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Short stature Homeobox-containing gene (SHOX) Deficiency

What is SHOX?

  • SHOX is an acronym for the short stature homeobox-containing gene.
  • The SHOX gene codes for a key transcription factor that plays a critical role in controlling human stature primarily through regulation of chondrocyte development.1
  • The SHOX gene is located on the human sex chromosomes (X and Y), and two functional copies of the gene are required for normal growth.

What is SHOX Deficiency?

  • SHOX deficiency (SHOX-D) is present when one copy (or very rarely, both copies) of the SHOX gene has undergone deletion or mutation.
  • SHOX deficiency may be inherited in a dominant fashion from an affected parent and passed on to offspring, or may occur spontaneously in a family with no other affected members.
  • Patients with SHOX deficiency may present with a broad phenotypic spectrum ranging from isolated short stature with no distinguishing clinical features* to short stature with moderate to severe skeletal dysplasia (Léri-Weill syndrome).2

*approximately 2-3% of patients with clinical features consistent with idiopathic short stature may test positive for SHOX deficiency.3

Potential Indicators of SHOX Deficiency

Clinical features that may be associated with SHOX deficiency include:2,4

  • Disproportionate short stature (greater shortening of the limbs than trunk)
  • High-arched palate
  • Cubitus valgus (increased carrying angle of the elbow)
  • Madelung (dinner fork) wrist deformity
  • Bowing of the forearm or tibia
  • Appearance of muscular hypertrophy in the calves
  • Family history of Léri-Weill syndrome (or Langer syndrome, a very rare disorder resulting from complete deficiency of both SHOX genes)
  • Radiographic anomalies, e.g. triangularization of the radial epiphysis (see figure), radial and/or tibial bowing, shortening of the 4th or 5th metacarpals

Triangularization of the radial epiphysis

Diagnosing SHOX Deficiency

  • Diagnostic testing for SHOX deficiency (SHOXDNAdxSM) is available through Esoterix, Inc. (Calabasas Hills, CA).
  • Diagnosis of SHOX deficiency clearly identifies the underlying cause of short stature for the patient, family, and health care provider.
  • Because SHOX deficiency is a heritable condition, definitive diagnosis of SHOX deficiency may have implications for genetic counseling for the patient and family members.

Efficacy of Humatrope Therapy6

  • 52 patients with SHOX deficiency were randomized to either two years of Humatrope treatment at a dose of 0.35 mg/kg/wk (50 μg/kg/day) or non-treatment control.
  • Humatrope-treated patients with SHOX deficiency responded with highly significant increases in height velocity and height SDS (figure). Over the 2-year study period, Humatrope-treated patients with SHOX deficiency gained an average of 5.8 cm more in height than untreated patients.
  • The response to Humatrope therapy was similar for patients with SHOX deficiency and patients with Turner syndrome.
  • No significant Humatrope effect on bone age was observed.

Treatment Duration Graph

Safety of Humatrope Therapy6

  • No new safety concerns were observed in the SHOX-deficient patient population that were not already known.
  • No serious adverse events were reported for patients with SHOX deficiency.

Adverse Events Graph

References

  1. Munns CJF, Haase HR, Crowther LM, et al. Expression of SHOX in human fetal and childhood growth plate. J Clin Endocrinol Metab. 2004;89(8):4130-4135.
  2. Ross JL, Scott C Jr, Marttila P, et al. Phenotypes associated with SHOX deficiency. J Clin Endocrinol Metab. 2001;86(12):5674-5680.
  3. Rappold GA, Fukami M, Niesler B, et al. Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature. J Clin Endocrinol Metab. 2002;87(3):1402-1406.
  4. Ross JL, Kowal K, Quigley CA, et al. The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Léri-Weill dyschondrosteosis and Turner syndrome. J Pediatr. 2005;147:499-507.
  5. Binder G, Fritsch H, Schweizer R, Ranke MB. Radiological signs of Léri-Weill dyschondrosteosis in Turner syndrome. Horm Res. 2001;55(2):71-76.
  6. Blum WF, Crowe BJ, Quigley CA, et al. Growth hormone is effective in treatment of short stature associated with SHOX deficiency: two-year results of a randomized, controlled, multi-center trial. J Clin Endocrinol Metab. 2007;92(1):219-228.
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