Turner syndrome is one of the most frequent chromosomal disorders and has an increased associated morbidity. The clinical picture of Turner syndrome reveals itself gradually, not every patient exhibits the full clinical picture, but gonadal dysgenesis and short stature are invariably present. We describe the long-term outcomes in a cohort of 41 patients with Turner syndrome followed at the Regional Center for Medical Genetics Bihor. A retrospective study was performed using the medical records; epidemiological, clinical, laboratory, cytogenetic, and imaging data were analyzed. The frequency of congenital heart abnormalities and intellectual disability was increased in the study group, necessitating a more effective screening technique in our country, to identify all the cases with TS. Early diagnosis and hormonal treatment are critical for a patient's favorable prognosis in stature, bone metabolism, cardiovascular system, and quality of life. Patients with TS have higher rates of related morbidity, especially skeletal, kidney, ophthalmological, and dermatological and a multidisciplinary team is essential for the management of TS cases.
INTRODUCTION
Turner syndrome (TS) is one of the most frequent chromosomal disorders, with a birth incidence of 1 in 2000 live-born girls [1, 2]. Incidence at birth is much higher, about 98% of pregnancies with Turner syndrome are lost as miscarriages and stillbirths [3]. In half of the cases, it is caused by the absence of a sexual chromosome due to meiotic nondisjunction [4]. Mosaic Turner syndrome occurs due to mitotic nondisjunction, and the patient exhibits different combinations of monosomy cell lines with normal cell lines or other abnormal cell lines. Mosaicism has been reported frequently in aneuploidies and it seems to influence the survival rate [5, 6]. Rarely, it is caused by partial deletions which include pseudoautosomal regions 1 and 2 (PAR1, PAR2), or structural anomalies like isochromosome Xq and ring chromosome X [7]. The clinical picture of Turner syndrome reveals itself gradually: at birth borderline small for gestational age, broad chest with widely spaced nipples, congenital lymphedema, and congenital heart defects (coarctation of the aorta, bicuspid aortic valve); in infancy short stature, recurrent ear infections and sometimes hearing loss; in adolescence absent or incomplete puberty, specific learning difficulties, and immune disorders; in adulthood fertility problems, aortic dilatation, hypertension and many more [2]. Not every patient exhibits the full clinical picture, but gonadal dysgenesis and short stature are invariably present. Traditional treatment aims to treat the complications, and the modern approach includes also medical treatment with growth hormone and estrogen-progesterone substitution [8, 9]. The study aims to evaluate the long-term outcome in a cohort of 41 patients with Turner syndrome registered between 1983 and 2023.
MATERIALS AND METHODS
Subjects
We have conducted a retrospective study involving the medical records of 41 patients registered with the Regional Center for Medical Genetics Bihor, part of the Emergency Clinical County Hospital Bihor, Oradea, Romania. In the study, we included patients with a cytogenetically confirmed diagnosis of TS and were reevaluated regularly.
Data
Epidemiological, clinical, laboratory, cytogenetic, and imaging data from the medical records were analyzed.
Cytogenetics
All the patients had been genetically investigated by peripheral blood karyotype using standard cytogenetic methods (lymphocyte cell culture and G-banding karyotype analysis). Fluorescence in situ hybridization (FISH) tests using CytoCell Y chromosome-specific probes were performed in selected patients.
RESULTS AND DISCUSSION
The Regional Center for Medical Genetics Bihor has 52 patients with TS registered between 1983 and 2023. From this lot, 11 patients (21%) have been lost during the transition to adulthood and only 41 patients had followed periodic reevaluations. Some of the patients have been followed for over 30 years, the distribution of patients by age is presented in Table 1.
Table 1. Distribution of patients by present age |
||
Present age |
Number of cases |
% |
5 |
14% |
|
Between 11-30 years |
13 |
32% |
Between 31-60 years |
23 |
54% |
Total |
41 |
100% |
Note. %= Percentage
The diagnosis was established at birth, in about a third of the patients, the rest being diagnosed at puberty or in adulthood (Figure 1). None of the cases benefitted from prenatal diagnosis. Compared to other studies [10, 11] the diagnosis was late and was driven by short stature in childhood, respectively short stature and delayed puberty later.
Figure 1. Distribution of patients by age at diagnosis |
Regarding the age of the mother at conception we noticed that in more than half of the cases, the age of the mother was over 30 years, with the presence of the maternal age effect, as described in other aneuploidies [12, 13] (Table 2).
Table 2. Distribution of patients by maternal age at conception |
||
Maternal age |
Number of cases |
% |
18 |
44% |
|
31-40 years |
19 |
46,3% |
41-50 years |
3 |
7,3% |
Over 50 years |
1 |
2,4% |
Total |
41 |
100% |
Note. %= Percentage
Clinical features at birth described in the literature were present in our lot as follows: prenatal growth deficiency (14 cases, 34%), congenital lymphedema (4 cases, 9,7%), and congenital heart anomalies (40 cases, 97%). Compared to other studies in the literature, the incidence of congenital heart anomalies is very increased [14]. We suspect that only the severe cases of TS have been registered with the genetic department, while the mild cases, without heart anomalies, are underdiagnosed.
The karyotype revealed monosomy X in more than half of the cases (51%). In a third of the cases (13 cases), mosaicism was detected as follows: 45, X/46, XY (1 case), 45, X/46, Xi(Xq) (1 case), and 45, X/46, XX (11 cases). Structural anomalies such as ring chromosome X or isochromosome Xq were found in 17% of the cases (Figure 2).
Figure 2. Distribution of patients by karyotype |
Genotype-Phenotype Correlations
Isochromosome Xq usually is associated with an increased risk of autoimmunity, particularly thyroiditis, and deafness, and the risk increases with age [4]. Women with the ring X chromosome are more likely to have psychological sequelae but are less likely to have structural congenital abnormalities, and spontaneous menses occur in about a third. Mosaicism 45X/46, XY is associated with an increased risk of developing gonadoblastoma, and a minority of these women are masculinized [4].
In our study group, there were no significant variations between the clinical pictures of patients with monosomy 45, and X and those with structural anomalies. A milder clinical picture was seen in cases of mosaicism with normal cell lines 45, X/46, and XX. Morbidity was increased, but the severity of accompanying problems was usually mild, and no patients died.
Phenotype-Treatment Correlations
Short stature with more than minus 3 standard deviations (-3SD) was present in all the cases. The safety and efficacy of growth hormone (GH) therapy were demonstrated in several studies [15-20]. 27% of the patients have followed GH treatment and have exhibited better growth (average of +1DS) compared to patients who did not follow GH treatment. The best outcome was a 30 cm growth in 5 years, and the final stature of the patient was 158 cm (-1 SD). Early diagnosis and treatment are essential for the good prognosis of a patient with a TS [21].
Gonadal dysgenesis with primary amenorrhea was observed in all the cases. Estrogen deficiency causes three specific problems: short stature, cardiovascular disease, and developmental differences in the brain [18]. Long-term estrogen replacement therapy is necessary in TS cases after puberty and completion of growth as it reduces osteoporosis and atherosclerosis. Recently, it has been shown that estrogen replacement may improve aspects of cognitive function in women with TS [22-25]. Estrogenic therapy was provided in 17 cases (41%). A combination of growth hormone and estrogen is recommended as it increases bone mineralization in girls with TS [9].
Other Features
Intellectual disability (ID) is not a mandatory feature in TS. Most patients have normal intelligence but may exhibit learning difficulties, and up to 10% can present ID. In our study lot, intellectual disability was noticed in 10 cases (24%), mostly mild ID (12%) (Table 3).
Aside from ID, behavioral issues and social isolation were reported in 17 cases (41%), primarily in patients who did not receive any hormonal treatment.
Table 3. Distribution of patients by intellectual development |
||
Number of cases |
% |
|
Normal |
31 |
76% |
Mild intellectual disability |
5 |
12% |
Moderate intellectual disability |
3 |
7% |
Severe intellectual disability |
2 |
5% |
Total |
41 |
100% |
Note. %= Percentage
All the patients had at least one skeletal anomaly such as anomalies of the chest, scoliosis, genu valgum club foot, congenital hip dysplasia, and polydactyly or syndactyly. Other features observed in our study lot were: kidney disorders like polycystic kidney and renal microadenomas (13 cases, 32%); ophthalmological disorders such as strabismus, astigmatism, myopia, and congenital cataract (33 cases, 80%); and dermatological features like melanocytic naevus and hemangiomas (13 cases, 32%), webbed neck (7 cases, 17%), seizures (1 case, 9,7%), and schizophrenia (1 case, 9,7%). Type 2 diabetes mellitus is 2-4 times more frequent in TS cases and the onset age is at a young age [23, 26]. None of the cases we studied were associated with diabetes.
Long-term complications included high blood pressure (21 cases, 51%) and arthritis which required physiotherapy (17 cases, 41%).
CONCLUSION
Besides short stature and gonadal failure, patients with TS have higher rates of related morbidity, especially skeletal, kidney, ophthalmological, and dermatological and a multidisciplinary team is essential for their management. The frequency of congenital heart abnormalities and intellectual disability was increased in the study group, necessitating a more effective screening technique in our country, to identify all the cases with TS. Early diagnosis and hormonal treatment are critical for a patient's favorable prognosis in stature, bone metabolism, cardiovascular system, and quality of life.
ACKNOWLEDGMENTS: None
CONFLICT OF INTEREST: None
FINANCIAL SUPPORT: None
ETHICS STATEMENT: The study was conducted under the Declaration of Helsinki and approved by the Institutional Ethics Committee of Emergency Clinical County Hospital Bihor (protocol code 23395/06.07.2023).
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