Leri-Weill Dyschondrosteosis Caused by SHOX GeneDeletion: A Case Report
Bharti Singh and Shubha R Phadke Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow Email:shubharaophadke@gmail.com
1 Abstract
Leri-Weill dyschondrosteosis is a dominantly inherited skeletal dysplasia characterized by the classic triad of short stature,
mesomelia and Madelung wrist deformity, which is caused by mutation in the SHOX gene. We report the case of a 14
years old girl with short stature and forearm deformity, with radiographic evidence of bilateral bowing of the radius and
Madelung deformity. Multiplex Ligation Probe Amplification (MLPA) with the probe set for subtelomeric deletions
showed deletion of the SHOX gene. The patient’s mother also had short stature with limb shortening with predominant
involvement of the mesomelic segments. The association of short stature with typical X ray abnormalities with SHOX
deletion suggested the diagnosis of Leri Weill dyschondrosteosis. We recommend careful clinical and radiological
evaluation and use of MLPA in the diagnostic work up of girls with short stature if the karyotype is found to be
normal.
2 Introduction
Leri-Weill dyschondrosteosis (LWD, OMIM #127300) is a dominantly inherited skeletal dysplasia characterized by the
classic triad of short stature, mesomelia and Madelung wrist deformity. The causative gene, the SHOX gene, is present in
the pseudoautosomal region of the X chromosome and the SHOX(Y) gene is present in the pseudoautosomal region on the
Y chromosome. Thus, there are 2 copies of the gene in both males and females. The disorder is usually more severe in
females. The mesomelia, i.e. shortening of the middle segment of limbs in relation to the proximal segment, can be evident
first in school-aged children and increases in severity with age. The Madelung deformity (abnormal alignment of the
radius, ulna, and carpal bones at the wrist) develops in mid-to-late childhood and is more common and severe in
females.
Most cases of Leri-Weill dyschondrosteosis result from mutation in the SHOX gene. The protein produced from this
gene plays a role in bone development and is particularly important for the growth and maturation of bones in the arms
and legs, by acting as a transcription factor and regulating the activity of other genes.
3 Case report
This case, a 14 year old girl, visited the medical genetics department with short stature and deformed forearm bones (Fig
1). She had attained menarche. Her mother also had short stature. Her birth history and developmental history were
normal.
Figure 1: Photograph of the patient with her mother: both have short stature and Madelung deformity of the
forearm.
Her height was 128 cm (3.5 S.D. below mean for age and sex) with the ratio of upper to lower segment being 1. Her
weight was 27 kgs (3 S.D. below mean for age and sex). The forearm bones were deformed and lower ends of ulna were
prominent and showed projections dorsally and distally giving a characteristic dinner-fork appearance. Her intelligence
was normal.
Radiographs of the upper limbs showed bowing of the radius and Madelung deformity bilaterally. The radii on both
sides were bent and the distal epiphyses of the radii were triangular. The carpals had a characteristic pyramidal
configuration with the lunate bone forming the tip of the pyramid. The medial parts of the lower ends of radii showed
lucent areas (Fig 2).
Figure 2: X ray of the upper limb showing bilateral bowing of the radius, Madelung deformity, triangular distal
epiphyses of the radii, pyramidal configuration of the carpals with the lunate forming the tip of the pyramid, and
lucent areas in medial parts of lower ends of radii.
Her routine hematological and biochemical investigations including serum calcium and phosphorus were normal. Her
karyotype was 46, XX. Multiplex Ligation Probe Amplification (MLPA) using the probe set for subtelomeric regions
(P036, MRC-Holland; https://www.mlpa.com/) was carried out which showed deletion of the SHOX gene in the patient
(Fig 3). This confirmed the diagnosis of Leri Weill dyschondrosteosis.
Figure 3: MLPA showing deletion of the SHOX gene.
Her mother also had short stature with limb shortening with predominant involvement of the mesomelic segments, but
radiological and genetic evaluation could not be done for her.
4 Discussion
The girl in this report had characteristic clinical and radiological features of Leri-Weill dyschondrosteosis.
Seventy to 90% of cases of Leri-Weill dyschondrosteosis are caused by haploinsufficiency of the SHOX gene, with
deletions accounting for 80% of them. Gene deletions of different sizes encompassing the gene itself or a regulatory
enhancer region which is located 50-250 kb downstream of the coding region are reported. Missense and nonsense
mutations, mostly located within exons 3 and 4 and also partial duplications of the gene, or heterozygous
deletions upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory
DNA elements that have enhancer activity are causative in the rest (Sabherwal et al., 2007; Bunyan et al.,
2015).
The diagnosis in this case was confirmed by MLPA which is a reliable, easy and less expensive technique. Point
mutations in the SHOX gene account for some cases and need sequencing of the gene which has 6 exons (Funari et al.,
2010).
SHOX deficiency leads to short stature with variable phenotypes with the main characteristics of mesomelic
shortening of the limbs. Madelung deformity of the forearm develops over time and appears during the second decade of
life in a proportion of cases (Choi et al., 2015). There can be great intrafamilial variability of the phenotypes as reported
by Gatta et al. (2014). SHOX mutations are also detected in about 15% of cases with isolated short stature without any
other features of Leri-Weill dyschondrosteosis and need to be tested even if there are no clinical clues (Rosilio et al., 2012).
Careful evaluation of the wrist radiographs is a must, as the typical radiographic findings of the wrist provide an
important clue to the diagnosis. Presence of muscular hypertrophy, cubital valgus, short neck, increased body
mass index and decreased arm span height ratio are some further clues to the diagnosis (Rappold et al.,
2007).
SHOX haploinsufficiency is an FDA approved indication for growth hormone therapy. However, some studies have
shown limited utility of growth hormone therapy in patients with SHOX mutations. In contrast to many other growth
disorders like growth hormone deficiency or even idiopathic short stature, in SHOX deficiency females outnumber males.
Ascertainment bias can be one explanation as more severe phenotype is seen in females. However, female predominance
was also observed in SHOX mutation screening studies where the only phenotype targeted was short stature. Therefore,
ascertainment bias alone cannot explain gender variation in this disorder. Another explanation for this can be the fact
that SHOX on the X chromosome is more prone to getting deleted than the SHOX on the Y chromosome (Binder et al.,
2011).
SHOX deficiency disorders are inherited in a dominant manner, even when the gene is present on the sex chromosome.
The gene is situated on the pseudoautosomal region and hence, it is one of the 15% genes on X chromosome which
escape lyonization. The homozygotes with mutations on both the copies of the gene are more severely
affected and the disorder is known as Langer mesomelia. An individual with Leri-Weill dyschondrosteosis has
a 50% chance of transmitting the pathogenic variant to the offspring and genetic counseling should be
offered.
5 Conclusion
Leri-Weill syndrome (LWS) is an uncommon genetic disorder caused by deletions or mutations in the SHOX gene or by
deletions downstream of the SHOX gene in most of the cases. Identification of the short stature homeobox-containing
gene (SHOX) deficiency in children, mainly females with growth problems, is vital for appropriate initiation of growth
hormone therapy. SHOX gene evaluation by MLPA should be included in the diagnostic work up of girls with short
stature if the karyotype is found to be normal.
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