Double Isochromosome X, a Rare Cytogenetic Variant of Turner Syndrome: A Case Report and a Review of the Literature

Abstract

Turner Syndrome (TS) is a genetic disorder caused by total or partial loss of an X chromosome. The isochromosome X (i(X)) is a known variant of TS, however, double i(X) is a very rare variant, reported very few times in the literature. We report on a rare case of TS with double i(X). This is an 11-year-old female patient , addressed to the medical genetics consultation for short stature and facial features suggestive of TS. We performed a constitutional postnatal karyotype from a peripheral blood sample, with lymphocyte culture, and an R band analysis, performed on 70 metaphases. Metaphases analysis in our patient identified the presence of three cell populations: 45,X[22]/46,X,i(X)(q10)[30]/47,X,i(X)(q10),i(X)(q10) [18]. The first has total chromosome X monosomy, the second with a normal X chromosome and one isochromosome of the long arm of the other X chromosome and the third with a normal X chromosome and two isochromosomes of the long arm of the X chromosome. A control cell culture was performed from a second blood sample of the patient and confirmed the abnormality. This paper will discuss this case in comparison with other rare cases described, as well as the formation of the double isochromosome, based on the literature.

Introduction

Turner Syndrome (TS) is a genetic disorder caused by total or partial loss of an X chromosome(1). Its first clinical description was in 1938 by Henry Turner and the chromosomal abnormality was found in 1956 by C.E Ford (2). This is the most common chromosomal abnormality in girls. It occurs in 1 in 2,500 live-born females (1,3). Phenotypical presentation is heterogeneous (4). A chromosomal analysis (karyotype) confirms the diagnosis and shows a total monosomy of the X chromosome (45,X) in about 50% of cases, or with other forms represented by mosaic formulas and structural anomalies of the X chromosome (deletions, ring, isochromosome). The isochromosome X (i(X)) is a known variant of TS, however, double i(X) is a very rare variant, reported very few times in the literature (5). We report on a rare case of TS with double i(X), and we review the literature regarding this rare anomaly.

Patients and methods

An 11-year-old female proband, the second of her siblings, non-consanguineous, her father (60 y/o) and mother (50 y/o). The pregnancy was well followed. The mother had a full term birth by a cesarean delivery due to the mother’s narrow pelvis. There was no neonatal distress. The child’s birth weight was 1500 g. Psychomotor development was normal except a delayed walk at the age of 3 years a half.

The clinical examination of the patient showed short stature, with a height of 115 cm (-3 SD) and a weight of 21 kg (-2 SD), palpebral slits slightly oriented up and out, low posterior hairline, broad chest with widely spaced nipples and a pectus excavatum. The patient is not yet pubescent (B1P1 according to tanner classification). These clinical findings have led us to suspect Turner Syndrome.

We performed a constitutional postnatal karyotype from a peripheral blood sample with a lymphocyte culture in our laboratory, using conventional RHG banding, and we analyzed 70 metaphases.

Results

Metaphases analysis in our patient identified the presence of three cell populations:

• −The first one has total chromosome X monosomy and represents 31% of the metaphases analyzed (Figure 1).
• −The second, with a normal X chromosome, and one isochromosome of the long arm of the other X chromosome, found on 43% of the metaphases analyzed (Figure 1).
• −The third one, with a normal X chromosome and two isochromosomes of the long arm of the X chromosome, found on 26% of the metaphases analyzed (Figure 1).

Figure 2.

Diagram showing mitotic nondisjunction from gametes having a double isochromosome.

A control cell culture was performed from a second blood sample of the patient and confirmed the chromosomal abnormality.

Discussion and conclusion

Isochromosome X is a structural chromosomal abnormality of the X chromosome that consists of two copies of either the p arm or the q arm, derived by centromere division (5). This results in an abnormal X chromosome whose two arms are genetically identical and causes TS. The most common isochromosome observed in the literature is the isochromosome for the long arm of the X chromosome (6). With or without mosaicism, its frequency was reported to be 15-18% in TS cases (7).

To our knowledge, the double i(X) is a very rare entity, described less than 10 times in the literature. The percentage of double i(X) ranges from 5% in Howell et al. to 36% in Melaragno et al. (8,9). The percentage of double i(X) is 26 % in our case (Table 1).

Table 1.

Phenotype and Karyotype summary of cases with double Isochromosome X.

			Phenotype						Karvotype (percentage of cell)
	Age	Psychomotor development	Stature	Spaced nipples	Low-set hairline	Others	Thyroid finction	Tanner	45,X	46X.i(X)	47,X,i(X), i(X)	48,X, i(X), i(X), i(X) i(	49.X, X), i(X), i(X), i(X)
Our case	11	Normal	-3SD	+	Posterior	Up-slanting palpebral fissures	Euthyroids	B1P0	31	43	26	-	-
	25	NA	<-3 SD	NA	NA	NA	Hyperthyroidism	B3P4	44,5	21,6	33,3	0,6	-
Melargno 1993(9)	11	NA	<-3 SD	NA	Posterior	Cubitus pigmented valgus, nevi	NA	B1P1	53,3	25,3	19,3	-	-
Margaret all 2010(19et )	17	NA	<-3 SD	NA	NA	NA	NA	developped Poorly	4	88	8	-	-
Howell 1976el (8) al,	18	Normal	<-3 SD	NA	NA	NA	NA	Development after therapy	19	82	5	-	-
Palmer and Reichmann 1976(20)	NA	NA	NA	NA	NA	NA	NA	NA	50 5 18	48 90 78	2 5 2	- - 2	- - -
Niebuhr et al. 1977(21)	10	Normal	<-3 SD	+	NA	Labia majora clitoris absent, cubitus valgus.	NA	NA	18	78	4	-	-
	16	NA	<-3 SD	-	+	NA	NA	B1	72	25	3	-	-
	8	NA	NA	NA	NA	NA	NA	Pubic hair	47	46	7	-	-
Lillian 1978(et 22al. )	NA	NA	<-3 SD	-	+	Cubitus valgus	NA	NA	36	62	2	-	-
Huang 2020(etal. 23)	30	Normal	-2 DS	NA	NA	NA	hypothyroidism	NA	1	49	1	-	49

NA: not available, SD: standard derivation, (B: Breast, P: Pubic hair: Tanner classification)

The absence of a normal population 46,XX indicates that the formation of i(X) occurred during meiosis by an isochromatid break and fusion of the daughter chromatids above the centromere or, by transverse division instead of longitudinal division of the centromere during cell division (10). We noticed that in all previously reported cases of TS with double i(X), the isochromosomes were dicentrics. This suggests that mosaicism is a consequence of the instability of the dicentric chromosomes (9). We could pretend, in our case, that the i(X) is dicentric resulting in fusion of daughter chromatids. The segregation of the chromosome during cell division is normal due to one of the two centromeres of the dicentric isochromosome usually becoming non-functional (5) . However, in this case, there is a failure of homologous chromosomes or sister chromatids to separate properly during cell division. There are three forms of nondisjunction: failure of sister chromatids to separate during mitosis (10,11). This latter mechanism is responsible for the presence of these three cell populations in our patient (Figure 2). Failure of a pair of homologous chromosomes to separate in meiosis I and failure of sister chromatids to separate during meiosis II.

Figure 1.

Results of R banding Karyotype: a) The first cell population: 45,X; b) The second cell population: 46,X,i(X)(q10); c) The third cell population: 47,X,i(X)(q10),i(X)(q10).

The structural or numerical abnormality of X chromosome causes TS (4). The phenotypes of TS are very heterogeneous depending on the type of abnormality (12). The most common feature is short stature, which is found in 95% of patients, especially in patients with 46,X,i(Xq).

This can be explained by the haplo-insufficiency of the short stature homeobox gene (SHOX), that is in the pseudoautosomal region (PAR1) (refractory to X inactivation) in the short arm of X chromosome (13, 14, 15, 16).

Ovarian dysgenesis, congenital lymphedema, pterygium colli, and some facial features are also described in TS (17). Some physical appearances of patients are generally related to bone abnormalities such as a short neck, cubitus valgus, and Madelung deformity. In our case, the proband has a short stature, some facial features, and delayed development of secondary sex characteristics, yet she has no heart disease, no bone abnormalities, thyroid function tests are normal and she does not complain from digestive symptoms. In general, the 46,X,i(Xq) and 45,XO karyotype show the same clinical manifestations of Turner’s Syndrome (18). The other patients described with the 3 cells lines with double i(X) have also a phenotype suggesting TS.

Most often, Turner Syndrome is a sporadic event, and the risk of recurrence is not increased in subsequent pregnancies (4). As we explained above, the formation of the iso X in our patient took place during meiosis, therefore a karyotype of the parents is not necessary.

The parents benefited from a genetic counseling consultation and the patient has regular medical follow-ups with the pediatricians to screen for other possible clinical manifestations and to establish hormonal treatment.

List of abbreviations

TS

Turner Syndrome

i(X)

isochromosome X

SD

Standard deviation