This is a very exciting special section in the American Journal of Medical Genetics Part A that expands our understanding of 49, XXXXY, the most uncommon variant of Klinefelter's syndrome (KS). Due to the rarity of this sex chromosome aneuploidy, there has been relatively limited research conducted on this population. Previous research has consisted of small case studies, which are prone to the skewing effects of biased samples with wide age ranges, variable timing of diagnosis, and unknown level and frequency of early intervention services. Subsequently, the findings from such studies may not always be generalizable to the entire 49,XXXXY population. Thus, this special section affords us the opportunity to draw on the extensive experience of a multidisciplinary team of more than10 pediatric specialists who have evaluated more than 100 boys with 49,XXXXY from all over the world for the last 16 years. These collective experiences and findings are described in six articles ranging in topics from behavioral to orthopedic to endocrinological on the child with 49,XXXXY. These large and in-depth studies allow for greater understanding of both the variability and specificity of this disorder and provide preliminary guidelines for the management of neurodevelopmental concerns prevalent in this population (Table 1).

The additive X, whether one, two, or three in number, has a pervasive impact on multiple developing systems of the child. Aspects of the clinical phenotype, in addition to the variability seen in patients with 49,XXXXY, are similar, albeit more complicated, to the phenotypic variability seen in the 47,XXY population, potentially due to a dosage effect of the extra X chromosomes, or in combination with external factors. With more focused attention to the medical, biological, and developmental health of 49,XXXXY males, the care and the outcome of the individual patient and family may be enhanced. This highly focused approach has increased our understanding of the variability in other chromosomal disorders such as trisomy 21 (Down syndrome), trisomy 13+ and trisomy 18 (Carey & Kosho, 2016).

In this special section, 49,XXXXY phenotypic strengths and vulnerabilities are analyzed across multiple domains and delineated by the various topics. Each article addresses one particular area of interest in relation to the 49,XXXXY phenotype; specifically, neuromotor and neurologic function, musculoskeletal, endocrinological function, speech and language, neurocognition and behavior. Two of the articles, Tosi et al., 2020 and Lasutschinkow et al., 2020, which address the musculoskeletal and behavioral phenotypes of 49,XXXXY respectively, were published ahead of this section and can be found in the online version of this special section. These articles provide evidence of the similar effect of testosterone replacement on the 49,XXXXY population as compared to the 47,XXY population. This research is unique because it utilizes large sample sizes while minimizing confounding variables, allowing for more refined generalization of the findings to the 49,XXXXY population.

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%). Furthermore, the findings reveal that visual perception is significantly more intact than motor coordination in boys with 49,XXXXY, which is also consistently observed in 47,XXY (Simpson et al., 2003). In addition, this study shows that preschool boys with 49,XXXXY who received early hormonal treatment (EHT) exhibit significantly more intact motor capabilities than those who did not receive testosterone replacement.

Tosi et al. (2020) described a large cohort of boys with 49, XXXXY and identify numerous musculoskeletal anomalies, including increased rates of torticollis (32.4%), hamstring tightness (42%), radioulnar synostosis (67%) and pes planus (65.2%), some of which are abnormalities also commonly noted in the 47,XXY population (Samango-Sprouse et al., 2019; Simpson et al., 2003; Tartaglia, Ayari, Howell, D'Epagnier, & Zeitler, 2011). These findings also demonstrate that older 49,XXXXY boys have more hip and knee anomalies than the younger boys. The positive effects of testosterone are highlighted again as the individuals who had been treated with EHT achieved motor milestones consistently earlier than those who had not received EHT. This study discusses the many effective ways to minimize musculoskeletal issues in the 49,XXXXY population, including early intervention, testosterone replacement and an increase in motor activity.

Counts, Yu, Lasutschinkow, Sadeghin, and Samango-Sprouse (2020) discuss new findings regarding growth as well as potential increased incidence of growth hormone deficiency (GHD) in boys with 49,XXXXY. This study reports on an increased incidence of boys with 49,XXXXY below the third percentile in height (45.2%), which is particularly intriguing due to past studies demonstrating that disorders involving extra X chromosomes are typically long boned disorders (Ottesen et al., 2010). This study outlines the importance of screening for GHD in boys with 49,XXXXY, particularly if there are growth abnormalities.

Samango-Sprouse et al. (2020) investigated the development of speech and language of boys with 49,XXXXY. This study finds that the majority of evaluated 49,XXXXY individuals have Childhood Apraxia of Speech (CAS) (92.1%), which results in complex language-based learning dysfunction. CAS leads to pervasive communication difficulties and may be associated with behavioral disturbances in 49,XXXXY. Testosterone replacement therapy was associated with significantly increased speech and language capacities of boys with 49, XXXXY, particularly in expressive language.

In addition, Porter et al. (2020) explored the neurocognitive functioning of the 49,XXXXY population. This article demonstrates that boys with 49,XXXXY are more cognitively capable than previously appreciated and simultaneously recognizes the profound influence of complex language-based learning dysfunction on neurocognitive performance. Nonverbal IQs for preschool boys with 49,XXXXY in this cohort are, on average, within normal limits with median standard scores of 90. These results provide further support to the true capabilities of these populations when the verbal demands of cognitive assessment are reduced, in many ways supporting the idea that “they hear with their eyes”. There is a wide variability in all testing, but particularly in verbal performance, with Verbal IQ composite scores ranging from 51 to 110. In addition, the impact of testosterone is seen in toddlers, with EHT-treated children having better cognitive composite scores on the Bayley Scales of Infant and Toddler Development than their untreated counterparts (p = .013).

Lasutschinkow, Gropman, Porter, Sadeghin, and Samango-Sprouse (2020) analyzed the behavioral phenotype of boys with 49,XXXXY by examining anxiety-related symptoms as well as social competency. This study reveals a novel finding that boys with 49,XXXXY have consistent social awareness and motivation throughout childhood and adolescence, yielding a desire to be more social while lacking the expressive capabilities to be so. Frustration over the inability to communicate effectively leads to increased incidences of internalizing and externalizing behaviors. Moreover, this study reveals that as these boys age, there is a notable increase in internalizing problems that can hinder academic success and further disrupt their social interactions. This increase in internalizing symptoms is also seen in 47,XXY and past studies have demonstrated that boys who received testosterone replacement had decreased internalizing behaviors (Samango-Sprouse, Lasutschinkow, Powell, Sadeghin, & Gropman, 2019).

The positive effect of testosterone has been researched in the 47,XXY and 49,XXXXY populations via case studies for over 20 years. Recent research has revealed that the 49,XXXXY population seems to share similar, albeit more complicated, aspects of the 47,XXY phenotypic profile. Past research has shown an association between testosterone replacement in boys with 47,XXY and improved outcomes, therefore investigation into the effect of testosterone on the 49,XXXXY population is warranted and is considered throughout this special section. The common finding is that testosterone is associated with significant improvements across multiple domains in 49,XXXXY. The level of function among 49,XXXXY individuals is highly variable, although the factors influencing this variability are not well understood. More research is required to better understand the effect of testosterone on the 49,XXXXY population, as well as 47,XXY and 48,XXXY populations. Additional research in 49,XXXXY is underway, including investigations on immunological deficits commonly seen in this population and studies researching the impact of familial learning disabilities, copy number variants, and testosterone replacement at variable times and dosages.

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.