Many of the physical stigmata of TS are a result of structural bone defects. Typically, females with TS have disproportionately short legs and an abnormal upper-to-lower segment ratio. This results in the appearance of a squarely shaped chest and widely spaced nipples. Cervical vertebral hypoplasia contributes to the short stature and also causes the short neck often seen in females with TS. Scoliosis may be present in approximately 10% of females, and it may or may not be associated with vertebral abnormalities.
Just under half of females with TS have cubitus valgus, or a wide carrying angle, as a result of a developmental defect of the head of the ulna. Similar abnormalities of the medial tibial and femoral condyles may also be present, resulting in a genu valgum. Short metacarpals and metatarsals are found in a proportion of women with TS, and a “bayonet deformity” (also known as Madelung deformity) of the wrists may be present as a result of lateral and dorsal bowing of the radius and subluxation of the distal ulna. These features may also be seen radiologically, in addition to crowding of the carpal bones and an osteoporotic appearance. Interestingly, the bone deformities do not cause disability in adults. In particular, an excess of osteoarthritis has not been reported in TS.
The characteristic facies of a female with TS is also primarily due to skeletal malformations. These result in micrognathia, a downward droop of the outer corner of the eyes and epicanthic folds, a high arched palate, and low-set ears.
A primary defect in bone formation is thought to exist in TS because of the numerous skeletal dysplasias associated with the syndrome in addition to short stature and a propensity for osteoporosis (see below). However, the molecular defect has not yet been characterized, although it has been hypothesized that deletion of a gene on the X chromosome may be responsible for such connective tissue abnormalities.
Bone mass increases steadily during childhood and adolescence to peak in the second decade when it plateaus. Peak bone density attained is therefore an important determinant of ultimate skeletal health. There is a reduction in peak bone mass by 25% in women with TS. There remains a great deal of speculation as to whether the reduction in bone mass seen in TS is a result of poor bone mineralization, and thus increases the risk of fractures, or is solely a consequence of delayed skeletal maturation and small bones. Ross and colleagues noted a significantly decreased bone density in prepubertal girls with TS compared with chronological and bone age-matched controls. However, bone density in girls with TS is normal when compared with height-matched controls, suggesting that at least part of the reduction of bone mass is a result of delayed skeletal maturation. Significantly, however, the girls studied by Ross et al. also had a fracture incidence that was 3 times that of normal controls. Furthermore, Shore and colleagues showed that bone density remained low even after correction for height and skeletal maturation.
Adults with TS continue to show evidence of a reduced bone mass and this has also been shown to be associated with an increased risk of fractures. Davies et al. showed a fracture frequency of 45% in women with TS and of 33% in women with other causes of primary amenorrhea, both rates being far higher than the fracture rate seen in a control group. In contrast, Landin-Wilhelmsen and colleagues found a lower 16% fracture prevalence in women with TS; however, this was still greater than the 5% prevalence in the control group. Gravholt and colleagues have estimated that women with TS are 10 times more likely to develop osteoporosis and are twice as likely to sustain a fracture. In summary, although delayed skeletal maturation and small bones may result in an underestimation of bone mineral density, women with TS are at increased risk for fractures, and thus all efforts should be made to treat underlying osteopenia.
The effect of GH therapy on bone mass in girls with TS has been studied by several groups. GH treatment for at least 1 yr improves bone mineral density, although the bone mass remained below the normal value for age. Early estrogen therapy has also been shown to improve, but not normalize, bone density. Mora and colleagues found that girls who had started sex steroids before the age of 12 yr had a higher bone mass than those who started treatment after the age of 12 yr. The combination of estrogen replacement therapy and GH treatment results in a greater gain in bone mass. In girls with TS who enter puberty spontaneously, bone mass has been found to be within normal limits.
After adolescence, estrogen replacement therapy seems to be the single most important factor in maintaining peak bone mass. Sylven and colleagues looked at bone mineral density in 47 middle-aged women with TS and found that women with TS had a bone mass less than age-matched normal values. They also found that the duration of hormone replacement therapy (HRT) was the significant factor in maintaining bone mass. Stepan and co-workers also demonstrated that women with TS have a lower bone mass compared with age and sex-matched normal values, but those women receiving HRT had a higher mean bone mineral density compared with those who were untreated. Finally, Davies et al. did not show a significant difference in bone mineral density or fracture risk in women with TS compared with women with other causes of primary amenorrhea, suggesting that estrogen deficiency is an important factor in the pathogenesis of osteopenia in TS.
Since bone mass is improved but not normalized after hormonal therapy, an intrinsic bone defect is likely. The cause of osteopenia in TS is probably a result of the combination of an intrinsic bone defect in addition to estrogen deficiency. However, if this were the case, one would expect bone density to be higher in women with a mosaic karyotype compared with 45,X monosomy, but there are no data correlating bone density in TS with karyotype. Further research is required to determine whether loss of genes on the X chromosome may predispose women with TS to osteopenia. Additionally, further longitudinal studies are required to assess the prevalence of clinically significant osteoporosis and osteoporotic fractures in TS.
Estrogen replacement should be optimized and lifestyle advice given with regards to exercise and adequate calcium intake. Weight-bearing exercise has been shown to improve bone mass in women with TS. All women with TS should have a bone densitometry performed on transfer to an adult clinic, and bone mass should then be monitored, although the frequency of monitoring remains controversial. The role of bisphosphonates in the treatment of osteoporosis in women with TS has yet to be clarified.
This information was taken directly from Endocrine Society, Volume 23, Issue 1, First Published Online: July 01, 2013, “Turner’s Syndrome in Adulthood”. http://press.endocrine.org/doi/full/10.1210/edrv.23.1.0457
