Division of Pediatric Endocrinology, Albert Einstein College of Medicine, Montefiore Hospital Medical Center, Bronx, New York 10467
Address correspondence and requests for reprints to: Division of Pediatric Endocrinology, Albert Einstein College of Medicine, Montefiore Hospital Medical Center, 111 East 210th Street, Bronx, New York 10467.
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Introduction |
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Molecular studies have shown that the maternal X is retained in two thirds of patients with Turners syndrome and the paternal X in the remaining one third (10, 11). More than half of all patients with Turners syndrome have a mosaic chromosomal complement, (e.g., 45,X/46,XX) (12, 13, 14). Mosaicism with a normal cell line in the fetal membranes may be necessary for adequate placental function and fetal survival (15, 16).
The identification of mosaicism depends directly on the method of ascertainment. It varies from 34% with conventional cytogenetic techniques to 60% with fluorescence in situ hybridization techniques to 74% in a study in which RT-PCR assays were used (17).
Many patients with Turners syndrome lack only part of one X chromosome, and the Turners syndrome phenotype can be seen with a variety of structural abnormalities, such as rings, isochromosomes, or terminal deletions. A rare but very informative class of Turners syndrome includes patients who have deletions of the Y chromosome that remove the testes determining gene SRY. These individuals develop as females. Based on this finding and the fact that males require only one X chromosome for normal development, Ferguson-Smith (13) hypothesized more than 30 yr ago that copies of Turners syndrome genes are also present on the Y chromosome.
Specific localization of Turners syndrome genes proved elusive until recently when one group successfully demonstrated that a gene located in the pseudoautosomal region (PAR 1) at the tip of the short arm of the X chromosome (Xp 22.3) is related to short stature in Turners syndrome. This pseudoautosomal deletion encompassing a novel homeobox gene, SHOX (short stature homeobox containing gene on the X chromosome), is associated with short stature in Turners syndrome and also with some cases of idiopathic short stature (18). Independently, the same gene was identified by a different group and was termed pseudoautosomal homeobox-containing osteogenic gene (PHOG). The SHOX gene encodes a homeodomain-containing protein that most likely functions as a transcription regulator. Dosage sensitivity is a common feature of such regulatory genes in the pseudoautosomal region. They escape X inactivation and have functional homologs on the Y chromosome (19, 20, 21). It is, therefore, hypothesized that haploinsufficiency of the SHOX gene is the underlying cause of growth impairment in patients with Turners syndrome (18, 22).
The tips of the short arms of the chromosomes X and Y are logical sites for Turners syndrome genes, as sex chromosomes undergo meiotic recombination within the pseudo-autosomal region and all genes in this region that have been examined escape X inactivation. Characterization of XYP females provides additional support for the hypothesis of a distinct Turners syndrome stature locus: most of these patients have unbalanced X,Y translocations and, in the most fully documented patients with this karyotype, two intact copies of the pseudoautosomal region are present. It is not surprising that these patients attain normal stature despite the presence of features consistent with Turners syndrome. A 700-kb interval in the pseudoautosomal region is, therefore, the most probable site for a Turners syndrome stature locus, and SHOX is an excellent candidate for a Turner syndrome stature gene (18, 23).
Studies that have examined the relationship between the chromosomal and karyotypic abnormalities and clinical findings in patients with Turners syndrome have been disappointing.
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Endocrine Manifestations of Growth Failure |
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Many patients with Turners syndrome are also stocky and have a squarely shaped chest. Affected neonates have congenital lymphedema of the hand and feet, a webbed neck, and a low hairline. Short stature is the single most common physical abnormality in Turners syndrome, and individuals not treated with growth-promoting techniques achieve an adult stature 20 cm shorter than that of the normal population. The height of patients with Turners syndrome, when plotted on growth curves specific for this disorder, show that growth velocity declines often as early as 24 yr of age below the growth curve normal for females.
In patients with Turners syndrome, adult height is short due to poor growth rates in utero in infancy and childhood and a pronounced lack of pubertal growth. The normal pubertal growth spurt does not occur in Turners syndrome. Bone age is further delayed during adolescence due to the lack of estrogenic influence on the skeleton. However, adult final height of untreated patients is not greater in the approximately 25% of girls with Turners syndrome who experience spontaneous puberty. Final height of untreated patients correlated significantly with midparental height (r = 0.7) (26). Recent data (27) indicate that growth failure is already present in the first 2 postnatal yr. Furthermore, growth charts for individuals 218 years of age demonstrate that the majority of girls with Turners syndrome are below the fifth percentile for height by the age of 2 yr. Davenport et al. (27) observed that mean height SDS fell from -0.5 at birth to -1.7 at age 1 yr and -2.0 at age 1.5 yr. Management of growth failure is now a common part of pediatric endocrine therapy for these patients although diagnosis and initiation of therapy is still, unfortunately, inexcusably delayed for many patients.
How short stature in girls with Turners syndrome is treated will affect many other aspects of this disorder, including the age at which estrogen replacement can be begun, socialization, and academic achievement.
There is no need to measure serum GH levels, except possibly in those who are growing more slowly than the average patient with Turners syndrome. Serum GH is usually normal, and measurement will not affect therapy. Third party payers should, therefore, not require GH secretory assessment of Turners syndrome before initiation of GH therapy.
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Growth-Promoting Strategies in Turners Syndrome |
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Subjects were randomly assigned to one of four study arms: 1) a control group receiving no therapy; 2) oxandrolone (125 mg/kg·day; 3) human GH (125 mg/kg three times per week; 4) combination of human GH and oxandrolone at the doses stated previously.
After 1 to 2 yr, in the first phase of the study, subjects receiving GH alone continued to receive this treatment, whereas all other subjects received the combination of oxandrolone, although the latter at a reduced dose of .625 mg/kg·day. After 2 yr in the second phase of the study, recipients of GH alone continued to receive only GH at a total weekly dose of 0.375/mg·kg ,which was divided into seven daily administrations. Subjects receiving GH plus oxandrolone were randomly assigned to continuing combination treatment with GH administered either daily or three times per week at the same total weekly dose of 0.375 mg/kg. Estrogen therapy was delayed in all subjects until they had reached a minimum chronological age of 14 yr and had been in the study at least 3 yr. Administration of conjugated estrogens was begun at 0.3 mg/day (Premarin) and increased to 0.625 mg/day after 6 months. After 1 yr, estrogen replacement was given cyclically and progesterone was added.
The mean adult height for recipients of GH alone was 150.4 ± 5.5 cm, 8.4 ± 4.5 cm above the projected adult heights. Thus, 58 of the 62 GH-treated subjects (94%) attained adult height greater than their projected adult heights (29). For the 43 subjects treated with a combination of GH and oxandrolone, the mean adult height was 152.1 cm ± 5.9 cm, 10.3 ± 4.7 cm taller than their projected adult heights. oxandrolone, a nonaromatizable androgen, is indicated particularly in Turners syndrome patients ascertained late with a limited amount of time for growth promotion available. In young children (under age 8 or 9 yr), it may not be necessary. In any case, after approximately 4 yr of therapy, growth velocity in the combination group (GH and oxandrolone) was identical to the GH alone group. These results compare favorably not only with the matched American control group, but also with previous reports of final heights of girls with untreated Turners syndrome from the United States and many other countries (30, 31, 32, 33, 34). The mean adult height attained by a retrospective control group as part of this study was 144.2 ± 6.0 cm.
These results compare also favorably with preliminary data from a second United States study in which 29 girls receiving GH alone (plus estrogen replacement at 15 yr of age) achieved a mean height at 16.3 ± .9 yr of 150.4 ± 6.0 cm, 8.4 ± 4.3 cm above their pretreatment projected adult heights (35, 36). The patients whose estrogen therapy was delayed until age 15 grew an average of 8.4 cm beyond their projected height, whereas those girls starting after age 12 grew only 5.1 cm, on average, beyond their projected height.
A multivariant analysis was used to examine several factors that might influence the gain in stature. The number of years of GH therapy before estrogen treatment was a strong predictor. These data show that the early induction of estrogen has a significant negative impact on adult height. A variety of published studies have reported that GH therapy results in an average height gain of 510 cm, a range that represents a surprising variability in outcome (37, 38, 39, 40, 41). It seems that at least some of this variability may be due to differences in the ages in which estrogen therapy was begun in these patients. Some of the reports that showed that patients who had more modest apparent gains in final height also had relatively short periods of GH administration before the introduction of estrogen therapy (39, 41).
Several studies that did not achieve such reassuring gains in final height (39, 41) were also using lower GH doses than the United States study groups. This became particularly apparent in several studies carried out by the Dutch Advisory Group on Growth Hormone (42, 43). Their final assessment clearly shows that in a carefully conducted frequency response and dose-response study the increased dose of GH led to impressive increases in final height, exceeding even the data seen in the United States study. Seven-year results and preliminary final height data of this ongoing dose-response study are now available.
These investigators treated 68 patients with chronological ages between 2 and 11 yr and heights below the 50th percentile for healthy Dutch girls. The dosages used were 1.3 mg/m2·day (0.23 mg/kg·week) to as high as 2.7 mg/m2·day (i.e., 0.6 mg/kg·week). It is clear from the Dutch data that there is a dose-response curve and that patients with the higher GH dose grew significantly better.
During the 1st yr of treatment, all groups received GH at a dose of 1.3
mg/m2·day; in the 2nd yr, two subgroups were
switched to doses of 2 mg/m2·day, and a third
group was switched to 2.7 mg/m2·day in the 3rd
yr. All were then treated at these doses for the remainder of the study
period. After 7 yr of GH treatment, mean final heights of 25 of the
girls were 159.1, 161.8, and 162.7, respectively, for the three groups.
These investigators concluded that after 7 yr of GH treatment most
girls with Turners syndrome are growing within the height range for
healthy normal girls. GH treatment increased predicted adult height,
and their preliminary results showed that long-term GH treatment
results considerably increase final height gain. For a review of these
study results, see Table 1.
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Compliance with medical therapy such as daily injections of GH is sometimes suboptimal. Anticipated introduction of long-acting GH therapy may obviate that concern to some extent.
Lastly, final height was reported by some investigators that may not have been the true final height for some subjects.
In general, treatment was remarkably safe. The following possibly related adverse events were observed infrequently: intracranial hypertension, slipped capital femoral epiphysis, progression of preexisting scoliosis, edema, and otitis media (45, 46). Preliminary studies of increased serum lipoprotein (a) levels after GH treatment were not confirmed in larger series (47, 48). Although glucose levels stay normal, insulin levels rise both pre- and postprandially. Hemoglobin A1c levels stay in the normal range. Insulin levels decline in many patients after GH is discontinued (49).
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Conclusions |
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Spontaneous puberty occurs in about 25% of patients with Turners syndrome (50). Final height in those with spontaneous puberty is not different from those with no puberty.
Thus, physicians should consider the diagnosis of Turners syndrome in any girl with an unexplained failure to thrive or with short stature even during the 1st yr of life. Therapy should be initiated when the child falls below the normal female growth curve. This may be as early as 24 yr of life, and it is in those patients that predictably the best outcomes, as far as height is concerned, will ensue.
Earlier correction of the height deficit might then also allow earlier introduction of physiological doses of estrogen replacement, thus achieving for most girls with Turners syndrome relatively normal growth and sexual maturation.
A meta-analysis is underway to analyze and reconcile historical treatment data from various studies (51). This study will undoubtedly confirm the efficaciousness of GH therapy in Turners syndrome as long as patients are treated early with appropriate doses of GH for prolonged periods of time.
The care of patients with Turners syndrome continues, of course, well beyond growth promotion and requires long-term estrogen and progestin replacement. The care should be placed in the hands of physicians knowledgeable about the natural history of the unique medical and behavioral problems and medical needs associated with the syndrome (9). To improve the quality of life requires a team approach of physicians together with the efficient and compassionate support groups of the Turners Syndrome Society both in the United States and abroad.
Received September 2, 1999.
Accepted September 20, 1999.
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References |
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