Turner syndrome: mechanisms and management

Abstract

Turner syndrome is a rare condition in women that is associated with either complete or partial loss of one X chromosome, often in mosaic karyotypes. Turner syndrome is associated with short stature, delayed puberty, ovarian dysgenesis, hypergonadotropic hypogonadism, infertility, congenital malformations of the heart, endocrine disorders such as type 1 and type 2 diabetes mellitus, osteoporosis and autoimmune disorders. Morbidity and mortality are increased in women with Turner syndrome compared with the general population and the involvement of multiple organs through all stages of life necessitates a multidisciplinary approach to care. Despite an often conspicuous phenotype, the diagnostic delay can be substantial and the average age at diagnosis is around 15 years of age. However, numerous important clinical advances have been achieved, covering all specialty fields involved in the care of girls and women with Turner syndrome. Here, we present an updated Review of Turner syndrome, covering advances in genetic and genomic mechanisms of disease, associated disorders and multidisciplinary approaches to patient management, including growth hormone therapy and hormone replacement therapy.

Key points

  • Turner syndrome is a rare disorder caused by a completely or partially missing X chromosome; diagnosis of this condition is often delayed.

  • Growth is usually compromised and short stature can be treated with growth hormone and oxandrolone, usually leading to substantial increases in final height.

  • Congenital heart abnormalities are frequent and every woman with Turner syndrome should be seen by a cardiologist at least once.

  • Most women with Turner syndrome experience primary or secondary hypergonadotropic hypogonadism, which necessitates treatment with hormone replacement therapy.

  • Compared with the general population, morbidity and mortality are increased in women with Turner syndrome owing to a broad swathe of diseases, demanding vigilance as the individual ages.

  • Optimal care for Turner syndrome necessitates a multidisciplinary team optimally situated within the framework of one hospital.

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Fig. 1: The phenotype and current genomic understanding of Turner syndrome.
Fig. 2: The beneficial effects of hormone replacement therapy in Turner syndrome.
Fig. 3: Diseases and anomalies of the heart associated with Turner syndrome.
Fig. 4: Multidisciplinary management of patients with Turner syndrome.

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Acknowledgements

The authors acknowledge the support of the Novo Nordisk Foundation, Hede Nielsens Fond, the Lundbeck foundation, the Augustinus Foundation, the Aase and Einar Danielsen Foundation and Aarhus University.

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Nature Reviews Endocrinology thanks S. Christin-Maitre and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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C.H.G., M.H.V., S.B., K.S. and N.H.A. researched data for the article, made substantial contributions to discussions of the content and wrote the article. C.H.G. and N.H.A. reviewed and/or edited the manuscript before submission.

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Correspondence to Claus H. Gravholt.

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Glossary

Isochromosome

An unbalanced structural abnormality in which the arms of the chromosome are mirror images of each other, consisting of two copies of either the long (q) arm or the short (p) arm. This leads to partial trisomy of the genes present in an isochromosome and partial monosomy of the genes in the lost arm.

Ring chromosomes

Abnormal chromosomes whose ends have fused together to form a ring. Usually, a ring X chromosome contains much less genetic information than a normal X chromosome.

X-inactivation

In women with 46,XX karyotype, the majority of genes on the second X chromosome are usually inactivated to prevent overdosage of gene products, in comparison with men, who only have one X chromosome. Inactivation of an X chromosome is a random process and takes place in every cell.

Haploinsufficiency

Normally, two copies of all genes are present because two chromosomes harbour one copy of each gene. However, if a gene is mutated, haploinsufficiency can arise because only the wild-type gene on the other chromosome is expressed, resulting in a lower level of the gene product and, possibly, disease.

Triple test

A test originally used to detect the presence of a fetus with Down syndrome during pregnancy based on ultrasound measurement of the nuchal fold thickness of the fetus along with assessment of pregnancy-associated plasma protein A and free β-chorionic gonadotropin levels in the maternal circulation.

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Gravholt, C.H., Viuff, M.H., Brun, S. et al. Turner syndrome: mechanisms and management. Nat Rev Endocrinol 15, 601–614 (2019). https://doi.org/10.1038/s41574-019-0224-4

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