demonstrated until now for the discordant phenotype. ...
... microdeletion syndrome across unrelated, related or twins [7,18192021. The phenotypic variability is also reported in the monozygotic twins repeatedly6789101112. The frequent observation of variability of clinical symptoms with the 22q11.2 ...
Chromosome 22q11.2 microdeletion in monozygotic twins with discordant phenotype and deletion size
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We report on a pair of male monozygotic twins with 22q11.2 microdeletion, discordant phenotype and discordant deletion size. The second twin had findings suggestive of DiGeorge syndrome, while the first twin had milder anomalies without any cardiac malformation. The second twin had presented with intractable convulsion, cyanosis and cardiovascular failure in the fourth week of life and expired on the sixth week of life, whereas the first twin had some characteristic facial appearance with developmental delay but no other signs of the 22q11.2 microdeletion syndrome including cardiovascular malformation. The fluorescence in situ hybridization (FISH) analysis had shown a microdeletion on the chromosome 22q11.2 in both twins. The interphase FISH did not find any evidence for the mosaicism. The genomic DNA microarray analysis, using HumanCytoSNP-12 BeadChip (Illumina), was identical between the twins except different size of deletion of 22q11.2. The zygosity using HumanCytoSNP-12 BeadChip (Illumina) microarray analysis suggested monozygosity. This observation indicates that altered size of the deletion may be the underlying etiology for the discordance in phenotype in monozygotic twins. We think early post zygotic events (mitotic non-allelic homologous recombination) could have been played a role in the alteration of 22q11.2 deletion size and, thus phenotypic variability in the monozygotic twins.
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... However, hypothesis based on the effect of modifier genes cannot explain the variability of monozygotic twins. More discordant than concordant monozygotic twins are published because of the scientific interest [46][47][48][49][50][51]. Halder et al. reported a discordant monozygotic twin with different deletions in size [52]. ...
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PurposeWe aimed to present the fetal ultrasound, cytogenetic/molecular testing and postmortem or postnatal clinical findings of cases with 22q11.2DS diagnosed prenatally.Materials and methodsA retrospective medical record review of 48 prenatal cases diagnosed with 22q11.2DS were evaluated in our institution. Detailed ultrasound examination was performed on all fetuses. Postmortem and postnatal examinations were evaluated. The microdeletions were detected by karyotyping or microarray, then confirmed by FISH. Descriptive statistical analysis was performed.ResultsDemographic data of 48 prenatal cases including 46 singletons and 1 dichorionic diamniotic twin pregnancy were evaluated. The most common extracardiac anomaly was skeletal system anomalies (25%), in which PEV was the most frequent one (20.8%). Polyhydramnios rate was detected as 31%, in 6.6% as an isolated finding. Microdeletion has been detected by karyotyping in 13 cases (13/47, 27.7%) (including 2 unbalanced translocations), by FISH in 28 cases (28/48, 58.3%), by microarray/a-CGH testing in 7 cases. Microarray analysis showed that in one case with unbalanced translocation had two consecutive deletions; one was proximal and other one distal to critical region and not encompassing TBX1 gene but CRKL and LZTR1 genes.Conclusion The current study demonstrates the whole spectrum of atypical phenotypic and genotypic variations of 22q11.2DS in the largest prenatal case series reported to date. Therefore, differential diagnosis should be considered not solely in CHD, but also in the presence of isolated clubfeet and polyhydramnios. Establishing the diagnosis in the prenatal period may allow a postnatal multidisciplinary approach, as well as affect the actual prevalence of the disease.
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... These results suggested that the maintenance of Tbx1 levels within a certain range was required for the stability of the developmental system and that the sensitivity of an embryo to stochastic or environmental variation may be increased substantially when Tbx1 levels approached this critical threshold. This interpretation is consistent with a model whereby both genetic and stochastic factors could contribute to the severity of the disease, as is indeed suggested by observations of discordant phenotypes in monozygotic twins (Goodship et al., 1995;Yamagishi et al., 1998;Vincent et al., 1999;Hillebrand et al., 2000), and the variation in phenotypic severity in inbred mouse strains (Jerome and Papaioannou, 2001;Taddei et al., 2001). TBX1, therefore, appears to function as a central component that is required for the stability of the gene regulatory network(s) that control pharyngeal development (Baldini, 2005). ...
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22q11.2 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans, characterized by cardiovascular defects such as interrupted aortic arch, outflow tract defects, thymus and parathyroid hypo- or aplasia, and cleft palate. Heterozygosity of Tbx1, the mouse homolog of the candidate TBX1 gene, results in mild defects dependent on genetic background, whereas complete inactivation results in severe malformations in multiple tissues. The loss of function of two Sprouty genes, which encode feedback antagonists of receptor tyrosine kinase (RTK) signaling, phenocopy many defects associated with 22q11DS in the mouse. The stepwise reduction of Sprouty gene dosage resulted in different phenotypes emerging at specific steps, suggesting that the threshold up to which a given developmental process can tolerate increased RTK signaling is different. Tbx1 heterozygosity significantly exacerbated the severity of all these defects, which correlated with a substantial increase in RTK signaling. Our findings suggest that TBX1 functions as an essential component of a mechanism that protects the embryo against perturbations in RTK signaling that may lead to developmental defects characteristic of 22q11DS. We propose that genetic factors that enhance RTK signaling ought to be considered as potential genetic modifiers of this syndrome.
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... The correlation between genotype and phenotype can be low in 22q11.2DS, with even monozygotic twins demonstrating significant variability in symptom presentation (Goodship et al. 1995; Yamagishi et al. 1998; Hillebrand et al. 2000). However, similarities in brain morphometry exist between persons with 22q11.2DS ...
How might stress contribute to increased risk for schizophrenia in children with chromosome 22q11.2 deletion syndrome?
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Monozygotic twins with chromosome 22q11 deletion and discordant phenotype
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