Sex chromosome aneuploidy (SCA) syndromes refer to disorders with an abnormality of sex chromosome number. The most common are Klinefelter syndrome (KS), resulting from the gain of an X chromosome in males, and Turner syndrome (TS), reflecting the loss of an X chromosome or the presence of a structurally different X chromosome in females. Whereas most patients with KS have nonmosaic 47,XXY, only 40% of women with TS have 45,X; the remainder have a variety of mosaicisms. The syndromes also contrast in that males with KS are characteristically tall, whereas females with TS are typically short unless they receive hormonal treatment.Despite efforts to increase awareness, KS and TS are often underdiagnosed, leading to delayed care. Only 25% of men with KS are ever diagnosed, with fewer than 10% detected prenatally, and with a median age of 27 years for those identified later in life. For TS, the median age at diagnosis is 6.6 years. Although not exclusively, optimal neurocognitive outcomes depend on the timing of diagnosis and access to early targeted treatment, so fortunately the recent development of noninvasive prenatal screening is increasing the early identification of these disorders dramatically. Pediatricians should be aware of signs that allow for early detection, and the importance of prompt referral for testing and therapy.KS occurs in 1 in 660 live births, representing the most common SCA. Affected males have androgen deficiency, which affects endocrine, central nervous system, and neurodevelopmental function. Characteristics include increased height, clinodactyly of the fifth finger, pes planus, and hypogonadism manifesting as small or undescended testes and/or small phallus or micropenis.More than 80% of infants with KS have truncal hypotonia and delayed motor planning skills, and almost one-third have positional torticollis: physical therapy should be instituted immediately to prevent plagiocephaly and minimize additional gross motor delays. The combination of orofacial hypotonia, speech delays, and associated androgen deficiency can create the impression of a silent and inactive infant, the “quiet baby” phenotype. Genetic and environmental factors affect the neurocognitive profile, with variable language-based learning difficulties, developmental dyspraxia, executive dysfunction, and an increased risk of problems with social skills. Speech delays are usually identified by 18 months, and therapy should be initiated during the critical interval of 18 to 30 months. The characteristic speech/language profile includes delayed speech, expressive skills more delayed than receptive, and intact neurocognitive function. With the prevalence of language-based learning disorders in untreated children, verbal IQ is often lower than performance IQ but remains within normal limits. More severe problems may result from premature birth, a family history of learning disabilities, or other copy number variants in the genome, such as microdeletions or microduplications in the autosomes.The classic behavioral profile also shows variability because it is influenced by the timeliness of diagnosis, initiation of hormone replacement treatment, and participation in appropriate intervention services. Boys with KS are generally at increased risk for anxiety but decreased risk for autistic traits. They may present as timid and have emotional dysregulation if they have more difficulty identifying and vocalizing their emotions than neurotypical children.Boys with risk factors for KS, particularly if they have a reading disorder, should be screened before kindergarten. Chromosomal microarray analysis is recommended for those with complex presentations to identify the presence of, mosaicism, and copy number variants. Depending on learning delays and deficits in motor, social, and emotional coping skills, affected boys can benefit from educational support services, speech and language therapy, physical and occupational therapy, and behavioral interventions. In older boys with low levels of testosterone, replacement therapy can improve muscle mass and bone strength and promote pubertal development. Although not yet standard of care, several observational and retrospective studies suggest that early hormonal treatment can produce neurodevelopmental improvement in infants with KS. It consists of 3 monthly injections of 25 mg of testosterone enanthate administered between 4 and 12 months of age after evaluation by a pediatric endocrinologist.TS occurs in 1 in 2,000 to 2,500 live born females. Although there is no single phenotype for TS, common features in the pediatric population include short stature, left-sided congenital heart defects, characteristic facial features (including short neck with webbing), hearing loss, and delayed puberty. Fetuses with TS may display edema ranging from a nuchal cystic hygroma to severe hydrops, and lymphedema of the extremities may persist. Women with TS may present with infertility or, rarely, aortic aneurysm.In most girls, the diagnosis is made using postnatal peripheral blood karyotype. Increasingly, cell-free DNA analysis is identifying fetuses at increased risk for “monosomy X,” raising the possibility of TS. Prenatal genetic counseling offers the options of amniocentesis or chorionic villus sampling confirmation, and maternal karyotype to check for undiagnosed maternal aneuploidy.Unlike KS, internal malformations are common in TS, notably congenital heart defects. The risk of coarctation of the aorta, bicuspid aortic valve, other left-sided defects, and aortic dilatation (rarely, aortic dissection) requires transthoracic echocardiography at the time of diagnosis. Endocrine management focuses on the treatment of short stature with growth hormone, estrogen hormone replacement for ovarian insufficiency, and monitoring for hypothyroidism and diabetes. Gastrointestinal problems such as gluten intolerance and inflammatory bowel disease are common.The neurocognitive profile of females with TS includes stronger-than-average verbal skills and weaker nonverbal or visuospatial abilities. Their IQs are typically within the normal range, with verbal IQ higher than performance IQ. Girls with TS also commonly present with executive dysfunction and difficulties with processing speed. Deficits in nonverbal skills may translate into difficulty with spatial mathematics, such as geometry. Girls with TS should be screened for learning disabilities and mathematics difficulties before second grade for the appropriate services to be in place. Formal neuropsychological testing can be invaluable to highlight strengths and challenges.Overlooked in many girls with TS are their social, behavioral, and mental health vulnerabilities. They have a high lifetime risk of anxiety and depression, especially social anxiety, which can resemble autism spectrum disorder, as well as difficulty with sustained attention that puts them at risk for the hyperactive/impulsive subtype of attention-deficit disorder. However, before a diagnosis of attention-deficit/hyperactivity disorder is made, comorbid conditions such as hearing loss, learning disabilities, and anxiety must be considered.The current clinical practice guidelines were established at the 2016 International Turner Syndrome Meeting. Among the recommendations is the initiation of growth hormone treatment at approximately 4 to 6 year of age if there is evidence of growth failure or short stature. Estrogen replacement therapy is customized to the patient, often between 11 and 12 years of age, and dosage should be increased to adult dosing during the next 2 to 3 years. Once breakthrough bleeding occurs or after 2 years of estrogen treatment, progesterone should be added to the regimen. Neuropsychological and behavioral supportive services are also recommended as integral to the care of girls with TS.In the past few decades, significant advances have been made in the early detection and innovative care of children with KS or TS. With the exponential increase in noninvasive prenatal screening more children are diagnosed in utero. Long-term prognosis for these children is improved with early identification and targeted treatment. Medical providers need to be aware of early signs of KS and TS and the opportunities for interventions to promote the well-being of children with SCA syndromes and help ensure successful outcomes.Comment: The term aneuploidy refers to any abnormal number of chromosomes, in humans either fewer or more than 46. SCAs with an abnormal number of X or Y chromosomes seem to be the most common in humans, with an overall prevalence of approximately 1 in 400 to 1 in 500, probably more common even than any of the familiar trisomies 21, 18, and 13. SCAs other than KS and TS have been identified, including women with so-called triple X syndrome (47,XXX) and men with 47,XYY. A more precise prevalence for SCAs has not been determined because significant numbers of affected individuals have subtle enough phenotypes that they go undetected, although as the number of sex chromosomes increases it seems that so do the phenotypic characteristics that make the syndromes more obvious: the much rarer 48,XXYY, 48,XXXY, and even 49,XXXXY genotypes have all been described. The issue for pediatricians, as this In Brief makes clear, is that even when phenotypic differences are not grossly apparent the consequences for the well-being of children with SCAs can be real, meaning that early identification and intervention can be crucial in enabling our patients to thrive.