50 Years Ago in TheJournalofPediatrics: From Chromosomes to Clinical Care: Klinefelter Syndrome

Abstract

Caldwell PD, Smith DW. The XXY (Klinefelter's) syndrome in childhood: detection and treatment. J Pediatr 1972; 80:250-8. Classical dysmorphology was born, like so much of clinical medicine, from painstaking and careful clinical observation of unrelated individuals with shared clinical features. In this report, Caldwell and Smith take the subsequent steps toward broader understanding of the phenotype and treatment. They tackle the challenge of identifying individuals with a common syndrome before obvious presentation of features. They further dive into the now-modern era of treatment for genetic syndromes. Klinefelter syndrome was published in 1942 from observations during Klinefelter's fellowship at Mass General Hospital.1Klinefelter H.F. Reifenstein E.C. Albright F. Syndrome characterized by gynecomastia, aspermatogenesis without A-leydigism, and increased excretion of follicle-stimulating hormone.J Clin Endocrinol Metab. 1942; 2: 615-627Google Scholar Seventeen years later, the cause of Klinefelter syndrome was identified as an additional “X,” for a chromosome compliment of 47,XXY.2Jacobs P.A. Strong D.J.A. A case of human intersexuality having a possible XXY sex-determining mechanism.Nature. 1959; 183: 302-303Google Scholar This made Klinefelter syndrome the first sex chromosome aneuploidy identified—in predoctoral work by Patricia A. Jacobs. Prof Jacobs continues as a genomicist today, directing research at the University of Southampton in the United Kingdom. Despite the definition of Klinefelter syndrome as 47,XXY, the presence of a Barr body (“X chromatin positive”) in a phenotypic male subject often was used as an efficient “biomarker.” We now appreciate that this, in fact, included individuals with alternative diagnoses, including 46,XX sex reversal (eg, with SRY translocation). The challenge of parsing out a screen that merely suggests sex chromosome aneuploidy, and taking appropriate subsequent steps for a complete genetic diagnosis, continues today. In particular, this is an issue with noninvasive prenatal screening, where the positive predictive value for 47,XXY is a mean of 50%.3Cherry A.M. Akkari Y.M. Barr K.M. Kearney H.M. Rose N.C. South S.T. et al.Diagnostic cytogenetic testing following positive noninvasive prenatal screening results: a clinical laboratory practice resource of the American College of Medical Genetics and Genomics (ACMG).Genet Med. 2017; 19: 845-850Google Scholar We also understand now, in part thanks to efforts like that of Caldwell and Smith, that the phenotype of 47,XXY Klinefelter syndrome is broad. Even today, many individuals present initially for fertility evaluation, having experienced minimal learning or pubertal challenges, and yet more are identified now that noninvasive prenatal screening in pregnancy is commonplace regardless of maternal age. Treatment for Klinefelter is also broadening. Hormonal supplementation for those needing pubertal support is commonplace, and investigation is now focused on whether early pediatric hormonal support may benefit learning and neurologic outcomes.4Samango-Sprouse C.A. Tran S.L. Lasutschinkow P.C. Sadeghin T. Powell S. Mitchell F.L. et al.Neurodevelopmental outcome of prenatally diagnosed boys with 47,XXY (Klinefelter syndrome) and the potential influence of early hormonal therapy.Am J Med Genet A. 2020; 182: 1881-1889Google Scholar Where diagnosis using genetics and dysmorphology was once an end point unto itself, Caldwell and Smith's work is an early indication of the future of genomic medicine. Ultimately, prognostication alone is often insufficient. The goal of all pediatrics is improvement of health and outcomes, in this case using the identification of a syndrome as a tool to reach that goal.