Musculoskeletal anomalies in a large cohort of boys with 49, XXXXY

Abstract

49, XXXXY is a rare aneuploidy and variant of Klinefelter syndrome, occurring in 1 per 80,000-100,000 live births. We present a cohort of 40 affected males, focusing on musculoskeletal problems. Subjects were participants in an annual 49er family support group meeting. Children were examined in a multidisciplinary clinic by a pediatric neurologist and geneticist, a pediatric orthopedist, a neurodevelopmentalist, and two physical therapists. The patient data were collected from this clinic from 2004 to 2012. All patients were required to have karyotypes that confirmed the presence of XXXXY. There was a high prevalence of musculoskeletal disorders, particularly hypotonia (34 patients [85%]), radioulnar synostosis (30 [75%]), pes planus (26 [65%]), asymmetric hip rotation (27 [67.5%]), and clinodactyly (24 [60%]). Other, less common lower-extremity disorders, included, 5 patients (12.5%) with unilateral club foot, 5 boys (12.5%) with pes cavus, 10 patients (25%) genu valgum and 2 children with genu varus (5%). To our knowledge, this is the first large cohort of boys with 49, XXXXY that focuses on musculoskeletal disorders. There was an increased incidence of hypotonia, clubfoot, avascular necrosis of the femoral head, radioulnar synostosis, and pes planus compared to the normative population. Boys with 49, XXXXY would benefit from multidisciplinary evaluations, particularly from pediatric orthopedists, physical therapists, neurologists, and geneticists for appropriate medical care.

Testosterone replacement in 49,XXXXY syndrome: andrological, metabolic and neurological aspects

“…It is characterised by complex plurimalformative syndrome: musculoskeletal anomalies (3); alteration of neurocognitive development and brain malformations, such as white matter lesions (5); metabolic and hormonal alterations, such as hypergonadotropic hypogonadism, hypothyroidism and diabetes mellitus (6) (7) (8); and increased susceptibility to infection, atopy and immunodeficiency (9). For this reason, the treatment of these subjects requires a multidisciplinary team (endocrinology, psychoneurology, orthopedics, physical medicine, speech–language therapy).…”

“…This aneuploidy probably originates from non-disjunction of the X chromosome during both meiosis I and II. To date, few cases have been described (1) (2) (3) (4) (5) (6) (7) (8) (9); in such cases, the median age at the time of diagnosis was 4 months (2) (3). Some particular ultrasound findings (polyhydramnios or cystic hygroma) could be suggestive of this syndrome during pregnancy (4).…”

“…The clinical phenotype is characterised by complex plurimalformative syndrome: musculoskeletal anomalies (congenital talipes equinovarus, hypotonia, clinodactyly, radioulnar synostosis, scoliosis, hip dysplasia, pes cavus or planus) (3); alteration of neurocognitive development, mental retardation and brain malformations, such as white matter lesions (5); metabolic and hormonal alterations, such as hypergonadotropic hypogonadism, hypothyroidism and diabetes mellitus (6) (7) (8); and increased susceptibility to infections, atopy and immunodeficiency (9).…”

Impact of early diagnosis and noninvasive prenatal testing (NIPT): Knowledge, attitudes, and experiences of parents of children with sex chromosome aneuploidies (SCAs)

“…48,XXXY has an incidence of one in 40 000 to 60 000, while 49,XXXXY is the least common SCA, with an incidence of one in every 100 000 births. Both disorders include mild to severe dysmorphology, childhood apraxia of speech, and musculoskeletal problems that become more prevalent with age . Although the neurodevelopmental profiles of SCAs with multiple additive chromosomes are quite complicated, previous studies indicate the benefits to early detection and intervention for these populations …”

“…Both disorders include mild to severe dysmorphology, childhood apraxia of speech, and musculoskeletal problems that become more prevalent with age. 8,25,[28][29][30] Although the neurodevelopmental profiles of SCAs with multiple additive chromosomes are quite complicated, previous studies indicate the benefits to early detection and intervention for these populations. 23,28,31 Over 50 years of publications have demonstrated significant evidence to the importance of early identification of SCAs and the positive impact of early intervention on neurodevelopmental outcomes.…”