49,XXXXYsyndrome: A study of neurological function in this uncommon X and Y chromosomal disorder

Abstract

49,XXXXY is a rare chromosomal variation characterized by deficits in motor, language, and cognitive domains. This study reports on the neurological function and dysmorphic features in the largest cohort to date. Seventy-two boys with 49,XXXXY were evaluated on a variety of domains including a neurological examination and neuromotor assessments including the Beery Buktenica Developmental Test of Visual-Motor Integration, Sixth Edition, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), and the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition. Results supported previous literature by describing high occurrences of truncal and extremity hypotonia, which significantly impacts on motor milestones and ambulation in this population. The boys presented with dysmorphic features including epicanthal folds, frontal bossing, and synophrys. Visual perception skills were mildly impaired and cranial nerves were typically intact, however capabilities in motor coordination and fine motor precision were greatly delayed, supporting deficits in refined and controlled hand movements versus widespread visual deficits.Preschool boys treated with testosterone replacement had significantly increased scores when compared to the untreated group on the BSID-III Psychomotor Development Index, further supporting previous research indicating that testosterone replacement may have a positive impact on neurodevelopmental outcomes in males with additional X chromosomes.

Clinical, Cognitive and Neurodevelopmental Profile in Tetrasomies and Pentasomies: A Systematic Review

“…They show specific dysmorphic features, organ anomalies, severe mental retardation and congenital malformation, which can lead to a diagnosis in the first year of life. [ 18 ]. Some authors hypothesised that the overall features of affected patients were due to the abnormal dosage of genes beyond what is normally guaranteed between males and females by X-inactivation of the second X chromosome in females [ 21 ].…”

“…Common physical and clinical features of 49, XXXXY subjects include facial dysmorphisms (upslanting palpebral fissures in 100 % of cases, arched eyebrows, ocular hypertelorism, synophrys, flat nasal bridge, frontal bossing, low-set ears), cardiac defects, endocrinologic abnormalities (e.g., hypogonadism, hypogenitalism, growth retardation), microcephaly, short stature, multiple skeletal anomalies, mental retardation and speech delay [ 10 , 15 , 18 ]. Other features were less frequently observed and consisted of alterations in muscular tone (generalised hypotonia), joint laxity, cleft palate, bifid uvula, kidney and ear malformations, and other skeletal anomalies (such as plagiocephaly, pectus excavatum, pes cavus, radioulnar synostosis, fifth finger clinodactyly, syndactyly and genu valgum) [ 10 , 15 , 18 ]. In 2019, Burgemeister et al [ 15 ] focused on dental anomalies that can occur throughout life, such as delayed dentition and eruption, hypodontia and malocclusion [ 18 , 50 ].…”

“…Other features were less frequently observed and consisted of alterations in muscular tone (generalised hypotonia), joint laxity, cleft palate, bifid uvula, kidney and ear malformations, and other skeletal anomalies (such as plagiocephaly, pectus excavatum, pes cavus, radioulnar synostosis, fifth finger clinodactyly, syndactyly and genu valgum) [ 10 , 15 , 18 ]. In 2019, Burgemeister et al [ 15 ] focused on dental anomalies that can occur throughout life, such as delayed dentition and eruption, hypodontia and malocclusion [ 18 , 50 ]. Some features are similar to those found in Down syndrome patients, and as a result, 49 aneuploidies were sometimes previously diagnosed after chromosomal testing to evaluate the possibility of trisomy 21 [ 18 ].…”

Introduction: Comprehensive investigation into an international cohort of boys with 49,XXXXY

“…Samango‐Sprouse et al (2020) expanded on the dysmorphological and neurological profiles of males with 49,XXXXY. Several novel facial features are reported, including a smooth philtrum (29.17%), low hanging columnella (57.9%) and dystopia canthorum (42.86%).…”

Neurocognitive development and capabilities in boys with 49,XXXXY syndrome

“…Neurocognition in boys with 49,XXXXY may also be influenced by testosterone replacement therapy. Several research studies have indicated the restorative impact of hormonal replacement on the neurodevelopmental phenotype of boys with 49,XXXXY, including speech and language and motor development (Samango‐Sprouse et al, 2020; Samango‐Sprouse et al, 2020; Galasso, Arpino, Fabbri, & Curatolo, 2003; Linden et al, 1995; Mazzilli et al, 2016). However, research regarding the influence of the administration of testosteronne on the neurocognitive profile of 49,XXXXY is limited.…”