What other rare genetic disorders can cause hypercalcemia and short stature?

Rare Genetic Disorders Causing Hypercalcemia and Short Stature

Jansen's metaphyseal chondrodysplasia (JMC) is the most significant rare genetic disorder that causes both hypercalcemia and short stature, characterized by activating mutations in the PTH/PTHrP receptor (PTH1R). 1, 2

Key Genetic Disorders to Consider

• Jansen's metaphyseal chondrodysplasia (JMC):

  • Caused by heterozygous activating mutations in the PTH1R gene 1, 3
  • Features include:
    • Short-limbed dwarfism with abnormal metaphyses 1
    • Hypercalcemia despite normal/low PTH levels 1, 3
    • Hypophosphatemia 2
    • Disarrayed growth plates with reduced mineralization 2
  • Five different heterozygous activating PTH1R mutations are known to cause JMC, most commonly H223R 1
  • Severity varies - some patients may not exhibit overt hypercalcemia despite having the mutation 1

• 22q11.2 Deletion Syndrome (DiGeorge syndrome):

  • Features include:
    • Thymic and parathyroid hypoplasia leading to hypocalcemia (though rarely can present with hypercalcemia) 4
    • Short stature 4
    • Immunodeficiency 4
    • Characteristic facial features 4
    • Congenital heart defects (conotruncal anomalies) 4
  • Genetic testing is recommended for diagnosis 4

• Williams Syndrome:

  • Features include:
    • Infantile hypercalcemia 4
    • Short stature 4
    • Elfin facial features 4
    • Developmental delay 4
    • Supravalvular aortic stenosis and peripheral pulmonary stenosis 4

Diagnostic Approach

• Initial evaluation should differentiate between isolated short stature and short stature with other physical/developmental abnormalities 5, 6

  • Assess if short stature is proportionate or disproportionate 5
  • Document birth measurements (weight, length, head circumference) 5
  • Evaluate for dysmorphic features that might suggest a syndrome 5

• Laboratory evaluation for patients with short stature and hypercalcemia:

  • Serum calcium, phosphorus, and intact PTH levels 7
    • JMC typically shows hypercalcemia with suppressed PTH 1, 3
  • Vitamin D metabolites (25-OH and 1,25-OH) 8
  • Renal function tests 6
  • Thyroid function tests 6

• Radiographic evaluation:

  • Bone age assessment via wrist radiograph 5, 6
  • For disproportionate short stature, skeletal survey to evaluate for metaphyseal abnormalities characteristic of JMC 5, 4
    • Look for expanded metaphyses with disarrayed growth plates 2

• Genetic testing:

  • For suspected JMC: Sequencing of PTH1R gene, looking for activating mutations (H223R, T410P, T410R) 1, 3
  • For suspected 22q11.2 deletion: Chromosomal microarray analysis 4
  • For suspected Williams syndrome: Fluorescence in situ hybridization (FISH) for 7q11.23 deletion 4
  • SHOX gene testing for patients with dyschondrosteosis features 4

Management Considerations

• For JMC:

  • No specific treatment currently available 2
  • Experimental studies suggest PTH inverse agonist peptides may normalize calcium levels 2
  • Management focuses on treating hypercalcemia if symptomatic 7
  • Regular monitoring of growth and calcium levels 6

• For 22q11.2 Deletion Syndrome:

  • Multidisciplinary care based on specific manifestations 4
  • Genetic counseling for families 4
  • Calcium monitoring, especially perioperatively 4

• For Williams Syndrome:

  • Cardiovascular monitoring for aortic stenosis 4
  • Management of hypercalcemia if present 4
  • Developmental support 4

Common Pitfalls to Avoid

• Failing to consider rare genetic disorders in patients with both hypercalcemia and short stature 5
• Missing the diagnosis of JMC in patients without overt hypercalcemia 1
• Overlooking the need for genetic testing in patients with short stature and dysmorphic features 4
• Assuming all hypercalcemia is due to hyperparathyroidism or malignancy, which account for 90% of cases but miss rare genetic disorders 7
• Failing to recognize that some JMC patients may have normal calcium levels despite having the mutation 1