Neurodevelopmental outcome of prenatally diagnosed boys with 47,XXY (Klinefelter syndrome) and the potential influence of early hormonal therapy

Abstract

This cross‐sectional study examined the neurodevelopment of a large, prenatally diagnosed population of boys with 47,XXY; investigated the potentially positive effects of early hormonal therapy (EHT) on language, cognition, and motor in this population; and identified novel at risk biomarkers associated with 47,XXY. Two‐hundred and seventy two evaluations were collected from 148 prenatally diagnosed boys with 47,XXY between 0 and 36 months and separated into one of three groups, depending on visit age: Y1 (0–12 months; n = 100), Y2 (13–24 months; n = 90), and Y3 (25–36 months; n = 82). Those who received EHT (administered by 12 months) were further separated (Y1, n = 37; Y2, n = 34; Y3, n = 30). Neurodevelopmental evaluations consisted of Preschool Language Scales, Early Language Milestone Scale, and Bayley Scales of Infant and Toddler Development and evaluated the effect of EHT on auditory comprehension, expressive communication, receptive language, cognition, and motor. EHT was found to be associated with a positive effect within the first year of life in these domains, as well as in the second and third year of life. Additionally, three novel at‐risk biomarkers were identified in this cohort: feeding difficulties in infancy, positional torticollis, and the need for orthotics. The positive effects of EHT observed in language, cognition, and motor at variable stages within the first 3 years of life provide additional evidence into the possible efficacy of early biological treatment for boys with 47,XXY to address the neurodevelopmental dysfunction.

Pregnancies with positive non-invasive prenatal testing result for sex chromosome abnormalities in a tertiary hospital in Hong Kong

“…Four cases showed Three patients had NIPT results that showed copy number variants of X chromosome (Table 9). Amniocentesis confirmed de novo 46,X,idic(X)(p11.21) in patient 51, maternally inherited 46,X,del(X)(p21) in patient 52, and 45,X,inv(19)(p11q13.1)[15]/46,X,r(X)(p22.1q21),inv (19) [10]/46,X,inv (19),+mar [5] in patient 53. They opted for continuation of pregnancy.…”

“…Although the miscarriage risk of prenatal invasive diagnostic procedure is low (0.20% for chorionic villus sampling and 0.30% for amniocentesis) 16 , if the definitive diagnosis is unlikely to affect continuation of pregnancy, diagnostic testing may be deferred until after delivery. Knowing the genetic diagnosis can help timely interventions (such as hormone replacement therapy and educational support) and optimise clinical outcomes [17][18][19] . Patient autonomy should be respected, and their decisions should be supported.…”

Klinefelter Syndrome: What should we tell prospective parents?

“…Associations between exogenous testosterone administration in infancy and developmental benefits during childhood have been reported 42 . It is suggested that consideration of this treatment should be given to all infants with KS, based on an assumed testosterone deficiency.…”

“…Discussion is not recommended in routine clinical care around associations between exogenous testosterone administration in infancy and developmental benefits during childhood 42 as this treatment remains controversial 43 . At present, early review and assessment by a paediatric endocrinologist with individualised intervention on the basis of clinical need is recommended.…”

Speech and language development in children with 49,XXXXYsyndrome

“…Although not standard of care, hormonal treatment using testosterone has been associated with significant improvements in neurodevelopmental and behavioral outcomes in males with 47,XXY as well as 49,XXXXY for over 25 years (Galasso, Arpino, Fabbri, & Curatolo, 2003;Linden et al, 1995;Mazzilli et al, 2016;Patwardhan, Eliez, Bender, Linden, & Reiss, 2000). Studies in recent years have begun to investigate the possible benefits of testosterone treatment at younger ages in these disorders as well, including early hormonal treatment in infancy (Samango-Sprouse et al, 2013, 2015, 2020 and hormonal booster therapy in later childhood (Samango-Sprouse et al, 2018;Samango-Sprouse, Lasutschinkow, Powell, Sadeghin, & Gropman, 2019;Tran, Samango-Sprouse, Sadeghin, Powell, & Gropman, 2019). While many studies on the impact of testosterone have been completed on 47,XXY, studies on 49,XXXXY have been mostly limited to case studies, incidental reports, and small sample sizes.…”