Igor Alexander Harsch1, Thomas Heß2, Peter Christopher Konturek2

1Department of Internal Medicine II, Division of Endocrinology and Metabolism, Saalfeld/Saale, Germany

2Department of Internal Medicine II, Division of Gastroenterology, Saalfeld/Saale, Germany


Turner syndrome can be manifest with a considerable genetic and phenotypic variability. This merely accounts for about 50% of patients who do not have the “classic” 45 X genotype. We report the case of a 42-year-old female patient with a 46, X, del (X) q 21 genotype (deletion on the second X chromosome on the long arm). As the patient displayed a non-typical phenotype and was infertile, a diagnosis was established at the age of 24 with no follow-up treatment. As part of our therapy of the individual due to newly manifested diabetes mellitus, our diagnostic workup revealed a severe metabolic syndrome encompassing fatty liver disease, obstructive sleep apnea syndrome and hyperuricemia. Our observations should sensitize physicians treating female patients for one or more aspects of the metabolic syndrome and its presence in Turner syndrome. These patients have an unfavorable cardiovascular profile, in part due to the metabolic syndrome, but also due to factors intrinsic to Turner syndrome.

Key words: Turner Syndrome; metabolic syndrome; 46. X. del (X) q 21 subtype; morbid obesity; diabetes mellitus type 2; obstructive sleep apnea syndrome


Zespół Turnera może objawiać się znaczną zmiennością genetyczną i fenotypową. Problem ten stwierdza się u około 50% pacjentek, które nie mają „klasycznego” genotypu 45X. W poniższej pracy przedstawiono przypadek 42-letniej pacjentki z genotypem 46, X, del (X) q 21 (delecja na drugim chromosomie X na długim ramieniu). Ponieważ pacjentka charakteryzowała się nietypowym fenotypem i była bezpłodna, diagnozę postawiono dopiero w wieku 24 lat, jednakże chorą pozostawiono bez dalszego leczenia. W ramach objęcia pacjentki naszą opieką z powodu świeżo rozpoznanej cukrzycy, dalsza diagnostyka umożliwiła wykrycie ciężkiej postaci zespołu metabolicznego obejmującego stłuszczeniową chorobę wątroby, zespół obturacyjnego bezdechu sennego oraz hiperurykemię. Nasze obserwacje powinny uczulić lekarzy opiekujących się kobietami na jeden lub więcej aspektów zespołu metabolicznego i jego obecność w zespole Turnera. Pacjentki te charakteryzują się niekorzystnym profilem sercowo-naczyniowym, częściowo właśnie z powodu zespołu metabolicznego, ale także z powodu czynników charakterystycznych dla samego zespołu Turnera.

Słowa kluczowe: zespół Turnera, zespół metaboliczny, podtyp 46, X. del (X) q 21; chorobliwa otyłość; cukrzyca typu 2; zespół obturacyjnego bezdechu sennego

Wiad Lek 2019, 72, 1, 124-128


Turner syndrome (TS) occurs in one out of every 5000 live female births. The most common feature is a short stature. An early loss of ovarian function (ovarian hypofunction or premature ovarian failure) is also very common. About 30% of females with Turner syndrome have extra folds of skin on the neck (webbed neck), a low hairline at the back of the neck, lymphedema of the hands and feet, skeletal abnormalities, or kidney malformations. One third to one half of individuals with TS are born with a heart defect [1]. Apart from the phenotypical features, the unfavorable cardiovascular risk profile and the trend to develop obesity and other facets of the metabolic syndrome (MS) are noteworthy [2−4]. Hypertension affects up to 25% of the adolescents and 50% of the adults. It is mostly systolic and is often nocturnal [5]. The disorder is not that rare and the patients are not only treated by specialists or an interdisciplinary team, as guidelines suggest [6]. Physicians and primary care physicians in general should be aware of these non-gynecological problems, since there are sometimes significant differences between entitlement to care and care reality: This accounts for the case reported here of a patient with a severe metabolic syndrome as the main feature of her disorder and without gynecological co-treatment.

Next to the “classic” 45,X type, with one sex chromosome missing, that occurs in about the half of the cases, several different karyotypes exist. Some show deletions (del) on the second X chromosome on the short arm (p) or the long arm (q). Other striking features may be mosaicism of a 45,X cell line with another cell line, which might be 46,XX, 46,XY or have an abnormal sex chromosome rearrangement [7].

In case of the “rare” subtypes, several have been described in case reports, where the aspect of MS had not always been addressed. Such rare subtypes were reported by Sybert and McCauley [8], e.g.: 46,X,i(Xq) (the abbreviation i stands for “isochromosome”. The medical definition of an isochromosome is that of a chromosome produced by transverse splitting of the centromere so that both arms are from the same side of the centromere are of equal length and possess identical genes); (45,X/46,X,i(Xq); 45,X/46,X,+ring (ring means a breakage of chromosomes at both ends, and the ends of the chromosome join together to form a ring); 45,X/46,X,+mar (mar means marker chromosome which is a small fragment of a chromosome which generally cannot be identified without specialized genomic analysis due to the size of the fragment (the significance of a marker is variable as it depends on what material is contained within the marker); 45,X/46,XY or 46,X,Yvar/Ydel (var means a sequence variant); 45,X/46,XX/47,XXX; 45,X/46,XX; 46,X,Xp (short-arm deletions); 46,X,Xq (interstitial long-arm deletions); and others. In the report of Akbas et al. [7] the authors quote literature that indicates that patients with the 46,X,i(Xq) karyotype have characteristics similar to those observed in classical TS. The aspect of MS was not addressed in detail, maybe since many patients were very young. Some patients with deletions of Xq may merely have gonadal dysfunction as was reported e.g. by Kara et al. in the case of a 22-year-old female [9] or by Seki et al. [10] in the case of a 28-year-old old woman, or by Srivastave et al. [11] in a 19-year-old female.

As mentioned above, we transfer these descriptions of patients with a q deletion by the case on a 42-year-old, therapy naïve (!) woman with primary amenorrhoea and severe metabolic syndrome.


To highlight the presence of MS in TS and the elevated cardiovascular risk in TS. This does not only account for the „classic“ 45,X genotype, but also for rarer subtypes as reported here.


A 42-year-old Caucasian female was admitted to the outpatient department of our clinic due to newly manifested diabetes mellitus type 2 and intolerance against metformin (diarrhea). In assessing her further medical history, she also reported primary amenorrhea. As for the primary amenorrhea, she had presented herself to a gynecologist because of an unfulfilled desire to have a baby when she was 24 years old. The ovaries had been described as hypoplastic by her gynecologist and, to our surprise, she presented a chromosomic photograph with a diagnosis of 46,X,del (X) q 21 syndrome from 2003 (Fig. 1). Since the unfulfilled desire to have a baby was the main focus of her interest those days, no further diagnostic or therapeutic action had been taken.

She finished her school education at the age of fifteen (certificate of secondary education) and has been working as a caregiver for senior citizens ever since. In day-to-day interaction she shows a moderate cognitive impairment. A considerable weight gain has been taking place for 10 years. It is worth mentioning that a lipedema of the legs was diagnosed in 2012. She also consumes about 15 cigarettes daily. She had no cardiovascular events in her medical history.

Physical examination

The patient was 167 cm tall and weighed 124 kg (BMI 44 kg/m2 _ Obesity III° or morbid obesity according to the WHO’s definition). The waist circumference was 136 cm, the hip circumference was 130 cm. The blood pressure was 170/95 mm Hg. The typical short stature and the webbed neck was missing, but further physical examination showed the following features attributable to TS:

Several multipigmented naevi;

Low posterior hairline;

Flat nasal bridge;

Lipedema of the legs (Fig. 2, 3).

Instrumental diagnostics

In the ultrasonography of the abdomen, the sole pathological finding was a fatty liver and gallstones, the ovaries were not visualized.

The ultrasonography of the thyroid showed the right lobe with 20 x 20 x 50 ml, with an unremarkable and normal, perfused thyroid structure in the right lobe and a hypoechoic, well demarcated, 8 mm diameter nodule without increased blood flow. The thyroid volume of the left lobe was17 x 17 x 50 mm. No sonographical signs of autoimmune thyroiditis were observed.

The echocardiography showed no structural abnormalities except a diastolic relaxation abnormality.

Due to obesity, an overnight screening for sleep-disordered breathing was done, indicative of a mild obstructive sleep apnea syndrome (MiniScreen PlusTM Heinen Löwenstein). The Apnea/Hypopnea Index was 13.3, Respiratory Disturbance Index 14.8, Apnea-Index 0.4, Hypopnea-Index 12.9. Since the patient reported no daytime sleepiness, no further action was taken.

The bone density was measured by dual-energy X-ray absorptiometry (DXA Lunar Prodigy AdvanceTM): The T-scores (the T-score is the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient) of the lumbar spine were: L(lumbar)1 – L4: -0.9, right femoral neck: +0.2, left femoral neck: +0.2

The corresponding Z-scores (The Z-score is number of standard deviations above or below the mean for the patient‘s age, sex and ethnicity) were: L1 – L4: -2.1, right femoral neck: +0.5, left femoral neck: +0.5. That said, the patient had a normal bone density.

Laboratory findings

Uric acid: 383 µmol/l (137-363); total cholesterol: 5.89 mmol/l (< 5.2); HDL-cholesterol: 1.02 mmol/l (> 1.2); LDL-cholesterol: 4.48 mmol/l; triglycerides: 1.80 mmol/l (<1.7); Hba1c: 7.6 % (4.8-6); Thyroid Stimulating Hormone: 3.12 mU/L (0.27-4.2); Luteinizing Hormone: 18.9 IU/L; Follicle Stimulating Hormone: 29.5 IU/L; Estradiol (E2): 24.5 ng/L; Testosterone: 0.24 µg/l (0.084-0.481) (comment: as to be expected in this clinical setting, the gonadotropins are elevated and estradiol is relatively low, indicating a residual function of the ovaries). Serum transaminase levels were within the normal range.


According to the National Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (NCEP-ATP-III) [12], the diagnosis of “metabolic syndrome” is made if at least three of the following five criteria are met:

Abdominal fat distribution, determined by an abdominal circumference of over 102 cm in men or over 88 cm in women (Caucasian).

Serum triglycerides greater than 150 mg / dL (> 1.7 mmol / L), or therapy already initiated to reduce triglycerides.

HDL cholesterol ≤ 40 mg / dL (<1.05 mmol / L) in men or <50 mg / dL (1.25 mmol / L) in women.

Blood pressure of 130/85 mmHg or more, or already initiated therapy to reduce hypertension.

Fasting blood sugar ≥ 110 mg / dL (5.6 mmol / L), or type 2 diabetes.

In the case reported here, the patient meets all 5 criteria. It is well known and has already been mentioned that TS predisposes the patients to obesity and related metabolic disorders [13]. The current epidemiological evidence suggests that patients with TS have unfavorable cardiometabolic risk factors predisposing them to adverse cardiac and cerebrovascular outcomes in ages as early as young adulthood. It remains to be clarified whether these risk factors are intrinsic to TS or whether risk factors such as obesity, hypertension and hyperglycemia are contributing to this risk [14]. Unfortunately, some study results in an investigation of 30 TS patients were indicative that adult patients with TS under hormone replacement therapy are connoted by a higher frequency of central obesity, insulin resistance, hypercholesterolemia, and hypertension [15]. Other authors reported in 26 TS patients that sex hormone administration causes a deterioration in glucose tolerance, increases fat-free mass and physical fitness, and has beneficial effects on blood pressure. The deleterious effect on glucose tolerance was discussed to be mediated by norethisterone, a gestagen known to have androgenic effects [16].

The case described here is unusual in that, up to the age of 41, there had been no specific therapy for the TS (for example sex hormone replacement therapy), nor any treatment for the several facets of the metabolic syndrome. As desirable as the recommendations in the guidelines with a therapy by interdisciplinary teams are [6], even including transition [17], this case illustrates that there may be significant differences between entitlement to care and care reality. Patient compliance with treatment is also responsible for this. Thus, the non-specialist physician, who initially only treats individual aspects of the metabolic syndrome, may suddenly be confronted with the clinical picture of TS.

It lies in the logic and the nature of the condition that patients who do not have the “classical” 45 X TS but a deletion in the second X chromosome as reported here are likely to express some features of the classic TS, although malformations did not occur in her case. As to be expected in an estrogen-deficient state, osteoporosis is considered a comorbidity of adult women with TS [18]. However, the patient reported here had normal bone density. As already mentioned in the laboratory data, estradiol was relatively low, but detectable in the serum, indicating a residual function of the ovaries that may have prevented osteoporosis yet.

Interestingly, case reports about patients especially affected with the 46, X, del (X) q 21 condition do not report such explicit metabolic syndrome characteristics as we observed in this case (e.g. Kara et al. in the case of a 22-year-old female (9) or by Seki et al. [10] in the case of a 28-year-old woman, or by Srivastave et al. [11] in a 19-year-old female). These patients may have been too young or just on the way towards developing MS. It remains speculative whether MS could have been delayed by sex hormone therapy in our very case. However, recent data suggest that sex hormone therapy may not have a preventive effect [2].

As shown in the literature, TS can be present with a great variety of chromosomal aberrations. It was not in the focus of the report to work out a precise update of the chromosomal defect in this very patient. To clarify the role of Xq in ovarian function the accurate description of such abnormalities requires a combination of cytogenetic and DNA-hybridization analysis [19]. Recently, clinical practice guidelines for the care of girls and women with TS were published and may also be helpful for a non-specialized physician having to treat a TS patient, as in our case [6].


In treating female patients with MS, physicians should be aware of TS in general. TS goes hand in hand with a considerable variability in the phenotype. As reported here, even a diagnosis of TS does not necessarily mean that a patient had or wanted an appropriate therapy in earlier years, given the discomforts caused by the disease were not high enough to desire therapy. In treating female patients with diabetes and/or MS physical examination and a history of amenorrhea or premature ovarian failure is mandatory. Depending on the ethnicity and classification criteria, the polycystic ovary syndrome is more frequent with estimates between 5.5-16% [20]. At first glance in this case, some metabolical and phenotypical features may share similarities, especially in TS patients that do not express the “classical” phenotypes. Since the therapeutic approach and the aftercare is different, both conditions need to be considered.


The patient gave written permission to publish her case.


The authors thank R. Harsch (BA Translation) for language editing and A. Ortloff for the help in organizing the diagnostic workup.


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Conflict of Interest:

There is no conflict of interest.

Corresponding author

Igor Alexander Harsch

Thuringia Clinic Saalfeld “Georgius Agricola”

Rainweg 68, D-07318 Saalfeld/Saale, Germany

tel.: +49[0]3671/541569; Fax.: +49[0]3671/541403

e-mail: iharsch@thueringen-kliniken.de

Received: 30.12.2018

Accepted: 16.01.2019

Fig. 1 Chromosomic photograph from the 42-year-old patient.

Fig. 2. The picture shows the patient from behind. Notice the rather android fat distribution.

Fig. 3. The picture shows the patient from the side. Notice the rather android fat distribution.