What is the approach and treatment for short stature?

Approach and Treatment to Short Stature

The comprehensive evaluation of short stature requires systematic genetic testing, including chromosomal analysis for all girls to rule out Turner syndrome, and appropriate growth hormone therapy for specific etiologies with dosages ranging from 0.3-0.375 mg/kg/week depending on the underlying condition. 1, 2, 3

Diagnostic Evaluation Algorithm

Initial Assessment

• Define short stature as height-for-age less than 2 standard deviations below the mean (below 3rd percentile) 1, 4
• Measure growth velocity over 4-6 months (crossing multiple centile lines after age 3 suggests pathology) 2
• Calculate midparental height to determine genetic growth potential 2
• Determine bone age to assess growth potential and expected final height 2

Categorization of Short Stature

1. Proportionate Short Stature:

   • Perform chromosome analysis to rule out Turner syndrome and other chromosomal disorders 1, 2
   • If negative, proceed with genomic array studies 2
   • Consider SHOX gene testing for children with subtle skeletal changes or significant short stature (>3 SD) 2

2. Disproportionate Short Stature:

   • Perform skeletal survey including AP and lateral skull views, AP and lateral spine views, AP chest with rib views, AP pelvis, AP long bones, AP hands and feet, and lateral ankle and knee 2

Laboratory Evaluation

• Thyroid function tests to rule out hypothyroidism 1
• IGF-1 and IGFBP-3 levels to screen for growth hormone deficiency 1
• Celiac disease screening (tissue transglutaminase antibodies) 5
• Complete blood count, comprehensive metabolic panel to rule out chronic disease 4

Treatment Approach

Growth Hormone Therapy Indications

1. Growth Hormone Deficiency (GHD):

   • Weekly dosage: up to 0.3 mg/kg divided into daily subcutaneous injections
   • For pubertal patients: up to 0.7 mg/kg/week 3

2. Chronic Kidney Disease (CKD):

   • Weekly dosage: up to 0.35 mg/kg divided into daily subcutaneous injections
   • Continue therapy up to renal transplantation 3

3. Idiopathic Short Stature (ISS):

   • Weekly dosage: up to 0.3 mg/kg divided into daily subcutaneous injections 3

4. Turner Syndrome:

   • Weekly dosage: up to 0.375 mg/kg divided into 3-7 doses per week 3

Monitoring Treatment

• Regular height measurements every 3-6 months 2
• Annual bone age assessment to monitor treatment effectiveness 2
• IGF-1 monitoring for safety and dosage adjustment 2
• Discontinue treatment when epiphyses are fused 3

Common Pitfalls and Caveats

• Missed Diagnoses: Almost 50% of patients referred for genetic evaluation of short stature have either constitutional delay of growth or familial short stature, which are non-pathological 1
• Incomplete Evaluation: Whole-exome sequencing can identify causative mutations in an additional 16.5% of patients who only manifest part of the symptomatology of known short stature syndromes 6
• Delayed Treatment: Failure to increase growth rate during the first year of therapy suggests poor compliance or other causes of growth failure such as hypothyroidism or under-nutrition 3
• Overlooking Carriers: Heterozygous carriers of recessive skeletal dysplasia alleles represent 3.5% of short stature cases 6

Special Considerations

• For dialysis patients, timing of growth hormone injections is critical:

  • Hemodialysis patients: inject at night before sleep or 3-4 hours after hemodialysis
  • CCPD patients: inject in morning after dialysis completion
  • CAPD patients: inject in evening during overnight exchange 3

• A combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows identification of the underlying cause in at least 33% of cases 6