50 Years Ago in TheJournalofPediatrics: To Every Season Turner, Turner, Turner

Abstract

Hsu LY, Hirschhorn K. Unusual Turner mosaicism (45,X/47,XXX; 45,X/46,XXqi; 45,X/46,XXr): detection through linear deceleration from normal linear growth or secondary amenorrhea. J Pediatr 1971;79;2:276-81. It is said that the “post-human genome-sequencing project era” of genomic medicine is like no other. New genes, genomic mechanisms, and associated human phenotypes are being deciphered at a staggering pace. In fact, we are walking a worn path, laid by pioneers of the medical cytogenetics era like Drs Hsu and Hirschhorn. The current number of human chromosomes were not accurately identified until 1956.1Tjio J.H. Levan A. The chromosome number of man.Hereditas. 1956; 42: 1-6Crossref Scopus (566) Google Scholar A short 3 years later, the association between 45,X and Turner syndrome was recognized and, along with it, the first report of sex chromosome mosaicism.2Ford C.E. Jones K.W. Polani P.E. De Almeida J.C. Briggs J.H. A sex-chromosome anomaly in a case of gonadal dysgenesis (Turner’s syndrome).Lancet. 1959; 276: 711-712Abstract Scopus (531) Google Scholar,3Ford C.E. Polani P.E. Briggs J.H. Bishop P.M. A presumptive human XXY/XX mosaic.Nature. 1959; 183: 1030-1032Crossref PubMed Scopus (36) Google Scholar Only 15 years after the number of human chromosomes was announced, Hsu and Hirschhorn described 3 unusual 45,X mosaic variants and their phenotypes. They identify that growth deceleration, not just short stature from birth, and secondary amenorrhea, not just primary, can be associated with variant Turner syndrome. This march of refining and expanding the phenotype and prognosis associated with a new genetic syndrome is familiar. In the same way today, new gene/disease associations are made based on the most “severely” affected individuals. Then, as less obviously affected individuals are confirmed or identified genetically, the list of features and our understanding of the highly variable expression of syndromic presentations expands. This process of phenotype identification, its refinement, and analysis of potential mechanism continues perhaps indefinitely. Even now, we are identifying new phenotypes associated with classical Turner syndrome (eg, hyperinsulinism).4Gibson C.E. Boodhansingh K.E. Li C. Conlin L. Chen P. Becker S.A. et al.Congenital hyperinsulinism in infants with turner syndrome: possible association with monosomy X and KDM6A haploinsufficiency.Horm Res Paediatr. 2018; 89: 413-422Crossref PubMed Scopus (16) Google Scholar In the most recent decade, with the advent of clinically noninvasive prenatal screening for approximate sex chromosome count, the phenotype of 45,X-mosaic individuals is widening yet further. Today, these patients would have been screened for further mosaicism and Y-chromosome by genome-wide array. Our nomenclature too has shifted, in ways small and large. Terms like “sexual infantilism” are considered value-laden and no longer acceptable, nor is revealing photography like the fully unclothed woman with a small black oval over the eyes. Yet many things are relatively unchanged. In conjunction with new diagnostic tools like noninvasive prenatal screening and genome-wide arrays, the karyotype is still key for diagnosis of structures like the ring-X described in patient three. By carefully, painstakingly phenotyping, and genetically characterizing their patients, Hsu and Hirschhorn were able to expand Turner variant phenotypes and the relationship to diagnostic karyotypes. The tools and knowledge base of genomic medicine are vastly expanded, but 50 years later, our approach is fundamentally the same.