MOLECULAR ANALYSIS OF RING Y CHROMOSOME IN A 10-YEAR-OLD BOY WITH MIXED GONADAL DYSGENESIS AND GROWTH HORMONE DEFICIENCY
Milenkovic T1,*, Guc-Scekic M2, Zdravkovic D1,3, Topic V4, Liehr T5, Joksic G6, Radivojevic D2, Lakic N2
*Corresponding Author: Tatjana Milenkovic, Department of Endocrinology, Institute for Mother and Child Healthcare of Serbia “Dr. Vukan Cupic,” Radoja Dakica 6-8, 11 070 Belgrade, Serbia; Tel.: +381-11-3018-109; Fax: +381-11-3108-257; E-mail: tanjamil@eunet.rs
page: 71

DISCUSSION

We present a male patient with MGD and a mosaic karyotype with a high percentage of monosomic 45,X cell line and two ring (Y) variants presented in different combinations within at least three cellular subpopulations. Cytogenetic, molecular cytogenetic and molecular analyses demonstrated that the two breakpoints on the Y chromosome were localized on the Yp arm (between the subtelomeric region and the telomere) and the Yq arm at Yq12 (the AZF region was present), respectively, leading to fusion of the broken ends and loss of genetic material. As the father’s karyotype is normal, ring formation occurred de novo in this patient. The presence of two ring (Y) variants, monocentric ring Y and dicentric ring (Y;Y), could result from the specific behavior of the ring chromosome during mitosis depending on the number of sister chromatid exchanges (SCEs). These SCEs could result in the formation of dicentric Y chromosomes, which would then undergo unequal partition during successive mitotic divisions inducing the formation of rings of different sizes [4,21]. Non disjunction could produce a general increase in the number of rings in different cellular populations, as was the case in our patient. The high percentage of the monosomic 45,X cell line in our patient, due to the instability of the ring chromosome during mitosis, could explain his short stature. The presence of subtelomere Yp signal on the r(Y) chromosome suggests that the genetic material loss implicated in ring Y formation did not include the SHOX/PHOG gene, which is localized in the PAR1 region [4,21,22]. Molecular analysis showed the presence of the SRY gene. The dicentric ring (Y;Y) found in one cell suggests the presence of a cell line with two copies of SRY. More cells carrying the SRY gene result in more testicular structures and increased virilization due to higher production of testosterone by Leydig cells [2]. Bettio et al. [23] indicated that phenotypic sex is determined by the presence of the 45,X vs. SRY-bearing cells and depends more on the number of copies of the SRY gene rather than on the percentage of 45,X cells, at least in the gonads. The degree of mosaicism varies between tissues, and a mosaic karyotype is often associated with MGD [24]. Molecular analysis showed the presence of AZF (AZFa, AZFb, AZFc), SRY and ZFY/ZFX genes that correlated with the pathological findings at testis biopsy, which revealed testicular tissue with initial spermatogenesis. Also, there was a normal testosterone response to a short HCG test. According to the literature, the association of mixed gonadal dysgenesis and ring Y chromosome is extremely rare [2,12]. Our patient is the third patient with such abnormalities to be described in the literature. All patients have been short for their target height, but the two previous cases were not reported to have GH deficiency (Table 1). In our patient, the diagnosis of severe GH deficiency was established according to results of clonidine test as well as results of overnight profile of GH. Thus, he is the first reported case of gonadal dysgenesis associated with a ring Y chromosome whose short stature could be explained not only by the presence of a high percentage of monosomic cells, but also by GH deficiency. The first-year response to GH treatment with a standard dose of GH was successful. Normal levels of IGF-1 and IGFBP-3 could be explained by obesity, insulin resistance and hyperinsulinemia [25]. As with one patient reported previously [12], our patient was obese with significant acanthosis nigricans and pseudogynecomastia. His obesity was secondary to excessive food intake, consistent with the family’s overall nutrition. Insulin resistance and acanthosis nigricans could be explaines as a common finding in obese children, as well as his advanced bone age. The obesity and acanthosis persisted after 1 year of GH therapy suggesting that the obesity at presentation was not a consequence of hypopituitarism. Although short stature in patients with MGD associated with ring Y chromosomes can almost always be explained as a consequence of the high percentage of monosomic cells, or loss of SHOX and other genes important for growth, test for GH secretion should be performed in each child with impaired growth. Further studies are necessary to define the importance of provocative tests and/or overnight profile of GH in short patients with MGD.



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