Chapter 32: Turner Syndrome

INTRODUCTION

Turner syndrome (TS) is the most common genetic disorder affecting only females, and occurs in approximately 1 in 2500 female live births.¹ The criteria for diagnosis include complete or partial absence of the second sex (X) chromosome (with/without cell line mosaicism) plus short stature and primary ovarian failure with/without the presence of other phenotypic TS features. The genotype in TS as tested in peripheral blood is most commonly 45,X.¹ A TS patient with mosaicism, on the other hand, will have two or more cell lines with different chromosome make-up. Thus, apart from 45,X monosomy, other karyotype abnormalities in TS patients include 45,X/46,XX (the most frequent form of mosaicism which often results in a milder clinical phenotype) and 45,X/46,XY (resulting in partial or mixed gonadal dysgenesis). Structural abnormalities of the X chromosome include deletions, rings (rX), and translocations. An isochromosome X (isoXq) is the most common structural chromosome X abnormality. It is an abnormal X chromosome caused by a transverse division of the centromere instead of the normal longitudinal division. The result is two copies of the long arm connected by the centromere, with possibly certain Xp sequences inserted. The most common occurrence of the isoXq is as part of 45,X/46,X, i(X)q mosaicism, because isoX is frequently lost during cell division.¹ Overall, mosaicism is found in approximately 80% of patients with 45,X when two or more tissues (eg, lymphocytes and fibroblasts) are examined.²

The frequency of TS at conception is approximately 3%; however, 99% of these fetuses are aborted spontaneously, and the disorder affects 1 in 1800 to 5000 live-born females based on assessment of several different patient populations.³ The prevalence of the syndrome (at birth) has thus been estimated in the Caucasian population at 25 to 55 cases per 100,000 females.⁴ However, we are seeing a significant difference both in prevalence and in incidence of X chromosome anomalies between prospective studies and analysis of case series and cohorts of patients at the time of presentation to endocrine/genetics clinics. In a 13-year prospective study of 17,038 girls born in Denmark who had karyotype testing done, the incidence of TS was 1 in 1893 live female births, with only 1 of the 9 detected cases having a 45,X karyotype and the remaining cases being mosaic and having a variety of X chromosome abnormalities.⁵ This differs from the case series and cohort studies where complete X chromosome monosomy is responsible for TS in approximately half of patients.⁶ Thus, ascertainment bias likely plays a significant role in the clinical detection of TS, as well as methods of detection.

The phenotypic characteristics of TS reflect the haploinsufficiency of specific genes located mainly in the pseudoautosomal region (PAR) of the X chromosome (Xp11.2-p22.1). Normally in females, one X chromosome is randomly inactivated, except in PAR, where both alleles are expressed. Loss of one of these genes in the PAR, the SHOX (short stature ...