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

INTRODUCTION

In 1942, Harry Klinefelter described a common set of symptoms in nine men, the majority of whom possessed testicular dysgenesis, elevated urinary gonadotropins, eunuchoidism, azoospermia, and gynecomastia [Klinefelter et al., 1942]. Although originally described as an endocrine disorder with a testosterone deficiency, Klinefelter syndrome was found to be the result of an additional X chromosome (XXY) [Jacobs and Strong, 1959]. 49, XXXXY results from the nondisjunction of the X chromosome during both meiosis I and meiosis II [Visootsak, 2006]. The rarest of the sex aneuploidy conditions, it was first described in 1960 [Fraccaro et al., 1960].

49, XXXXY occurs in 1 per 80,000–100,000 births; XXY, by contrast, occurs in 1 per 500–650 live births [Fraccaro et al., 1960; Barr et al., 1962; Cammarata et al., 1999; Simpson et al., 2003; Visootsak, 2007]. 49, XXXXY has become known as a severe variant of Klinefelter syndrome due to its characteristic features, central nervous dysfunction, congenital anomalies, and global developmental delays [Barr et al., 1962; Linden et al., 1995; Peet et al., 1998; Visootsak, 2007].

49, XXXXY has become known as a severe variant of Klinefelter syndrome due to its characteristic features, central nervous dysfunction, congenital anomalies, and global developmental delays.

At birth, subtle facial dysmorphism may be noted, such as epicanthal folds, upslanting palpebral fissures, or full upper eyelids [Simpson et al., 2003; Visootsak, 2007; Gropman et al., 2010; Samango-Sprouse et al., 2011; Tartaglia et al., 2011]. Associated orthopedic abnormalities include congenital hip dysplasia, torticollis, radioulnar synostosis, congenital talipes equinovarus (club foot), and clinodactyly [Barr et al., 1962; Okuyama, 1993; Linden et al., 1995; Cammarata et al., 1999]. As the boys mature, delay in motor and speech, along with other cognitive deficits and behavioral problems, are frequently reported. In addition, multiple orthopedic problems, including congenital hypotonia, radioulnar synostosis, tibulofibular synostosis, pes planus or pes cavus, avascular necrosis of the femoral head, or spinal deformities, may be noted [Dallapiccola and Pistocchi, 1968; Schmidt et al., 1978; Peet et al., 1998; Cammarata et al., 1999; De Rosa et al., 2001; Nishimura et al., 2008]. Orthopedic abnormalities affect activities of daily living, mobility, neurodevelopmental progression, and ultimately, quality of life. In an effort to aid clinicians and families with the early identification of musculoskeletal anomalies, this article sought to survey the common musculoskeletal anomalies in this population and to expand data on birth weight, birth height, etc., that have been previously presented by Gropman et al. [2010].

MATERIALS AND METHODS

RESULTS

Patient demographics are presented in Table I. Average age was 63 months (range 8–174 months) Thirty-four of the patients were Caucasian, three were Hispanic, two were African American, and one was Southeast Asian. Six of the participants resided outside the United States (three from Canada, and one each from Italy, England, and Honduras).

The average paternal age was 34 ± 7.03 years and the average maternal age was 31 ± 5.46 years at time of delivery, which is older than the mean age (25.4 years) of childbirth in the United States [Martin et al., 2012]. The average birth weight was 2.52 ± 0.44 kg (5th centile), with a range of 1.7–3.7 kg. The average gestational age was 37.1 ± 2.25 (n = 31) months with a range of 33–42 weeks, there were eight known children delivered prematurely. The average length at birth was 46.69 ± 2.70 cm (10th centile), with a range of 39–51 cm [Martin et al., 2012]. Fifty-eight percent of the deliveries were cesareans; higher than the average US rate, which, according to the most recent report from the Centers for Disease Control and Prevention, was 33% [Hamilton et al., 2011].

The mean age at diagnosis was 4 months (range: neonatal to 16 months). Typically children were first evaluated because of parental concerns regarding dysmorphic features, developmental delay, and/or microphallus.

The mean age at diagnosis was 4 months (range: neonatal to 16 months). Typically children were first evaluated because of parental concerns regarding dysmorphic features, developmental delay, and/or microphallus.

General appearance included a characteristic facial appearance (upslanting palpebral fissures, hypertelorism, synophrys, and arched eyebrows) (Fig. 1). Less common clinical features included cleft lip and palate (three participants) and ear malformations (ear tag, abnormal helix) in five children. The average head circumference was 32.64 ± 1.46 cm (7.5th centile), with a range of 30–36 cm.

Eighty-five percent of patients had generalized hypotonia (Table II). Tonus was decreased equally in the trunk, extremities, and oral facial musculature. Motor milestones were delayed in all patients; the average age at independent ambulation was 25.5 months (range 16–27 months).

Anomalies of the upper extremities were the most common among the participants (Table II). Clinodactyly was present in 60% participants. Loss of pronation and supination of the forearm, consistent with radioulnar synostosis, was noted in 75% of patients (Fig. 2). In addition, 32.5% had palpable radial head subluxation or dislocation.

Approximately 27.5% had a history of torticollis; all had been treated with physical therapy. Spinal abnormalities were uncommon (Table II). Increased lumbar lordosis was noted in 7.5% of patients, and there was a low incidence of scoliosis (5%) and kyphosis (2.5%).

Approximately 7.5% of patients had a history of developmental dysplasia of the hip, and 10% had X-ray confirmation of unilateral avascular necrosis of the hip (Legg–Calve–Perthes) (Fig. 3). Asymmetric rotation of the hips was displayed in 67.5% of the participants, characterized by reduced internal rotation, usually on the left. Of the children, 12.5% had a history of unilateral clubfoot. Sixty-five percent children had pes planus, while only 12.5% had pes cavus. Twenty-five percent of the children had genu valgum, and 5% had genu varum. Twenty-two percent had leg-length discrepancies (Table II).

Motor testing revealed significant asymmetry with shortened musculature in the pelvic region and upper trunk. Gait was characterized by a shortened stride with overutilization of extension and decreased truncal rotation and flexion. Dexterity and fine motor skills were more intact than locomotion and balance but were delayed in comparison to boys with 47, XXY and neurotypical children.

DISCUSSION

49, XXXXY is the most rare variant of Klinefelter syndrome and to our knowledge; this is the largest cohort of males with 49, XXXXY assembled to date. This is also the first report focused exclusively on the musculoskeletal abnormalities of these children.

Seventy-five percent of the participants in our study had clinical evidence of radioulnar synostosis; this rate is far higher than 50% prevalence reported in previous studies [Zaleski et al., 1966; Schmidt et al., 1978; Jones, 2006].

Seventy-five percent of the participants in our study had clinical evidence of radioulnar synostosis; this rate is far higher than 50% prevalence reported in previous studies.

Although radioulnar synostosis is typically treated with observation, this group of patients may present a unique challenge for orthopedic surgeons; for example, one older boy in our study, who had obvious bilateral radial head dislocations, complained of pain and difficulty with activities of daily living. Studies are needed to better track the natural history of this disorder as well as to explore surgical interventions that might preserve or improve existing function and comfort.

Hip disorders were also common in this cohort. Three children had hip dysplasia identified in infancy, a disorder which is typically far more common in girls. In addition, four (10%) children had radiographically confirmed avascular necrosis (AVN) of the femoral head, and 67.5% had asymmetric hip rotation (but otherwise asymptomatic). Previous authors have reported rates of AVN as high as 25% [Jones, 2006]. The lower incidence in our cohort may reflect the young age of our patient group (average 63 months), and future evaluation with X-rays may demonstrate that this number should be much higher.

The boys also displayed a wide range of other musculoskeletal anomalies: moderate hypotonia, leg-length discrepancies (not caused by hip dysplasia), pes planus, club foot, and genu valgum. Such abnormalities affect gross motor development, ambulation, and stride. Efforts to mitigate their impact through physical therapy, orthotics, and exercise should be utilized throughout their lifetime.

This study has several limitations. First, although this is the largest cohort reported to date, there were only 40 patients due to the rarity of this disorder. Second, the patients were seen outside a hospital, so X-rays were generally not available. Third, some data fields are incomplete as some parents were not knowledgeable of their child's complete history. Most important, the majority of the study cohort was very young, and additional musculoskeletal problems may be revealed as they age.

In summary, this article reports on the orthopedic anomalies associated with 49, XXXXY. The high incidence of these problems suggests a need for routine evaluations by a multidisciplinary team experienced with complex neurodevelopmental disorders. Attention should be directed at identification of musculoskeletal anomalies that might influence motor development; such as radioulnar synostosis, avascular necrosis of the femoral head, torticollis, club foot, and genu valgum. Anticipatory guidance should be provided to parents of boys with 49, XXXXY regarding the need for orthopedic mentoring during growth and development.