What is the primary treatment for short stature related to SHOX (Short Stature Homeobox) mutation?

SHOX Mutation Related Short Stature

Primary Treatment Recommendation

Recombinant human growth hormone (rhGH) therapy is the primary treatment for short stature caused by SHOX gene mutations, with demonstrated efficacy equivalent to that seen in Turner syndrome patients. 1

Evidence for Growth Hormone Therapy

The landmark randomized controlled trial demonstrated that GH-treated SHOX-deficient patients achieved first-year height velocity of 8.7 cm/year compared to 5.2 cm/year in untreated controls (P < 0.001), with sustained benefit in the second year (7.3 vs. 5.4 cm/year; P < 0.001). 1 This represents the highest quality evidence available, showing marked improvement in both height velocity and height standard deviation scores over a 2-year period. 1

The treatment effect in SHOX-deficient patients was equivalent to that observed in Turner syndrome patients receiving GH therapy, with no significant difference in first-year height velocity (8.7 vs. 8.9 cm/year; P = 0.592). 1 By the end of the second year, GH-treated subjects gained 16.4 cm compared to 10.5 cm in untreated subjects (P < 0.001). 1

Clinical Context and Diagnosis

SHOX gene mutations represent one of the most important monogenetic causes of short stature, occurring in approximately 2-15% of children with idiopathic short stature and up to 22% when selected for disproportionate features. 2, 3 The prevalence is similar to that of growth hormone deficiency or Turner syndrome among children with short stature. 3

Genetic testing for SHOX mutations should be considered when clinical or radiographic findings suggest dyschondrosteosis, particularly in familial short stature cases with subtle skeletal changes. 4 The frequency varies from 1.1% to 12.5% depending on selection criteria. 4

Key Clinical Features to Identify

• Skeletal abnormalities: Madelung deformity, mesomelia (short forearms), high-arched palate, short neck, cubitus valgus, genu valgum, short fourth metacarpals 5, 3
• Disproportionate short stature: Sitting height/height ratio >55.5% suggests disproportionate growth requiring skeletal survey 6, 5
• Familial pattern: Careful evaluation of family members often reveals previously undiagnosed Leri-Weill dyschondrosteosis in relatives initially classified as having idiopathic or familial short stature 2

Skeletal changes may not be apparent until late childhood or pubertal age and are less commonly noted in males, making early diagnosis challenging. 4

Diagnostic Algorithm

1. Obtain skeletal survey when disproportionate short stature is present or in cases of significant short stature (≥3 standard deviations below mean) without obvious diagnosis 4, 5

2. Perform SHOX gene testing if skeletal survey reveals subtle changes suggestive of dyschondrosteosis or in familial short stature cases 4, 6

3. Evaluate family members with short stature, as this frequently identifies additional affected individuals with SHOX mutations 2, 3

4. Assess bone age via left wrist radiography to determine remaining growth potential before initiating therapy 7, 5

Treatment Implementation

Initiate recombinant human growth hormone therapy promptly once SHOX deficiency is confirmed to improve adult height outcomes. 8, 2 The evidence supports GH as an accepted and effective approach for treating short stature associated with isolated SHOX defects. 2

Treatment should continue until height velocity drops below 2 cm/year and/or epiphyseal growth plates close. 7 Serial bone age measurements are critical during GH therapy to prevent premature epiphyseal closure. 5

Critical Pitfalls to Avoid

• Missing the diagnosis in families initially classified as idiopathic short stature: Family screening often reveals Leri-Weill dyschondrosteosis in relatives, changing the diagnosis from ISS to SHOX deficiency 2

• Delaying skeletal survey in disproportionate short stature: Subtle radiographic abnormalities may be the only clue to SHOX mutations, particularly when classic features are absent 4, 5

• Failing to obtain bone age before initiating therapy: This risks premature epiphyseal closure and compromised final adult height 5

• Overlooking SHOX testing in children with height ≥3 SD below mean: Complete gene deletions represent the majority of SHOX mutations and may present without obvious skeletal features at initial diagnosis 3

Mutation Spectrum

The vast majority of SHOX mutations lead to complete gene deletions, detected by fluorescence in situ hybridization rather than sequencing alone. 3 Intragenic mutations in coding regions are relatively rare, with exon 5 mutations having a pathogenic rate of only 1/50,000 to 1/100,000. 8 This biased mutation spectrum emphasizes the importance of comprehensive genetic testing including deletion analysis. 3