SHOX-associated short stature

SHOX deficiency disorders encompass a phenotypic spectrum ranging from isolated SHOX-deficient short stature to the more severe phenotype of Leri-Weill dyschondrosteosis (LWD). LWD is characterised by the classic triad of disproportionate short stature, mesomelia, and progressive Madelung deformity, with skeletal abnormalities becoming more apparent during childhood and adolescence and generally being more severe in females. Growth failure typically begins in infancy, with a progressive decline in height standard deviation score and a blunted pubertal growth spurt contributing to reduced adult height.

Additional features of LWD may include muscular calf hypertrophy, short fourth metacarpals, increased carrying angle of the elbow, high-arched palate, scoliosis, and increased body mass index, while intellect and visceral organ function are unaffected. In contrast, SHOX-deficient short stature is diagnosed in the absence of mesomelia and Madelung deformity and exhibits marked clinical variability, even among affected members of the same family. Overall, disease severity and clinical presentation are highly variable, reflecting the broad phenotypic spectrum associated with SHOX haploinsufficiency.

The estimated prevalence of SHOX deficiency is at least 1/1,000. Pathogenic SHOX variants are identified in 6-22% of children with idiopathic short stature.

The disorder is caused by heterozygous germline pathogenic variants in SHOX. SHOX is located in the pseudoautosomal region 1 (PAR1) at Xp22.3/Yp11.3 and escapes X-inactivation. SHOX deletions account for 80-90% of affected individuals, and intragenic pathogenic variants for 10-20%. SHOX encodes a nuclear transcription factor expressed in growth plate chondrocytes; haploinsufficiency reduces SHOX protein, leading to atypical chondrocyte proliferation and skeletal development.

SHOX-associated short stature is inherited in an pseudoautosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Prenatal molecular testing is possible once the familial pathogenic variant has been identified.

The diagnosis is established by molecular genetic testing. Radiographic Madelung deformity (triangulation of the distal radial epiphysis, dorsal subluxation of the ulna, and pyramidalisation of the carpal row) supports the diagnosis at the Leri-Weill dyschondrosteosis end of the spectrum but is typically absent in milder SHOX-deficient short stature.

Main differential diagnoses include:

• Turner syndrome
• Idiopathic: height below the third centile without identified skeletal, hormonal, chromosomal, or genetic aetiology

• Establishing the diagnosis: molecular confirmation of a pathogenic variant secures the clinical diagnosis.
• Specific and individualised surveillance and clinical management: identification of the underlying pathogenic variant is a prerequisite for targeted medical care, the nature and timing of which are determined by the treating physicians.
• Family member testing: once the familial pathogenic variant has been identified, predictive testing of at-risk relatives is possible.

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