Short stature and turner skeletal features in an 11-year-old boy with a ring y chromosome missing the short stature homeobox containing gene.

We report on an 11-yr-old boy with short stature and Turner skeletal features. Chromosome analysis revealed a 46,X,r(Y)(p11.3q11.2) karyotype, and FISH analysis showed loss of the Short stature homeobox containing gene (SHOX) from the ring Y chromosome. The results are consistent with the association of SHOX haploinsufficiency with short stature and Turner skeletal features, and suggest the importance of SHOX analysis in boys with Turner-like skeletal phenotype.

Introduction

In 1997, the Short stature homeobox containing gene (SHOX) was cloned from the pseudoautosomal region of the short arm of the X and the Y chromosome (PAR1) (1). Subsequent studies have shown that SHOX haploinsufficiency leads to short stature, Turner skeletal features, and Leri-Weill dyschondrosteosis (LWD) characterized by mesomelic limb shortening and Madelung deformity (2,3,4). Here, we report a boy with short stature, Turner skeletal feature, and a ring Y chromosome missing SHOX.

Case Report

The boy was the first child born to non-consanguineous parents after an uncomplicated term pregnancy. His birth length was 46.3 cm (–1.7 SD), and birth weight 2.9 kg (–0.6 SD). Subsequently, his clinical course was uneventful, although his height remained just below –2.0 SD. The paternal height was 169.4 cm, and the maternal height 161.0 cm.

At age 11, he was referred to us because of growth failure. Physical examination showed a prepubertal boy (testis size, 2 ml; pubic hair, Tanner stage 1) with proportionate short stature (127.3 cm, –2.3 SD) and mild cubitus valgus (Fig. 1A). Psychomotor development was normal. Radiological examination of the hands and wrists showed mild Madelung deformity (Fig. 1B). Bone age was 10 yr. Endocrine studies for short stature were normal, as were cerebral MRI scans. Chromosomal analysis showed a 46,X,r(Y)(p11.3q11.2) karyotype in all the 20 lymphocytes examined (Fig. 2), and fluorescence in situ hybridization (FISH) analysis with a SHOX probe (Yp11.3) (MBC, Tokyo, Japan ) and an Xq/Yq telomere probe demonstrated loss of SHOX from the ring Y chromosome (Fig. 3). FISH was also performed with an SRY probe, confirming the presence of SRY.

Fig. 1

A, Photographic appearance showing cubitus valgus. B, Radiological findings indicating bowing of the radius and dorsal dislocation of the distal ulna.

Fig. 2

G-banding karyotype showing the ring Y-chromosome (box).

Fig. 3

FISH analysis of this patient showing the presence of a single copy of the SHOX gene (green signal) on the X chromosome.

Discussion

SHOX haploinsufficiency resulting from a ring Y chromosome was identified in a boy with short stature, cubitus valgus, and mild Turner skeletal features (2,3,4). The results are consistent with the association of SHOX haploinsufficiency with short stature and Turner skeletal features. In addition, the mild skeletal manifestation in this prepubertal boy is compatible with the previous notion that skeletal maturing effects of gonadal estrogens induce the growth failure and skeletal anomalies in patients with SHOX haploinsufficiency (4). Indeed, severe phenotype in SHOX haploinsufficiency has usually been observed in pubertal to adult females with normal ovarian function (4, 5).

In this study, it is notable that SHOX haploinsufficiency was found in a prepubertal boy. Chromosome analysis is usually performed on girls with short stature because of the possibility of Turner syndrome, and SHOX analysis is frequently carried out on pubertal to adult females because of obvious skeletal manifestations. By contrast, such analyses remain rare for prepubertal boys primarily due to male sex development and mild skeletal phenotype. We recommend such analyses for boys with short stature and Turner-like skeletal features. Identification of SHOX haploinsufficiency will permit application of GnRH analog (6) therapy and appropriate genetic counseling.