Advances in endocrine care of girls with Turner syndrome (TS) have been incremental, rather than fundamental. Over the past 30 years growth hormone regimens have been massaged to optimize height outcomes, with recent evidence supporting treatment initiation in the preschool years to prevent growth failure, rather than waiting for the inexorable development of short stature. Similarly, sex hormone replacement has evolved from the intentionally delayed initiation of puberty in the mid-teens, using large doses of conjugated oral estrogens extracted from the urine of pregnant mares, to more physiologically-timed administration of transdermal low-dose synthetic estradiol.
However, the critical insights into TS pathophysiology have come from the field of genetics. After Ford’s 1959 discovery of the underlying ‘sex chromosome anomaly’ progress was slow, with almost 40 years elapsing until identification of the first gene unequivocally implicated in the TS phenotype: the short stature homeobox-containing gene (SHOX). Recent advances have been driven by sophisticated genetic technologies focusing on 3 groups of candidates: pseudoautosomal genes, X-Y gene pairs and genes that escape X-inactivation. These approaches have identified dosage-sensitive genes associated with conditions that contribute to the morbidity and early mortality of TS, including urinary tract anomalies, autoimmune disorders, sensorineural hearing loss, premature ovarian failure and aortopathy.
One of the most striking findings has come from epigenetic analyses that have revealed generalized hypomethylation of the 45,X genome, affecting the autosomes as well as the X chromosome. In addition to disturbing the regulation of downstream gene networks, this fundamental genetic malfunction may predispose to meiotic non-disjunction, resulting in the sex chromosome aneuploidy underlying TS. Complementing the basic molecular/genetic analyses, studies of clinical cohorts provide insights into neurodevelopmental variations associated with the cognitive and behavioral profile of TS. For example, high-resolution structural MRI scans have demonstrated region-specific reduction in brain grey matter growth during the teenage years in girls with TS, with differential effects associated with parent-of-origin of the retained X chromosome. The brain volume deficit was exacerbated by estrogen deficiency, raising further concerns regarding delayed estrogen replacement in these hypogonadal girls. In another study, reduced grey matter volume was detectable as early as one year of age, indicating likely prenatal onset of the TS neuroanatomic phenotype.
Despite these significant advances, diagnosis remains delayed for many affected girls and women, undermining the potential value of early intervention strategies. Non-invasive prenatal testing has so far shown limited predictive value for TS. However, an intriguing new bioinformatic approach to aid early diagnosis uses a highly accurate computer-based tool for pattern recognition of TS facial features. Unraveling the genetic and biological basis for TS pathophysiology, accompanied by earlier identification of those who escape perinatal diagnosis, offers the opportunity to mitigate some of the multisystem problems of TS.