Short stature, cubitus varus, foot deformity and intellectual disability with sexual infantilism: clinical clues to 49,XXXXY variant of Klinefelter syndrome ============================================================================================================================================================ * Md Ramiz Raja * Subhankar Chatterjee * Neeti Agrawal * Partha Pratim Chakraborty * Endocrinology * Sexual health * General practice / family medicine ## Description A boy in his early adolescence was referred for delayed development of sexual characters. He was born of a non-consanguineous union, and had delayed developmental milestones. He had received elementary school education only, and his IQ was 52. Clinical examination of this mid-teenager revealed the following: height: 150 cm; weight: 41 kg; arm span: 152 cm; lower segment: 82 cm; upper segment: 68 cm. He had facial asymmetry, gynaecomastia, bilateral cubitus varus and bilateral clubfoot with pes planus (figure 1). The epididymides were well formed and the testes were ‘shotty’ with a volume of 1 mL (figure 1). The auxological parameters (‘long-legged’, difference between arm span and height of less than 5 cm) and the testicular appearance led to a working diagnosis of Klinefelter syndrome (KS). However, short stature (height less than third percentile, height SD score: −3.1) was not consistent with the clinical diagnosis of KS. Hormonal evaluation was suggestive of hypergonadotropic hypogonadism (testosterone: 9.67 ng/dL, follicle-stimulating hormone: 76.52 IU/L, luteinising hormone: 56.81 IU/L); however, the karyotype revealed 49,XXXXY pattern (figure 2). The boy was treated with monthly injection of testosterone esters and referred for rehabilitation therapy. ![Figure 1](http://casereports.bmj.com/https://casereports.bmj.com/content/bmjcr/16/1/e253799/F1.medium.gif) [Figure 1](http://casereports.bmj.com/content/16/1/e253799/F1) Figure 1 (A) Clinical picture showing bilateral cubitus varus and lack of pubic hairs; (B) clubfoot and flat foot; (C,D) small testes having a volume of 1 mL; (E) appearance of pubic hairs with testosterone supplementation. ![Figure 2](http://casereports.bmj.com/https://casereports.bmj.com/content/bmjcr/16/1/e253799/F2.medium.gif) [Figure 2](http://casereports.bmj.com/content/16/1/e253799/F2) Figure 2 Peripheral G-banded karyotype showing 49,XXXXY pattern. KS is the most common form of sex chromosome aneuploidy, and the leading aetiology of primary male hypogonadism with an estimated prevalence of about 1: 2500; however, the condition often remains undiagnosed. The principal karyotype obtained from peripheral blood leucocyte in KS is 47,XXY (90%) and majority of the remaining 10% have 47,XXY/46,XY mosaicism. Rarely, they have more than one extra X (or Y) chromosome (48,XXXY, 48,XXYY, 49,XXXXY). The 49,XXXXY variant is rare with an incidence of 1 in 85 000–100 000 live births. Because of shared features of tall stature, long legs, gynaecomastia, small ‘shotty’ testes and hypergonadotropic hypogonadism, they are considered as variants of KS. Some of the non-gonadal features are relatively more common in these patients compared with classic KS. Interestingly, unlike other variants of KS, 49,XXXXY individuals often have short stature due to extreme overdosage of sex chromosomes genes, which was evident in this patient.1 KS with an extra X (or Y) chromosome often demonstrates one or more of the following dysmorphic features: hypertelorism, epicanthal folds, upslanting palpebral fissures, hooded eyelids, cleft palate, fifth-digit clinodactyly, short nail beds, pes planus, joint hyperextensibility, prominent elbows with cubitus varus, radioulnar synostosis, hip dysplasia, clubfoot, congenital heart defects and kidney dysplasia. In addition, inguinal hernia, cryptorchidism, cognitive impairment and psychological disorders are more frequent in 48,XXYY or 48,XXXY compared with 47,XXY. The prevalence is even higher in 49,XXXXY.1 Intellectual disability is almost universal in 49,XXXXY with speech delay, learning difficulties (100%), intellectual impairment (>95%) and a mean full scale IQ of 20–60 (verbal IQ