Correspondence *Department of Pediatric Endocrinology and Diabetes, Medical University of Silesia, Katowice, Poland

Email etendera@slam.katowice.pl

The case

A 15-year-old girl was referred to our clinic for evaluation of short stature and delayed puberty. Her height was 139.3 cm (13.2 cm below the 3^rd percentile on a standard growth chart), her BMI was 25.8 kg/m² and according to the Tanner staging system for puberty her breast development was at stage 1 and pubic hair development was at stage 1–2. The patient's bone age, estimated with the Greulich and Pyle method, corresponded to that of a girl aged 12–13 years.

On physical examination she had micrognathia, epicanthus, a short webbed neck as well as cubitus valgus, shield chest and lymphedema (Figure 1). A number of pigmented nevi were observed on her face and body. During auscultation a low-pitched systolic murmur was noticed and an echocardiography was subsequently performed. This revealed coarctation of the aorta, a normal aortic-root diameter and no evidence of any valvular abnormalities. Coarctation of the aorta was not hemodynamically significant, with normal blood pressure measurements in both arms. A renal ultrasound revealed a horseshoe kidney and an ultrasound of the patient's pelvis showed a prepubertal uterus, but the ovaries could not be visualized. The plasma levels of follicle-stimulating hormone and luteinizing hormone were increased (follicle-stimulating hormone 113.2 mIU/ml [normal range 2.15 1,14 mIU/ml]; luteinizing hormone 22.9 mIU/ml [normal range 0.03 0.03 mIU/ml]).

Figure 1 The patient's phenotype.

The arrows point to some of the classical features of Turner's syndrome: (A) short webbed neck; (B) cubitus valgus; (C) lymphedema.

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In view of the patient's clinical features a standard 30-cell karyotype analysis was performed. This revealed a 45,X karyotype with no evidence of mosaicism, confirming the diagnosis of Turner's syndrome. The patient's height standard deviation scores (hSDS) were assessed according to a standard growth chart for healthy girls (hSDS -4.77) as well as a growth chart for Turner's syndrome patients (hSDS_Turner 0.30). Projected adult height was estimated on the basis of the growth chart for girls with Turner's syndrome and was 148.1 cm.

The patient started growth hormone therapy at a dose of 1 IU/kg/week (0.05 mg/kg/day) and oxandrolone at a dose of 0.05 mg/kg/day. As a result of the patient's relatively advanced chronological age and her wish to start puberty, she was also prescribed estrogen therapy. She received 12.5 g/day of transdermal estradiol during the first 2 months and 25.0 g/day thereafter. One year later, when breakthrough bleeding occurred, she was prescribed 50.0 g/day of transdermal estradiol together with progesterone.

On growth-promoting therapy the patient's height increased by 9.2 cm and she reached a final height of 148.5 cm (hSDS -2.90; hSDS_Turner 1.33). Growth hormone and oxandrolone were both withdrawn after 1 year because the patient's epiphyses had fused by that time. The height gain was assessed by comparing the achieved height with the projected adult height and the difference was only 0.4 cm. She reached pubertal stage 3 of Tanner's classification and continued her estrogen and progesterone replacement therapy. The patient seemed satisfied with her height and appreciated the fact that she had entered puberty.

Discussion of diagnosis

Turner's syndrome is the result of a complete or partial X-chromosome monosomy, with or without cell line mosaicism, in phenotypic females and is associated with characteristic clinical features, the most consistent being short stature and gonadal dysgenesis.^{1, 2, 3} Turner's syndrome occurs in 1 in 2,000–2,500 live-born females and is one of the most frequent chromosomal disorders.⁴

When Turner's syndrome is diagnosed prenatally, the diagnosis is usually based on the observation of fetal nuchal edema on ultrasonography, or on an abnormal fetal karyotype when karyotype analysis is preformed because of advanced maternal age. One fifth to one third of affected girls are diagnosed as newborn babies during investigations for puffy hands and feet or redundant nuchal skin. Turner's syndrome should be suspected in any newborn girl with edema or a hypoplastic left heart or with coarctation of the aorta. About 30% of girls with Turner's syndrome are diagnosed in mid-childhood while being investigated for their short stature. In other girls with Turner's syndrome, as in the case patient, the condition is diagnosed in adolescence when they fail to enter puberty or in adulthood when they are investigated for recurrent pregnancy loss.⁵

Karyotype analysis should be performed in all individuals with suspected Turner's syndrome. According to current recommendations, the diagnosis of this syndrome should be considered, even when there are no classical stigmata for Turner's syndrome, in any female with unexplained short stature or with a growth velocity below the 10^th percentile and in girls with pubertal delay with or without elevated levels of follicle-stimulating hormone.⁵

A standard 30-cell peripheral blood karyotype is recommended. If there is a strong clinical suspicion of Turner's syndrome and the blood karyotype is normal then a second tissue, for example skin, may be examined. There is some correlation between the karyotype and the phenotype of patients with Turner's syndrome, but nonetheless phenotypic predictions for a given patient based on their karyotype are unreliable.^{5, 6}

In a North American study⁷ of 81 females with Turner's syndrome, the average delay in establishing the diagnosis during childhood and adolescence was 7.7 5.4 years (mean SD). The study also documented that the majority of patients had several stigmata of Turner's syndrome at the time of diagnosis and this would have been expected to facilitate an earlier diagnosis. Consequently, the delay in diagnosis of this syndrome could not simply be explained by a lack of manifestations in this population.⁷ The presented case of a 15-year-old girl with a classic phenotype and additional abnormalities, including coarctation of the aorta and a horseshoe kidney, confirms the fact that several patients may not be diagnosed despite a characteristic phenotype. Our previous study, in which we assessed 67 girls with Turner's syndrome, also demonstrated that the total number of typical symptoms did not influence the age of diagnosis.⁸

In a Danish study the median age at diagnosis was 15 years (range 0–86 years).⁹ Belgian Study Group data have also shown that about 20% of girls with Turner's syndrome are diagnosed after the age of 12 years, most of them with a serious height deficit.¹⁰ These patients, like the patient we describe here, have missed the opportunity of earlier growth hormone treatment, which would have lead to a normalization of height during childhood, and they have also missed the opportunity of an age-appropriate induction of puberty.¹⁰

In addition, an early diagnosis of Turner's syndrome has other potential advantages, including the early detection and management of comorbidities such as hearing loss or hypertension and the possible prevention of serious complications such as aortic aneurysm formation, aortic dissection and rupture.¹¹

Treatment and management

A Canadian study, the first randomized controlled trial evaluating the impact of growth hormone treatment on adult height in patients with Turner's syndrome, has confirmed that growth hormone supplementation with induction of puberty at a near physiological age is effective in increasing the final adult height in patients with Turner's syndrome.¹² The optimal age for initiation of growth hormone treatment in this syndrome has not been established, but treatment should be considered as soon as growth failure (decreasing height percentiles on a standard growth curve) is demonstrated.⁶ According to the latest recommendations, growth hormone therapy is generally initiated at a weekly dose of 0.375 mg/kg. This is most effective when given daily and when administered in the evening. The dose can then be adapted according to the patient's growth response and their serum levels of insulin-like growth factor I.⁶

In girls older than 9 years of age or in those with an extremely short stature, higher doses of growth hormone and the addition of a non-aromatizable anabolic steroid such as oxandrolone should be considered.¹³ Since higher doses of oxandrolone are likely to result in virilization and more rapid skeletal maturation, this drug should only be administered at a daily dose of 0.05 mg/kg or less. During treatment with oxandrolone the patient's liver enzymes should be monitored.⁶

Growth-promoting therapy may be continued until a satisfactory height has been attained or until little growth potential remains (bone age >14 years and growth velocity <2 cm/year).⁶ Controversy exists regarding the efficacy of growth hormone therapy in girls with a significantly advanced bone age (13–14 years). In the patient described we were in no doubt that growth-promoting therapy should be used and our treatment protocol was as described above.

Absent pubertal development is one of the most common features of Turner's syndrome, although about 30% of girls with Turner's syndrome will undergo some spontaneous pubertal development. Ultimately, over 90% of individuals with Turner's syndrome will have gonadal failure⁶ and the case we report here is one of these.

Before the initiation of estrogen therapy, serum gonadotropin levels should be measured to exclude the possibility of delayed spontaneous pubertal development. When estrogen therapy is required to induce pubertal development, the form, dosing and timing should reflect the process of normal puberty. Delaying estrogen therapy until 15 years of age to optimize height potential, as previously recommended,¹⁴ seems unwarranted, and it is currently believed that low-dose estradiol therapy can be initiated as early as 12 years of age.⁶ This is only possible, however, if Turner's syndrome is diagnosed early enough. The present case illustrates the fact that, when the diagnosis of Turner's syndrome is delayed, one should always take into account the patient's desire to start puberty.⁹

Many forms of estrogen are available, but the transdermal and injectable depot forms seem to be more physiological alternatives than oral estrogen. Replacement therapy is usually begun at 1/10 to 1/8 of the adult replacement dose and then gradually increased over a period of 2–4 years. The usual adult daily dose is 100–200 g of transdermal estradiol, 2–4 mg of micronized estradiol, 20 g of ethinyl estradiol or 1.25–2.50 mg of conjugated equine estrogen. It is important to inform the patient that estrogen replacement therapy is usually required until the time of the normal menopause in order to maintain feminization and to prevent osteoporosis. To allow for normal breast and uterine development it seems advisable to delay the addition of progestin for at least 2 years after starting estrogen therapy or until breakthrough bleeding occurs.⁶

The presented case shows that a late diagnosis of Turner's syndrome can make the choice of an optimal hormonal regimen even more difficult. Although the patient's final height was 0.4 cm greater than predicted, one can speculate that this could have been improved further by delaying estrogen administration.

During the process of pubertal development it is important to engage the patient in a discussion about how Turner's syndrome and its treatment might affect her sexual development and function as well as her reproductive potential.

In this Case Study we have mainly concentrated on the hormonal therapy in a patient in whom the diagnosis of Turner's syndrome was delayed. Taking into account, however, the latest guidelines published by the Turner's Syndrome Study Group⁶ and the age and clinical features of the presented patient it is worth detailing another two important issues, which are the evaluation and monitoring of co-existing cardiovascular abnormalities and the transition from pediatric into adult care.

An analysis of congenital cardiovascular disease in Turner's syndrome has led to the recent recommendation that MRI should be performed to evaluate the cardiovascular system in patients with Turner's syndrome. In addition, there should be an increased focus on the regular monitoring of the systemic blood pressure and the aortic diameter in children and adults with Turner's syndrome.⁶ As a result of these recommendations, the described patient will undergo an MRI in the near future and she will continue to receive regular cardiological follow-up.

Another important issue in the management of patients with Turner's syndrome is the transition from pediatric to adult health care that should occur at the completion of growth and puberty, during late-stage adolescence. This is an appropriate time to promote a healthy lifestyle and to assess the patient's risk of developing adult morbidities associated with Turner's syndrome, such as osteoporosis, hypertension, diabetes and dyslipidemia. During the late-stage transition the pediatric endocrinologist should develop an adult care plan in close collaboration with the affected patient and her new health care provider.⁶

Conclusions

According to the present recommendations, the diagnosis of Turner's syndrome should be considered and a cytogenetic analysis should be performed in girls with an unexplained short stature and/or with primary or secondary amenorrhea, even when they have no other obvious abnormalities associated with Turner's syndrome.

When hormonal therapy is started in patients who have been diagnosed with Turner's syndrome the dose and timing of estrogen therapy should reflect the process of normal puberty, but at the same time it should not interfere with the positive effect of growth hormone treatment on the patients' final adult height. In order to establish an optimal hormonal treatment plan for a patient with a delayed diagnosis of Turner's syndrome it is also important to take into account the individual's desire to begin puberty.

Acknowledgments

Consent for the publication of Figure 1 was obtained from the patient.

References

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Subject areas under which this article appears: Reproductive endocrinology (including placental hormones) | Growth and development (including growth hormone and insulin-like growth factors)