Shox Deficiency Disorders

Clinical Findings of LWD

Short stature is defined as height below the third centile of the reference population.

Mesomelia (disproportionate shortening of the middle portion of the limbs) is present in 60%-100% of females and 45%-82% of males with LWD older than age six years [Kosho et al 1999, Schiller et al 2000, Grigelioniene et al 2001, Ross et al 2001, Munns et al 2003b]. In rare cases, rhizomelic limb shortening (disproportionate shortening of the upper portion of the limbs) can be found [Deshwar et al 2018, Ramachandrappa et al 2018].

This shortening of the forearm and lower leg can be assessed by two ratios:

• Extremities-to-trunk ratio. An extremity-to-trunk ratio (sum of arm span and calculated leg length divided by the sitting height) less than 1.95 + 0.5 x height (metric) is indicative of shortening of arms and legs; it serves as a sensitive auxologic test to detect SHOX deficiency [Binder et al 2003].
• Sitting height-to-height ratio. A high sitting height-to-height ratio is indicative of shortening of the legs and can also be used as the first auxologic test when screening for short children with SHOX deficiency [Malaquias et al 2013, Wolters et al 2013].

Madelung wrist deformity, caused by an abnormal radial, ulna, and carpal alignment, is characterized by spontaneous dorsal subluxation of the distal ulna resulting in a lateral "dinner fork" appearance of the wrist first described by Madelung [1878].

Radiographic Findings of LWD

The radiographic criteria for Madelung deformity [Dannerberg et al 1939, Langer 1965, Fagg 1988] include the following main abnormalities:

• Radius
  • Triangulation of the distal epiphysis
  • Early fusion of the ulnar half of the distal epiphysis
  • Localized lucency at the distal ulnar border
  • Decreased length
  • Dorsal and ulnar curve
• Carpal bones. Pyramidalization of the carpal row becoming wedge-shaped with the os lunatum at its tip
• Ulna
  • Decreased length
  • Dorsal subluxation
  • Triangular deformity of the epiphysis

SHOX-deficient short stature should be suspected in children with a first-degree relative with clinical LWD or SHOX deficiency disorder and one of the following [Binder et al 2000, Ezquieta et al 2002, Ogata et al 2002, Rappold et al 2002, Binder et al 2003, Binder 2011]:

• Disproportionate short stature (young school age)
• Madelung deformity (older school age)
• Short stature and specific minor abnormalities (see Clinical Characteristics, Clinical Description)

The following two testing algorithms have been proposed:

• A scoring system based on various clinical signs including body disproportion, arm span:height ratio <96.5%, sitting height:height ratio >55.5%, body mass index >50th centile, the presence of cubitus valgus, short forearm, bowing of the forearm, appearance of muscular hypertrophy, and/or dislocation of the ulna [Rappold et al 2007]. Items scored and the scoring weight were derived by multivariate analysis in 1,608 individuals with short stature including 68 with molecularly confirmed SHOX deficiency (i.e., presence of pathogenic variants / deletions in the coding region; note that enhancers had not yet been identified). See Rappold et al [2007], Figure 1 and Table 7 (full text).
  While the values for body disproportions in children and adults are useful, they may not apply to very young children [Jorge & Arnhold 2007].
• A diagnostic algorithm (not yet evaluated) based on clinical, auxologic, and radiologic criteria [Binder 2011]. See Figure 1.

Figure 1.

This schema provides an algorithmic approach to SHOX pathogenic variant screening in a child with short stature. Minor abnormalities (*) in SHOX deficiency are shortening of the fourth and fifth metacarpals, high-arched palate, increased carrying angle (more...)

Note: The absence of the above signs does not exclude the diagnosis of SHOX deficiency, especially in very young children.

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of Leri-Weill dyschondrosteosis (LWD) or SHOX-deficient short stature, molecular genetic testing approaches can include methods to detect large deletions and methods to detect intragenic SHOX pathogenic variants.

Methods to detect large deletions. Overall, 80%-90% of individuals with SHOX deficiency have deletions that vary in size from an intragenic single-exon deletion to (more commonly) 10 kb to 2.5 Mb or more. Of note, deletions with the SHOX enhancer regions that leave SHOX intact have been reported.

• CMA, which uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including SHOX) that cannot be detected by sequence analysis, should be performed first.
• If a large SHOX deletion is not detected by CMA, perform gene-targeted deletion/duplication analysis next.
• Deletions can also be detected using SNP array analysis. Ideally, determining heterozygosity for (a) SNP(s) involves analysis of DNA from the proband and both parents.

Methods to detect intragenic pathogenic variants in the 10%-20% of individuals with SHOX deficiency who have an intragenic SHOX variant include the following:

• Sequence analysis, which detects small intragenic deletions/insertions and missense, nonsense, and splice site variants
• A multigene panel that includes SHOX and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When SHOX-deficient short stature is indistinguishable from many other inherited disorders characterized by short stature, comprehensive genomic testing –which does not require the clinician to determine which gene(s) are likely involved – is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Exome array (when clinically available) or alternatively CMA – if not previously performed – may be considered if exome sequencing is nondiagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Cytogenetic testing. If either a contiguous gene syndrome encompassing signs of a SHOX deficiency disorder (in addition to other distinctive features) or an X;Y chromosomal translocation is suspected, a G-banded karyotype should be carried out [Ballabio et al 1989, Shears et al 1998, Shears et al 2002]. Rarely, individuals with LWD may have one of the following:

• Balanced and unbalanced translocations involving X, Y, and other chromosomes [Shears et al 1998, Izumi et al 2007]
• Other complex sex-chromosome abnormalities [Wei et al 2001]

Leri-Weill Dyschondrosteosis (LWD)

Short stature. Natural growth in SHOX deficiency is not well studied. In a review of 129 individuals with SHOX deficiency, Munns et al [2003b] reported a progressive decline in the height standard deviation score from birth (-1.05), through childhood (female -2.23, male -2.10), and into final adult height (female -2.84, male -2.36).

• Antenatally detected shortening of the long bones attributable to SHOX deficiency was reported in five infants. In four of the five, SHOX deficiency was inherited from a previously undiagnosed parent with final height between -1.9 to -1.2, suggesting that SHOX deficiency can be well tolerated within a favorable genetic context [Ramachandrappa et al 2018].
• Mean birth length is only mildly reduced, at 0.6-0.9 SD below the mean [Munns et al 2003a, Binder et al 2004].
• Infancy is characterized by significant growth failure resulting in short stature in early childhood with mean heights of 2.1-2.2 SD below the mean [Ross et al 2001, Binder et al 2003, Munns et al 2003b].
• During childhood, there is probably no relevant additional loss of height.
• The pubertal growth spurt, however, appears to be blunted, resulting in an additional height deficit.

Mesomelia. Mesomelic disproportion of the skeleton with shortening of the extremities can be evident first in school-aged children and increase with age in frequency and severity [Ross et al 2001]. In very rare instances rhizomelic limb shortening can also be seen [Deshwar et al 2018, Ramachandrappa et al 2018].

Madelung deformity. Like mesomelia, Madelung deformity evolves with time and is generally more common and more severe in females. During infancy and early childhood, children with LWD may have subtle radiologic signs of Madelung deformity (i.e., lucency of the distal radius), but they are usually asymptomatic and the physical examination is normal.

Madelung deformity typically develops in mid-to-late childhood. The first common sign is a subtle reduction in pronation and supination of the forearm. The complete deformity with distal subluxation of the ulna (dinner fork sign) evolves during puberty and is associated with further restriction of forearm supination and pronation [Vickers & Nielsen 1992, Munns et al 2001].

Rarely, Madelung deformity causes joint pain in adolescence [Schmidt-Rohlfing et al 2001].

Other features of LWD [Rao et al 2001, Ross et al 2001, Munns et al 2003b, Rappold et al 2007, Rosilio et al 2012]:

• Hypertrophy of calf muscles
• Short fourth metacarpals
• Increased carrying angle of the elbow
• High-arched palate
• Scoliosis
• High body mass index (not caused by excess of fat mass)

No other visceral involvement occurs. Intellect is normal.

SHOX-Deficient Short Stature

When SHOX deficiency occurs in the absence of Madelung deformity and mesomelia excludes the diagnosis of LWD; in these instances, the diagnosis is SHOX-deficient short stature. The phenotype is highly variable, even within the same family [Rao et al 2001, Ross et al 2001, Munns et al 2003b, Rappold et al 2007, Rosilio et al 2012].

Short Stature

For prepubertal children with short stature, recombinant human growth hormone (rhGH therapy) (dose 50 µg/kg body weight/day) should be offered. The therapeutic effect is a gain in final height of 7 to 10 cm. Hand/wrist radiographs for bone age determination should be taken at the initial visit and annually during rhGH therapy to assess maturation tempo.

Treatment with high-dose rhGH augments the growth of children with SHOX deficiency to the same extent as in Turner syndrome according to a two-year randomized controlled trial [Blum et al 2007]. This effect caused a similar gain in final height as well [Blum et al 2013]. No adverse radiologic effects were noted in those who were treated [Child et al 2015].

Painful Bilateral Madelung Deformity (uncommon)

Conservative management consists of wrist splints and supports during periods of increased discomfort and the use of ergonomic devices such as ergonomic computer keyboards. These measures may reduce wrist discomfort but do not alter the natural history of the deformity [Fagg 1988, Schmidt-Rohlfing et al 2001].

Different operative procedures have been attempted to decrease pain and restore wrist function [Anton et al 1938]. Although Anton et al did not recommend operating until skeletal maturity because of concern that surgery at an early age may result in further deformity, Vickers & Nielsen [1992] and Schmidt-Rohlfing et al [2001] reported encouraging results from prophylactic physiolysis of the ulnar (lateral) aspect of the distal radius and excision of the Vickers ligament (an abnormal fibroelastic ligament that runs from the lunate to the ulna aspect of the distal radius) during mid-to-late childhood. Their rationale for early intervention is to alter the natural history of the deformity by excising the area of dyschondrosteosis in the distal radius, thus restoring growth in the distal radius [Vickers & Nielsen 1992]. They reported decreased pain, increased function, and a reduction in wrist deformity following surgery over a period of 15 months to 12 years of follow up. They also speculate that MRI may allow for the early detection and subsequent removal of the Vickers ligament, which may play a central role in the development of Madelung deformity [Vickers & Nielsen 1992]. Similar results have been reported by Carter & Ezaki [2000] when a dome osteotomy of the radial metaphysis is combined with release of the Vickers ligament [Carter & Ezaki 2000].