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Pseudohypoparathyroidism

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Topic updated on 07/03/16 11:45am
Introduction
  • Rare genetic disorder
  • Mechanism
    • PTH resistance
      • decreased target cell response to PTH 
Classification
  • Type 1a - Albright hereditary osteodystrophy 
    • defect in GNAS1 (Gsα protein)
      • defective gene from mother
      • upstream defect 
        • proximal to formation of cAMP
    • skeletal defects
      • short 4th, and 5th metacarpals and metatarsals or short 4th metacarpal only   
        • "knuckle, knuckle, dimple, dimple" sign on closed fist
        • differentials
          • Turner syndrome
            • short 4th metacarpal only  
            • "knuckle, knuckle, dimple, knuckle"
          • Down syndrome
            • short middle phalanx
      • brachydactyly
      • exostoses
    • round facies  
    • obesity 
    • short stature
    • diminished intelligence
  • Type 1b
    • defect in GNAS1 (Gsα protein)
    • normal appearance
  • Type 2
    • unknown gene defect
    • downstream defect
      • distal to formation of cAMP
    • normal appearance
Presentation
  • Symptom
    • symptoms of hypocalcemia
      • paresthesia 
        • fingertip, toes, perioral
      • abdominal pain, biliary colic
      • muscle cramps, tetany
      • dyspnea (laryngospasm, bronchospasm)
      • convulsions
      • mental status changes 
        • anxiety, fatigue, mood swings
  • Physical exam
    • findings of tetany
      • Trousseau's Sign post
        • carpopedal spasm after blood pressure readings
          • inflate BP cuff 20mmHg above systolic BP x 3-5min
        • hand adopts a MCP flexed, DIP and PIP extended position
        • more sensitive than Chvostek's sign 
      • Chvostek's Sign post
        • facial muscle contractions after tapping on the facial nerve
    • dermatologic 
      • fungal nail infections
      • hair loss
      • blotchy skin
        • pigment loss, vitiligo
Evaluation
  • Laboratory
    • high PTH
    • low calcium
    • high phosphate
    • low vit D
  • Ellsworth-Howard test
    • method to differentiate type 1 and type 2 by administering exogenous PTH 
      • Type 1
        • will show no increase in urinary cAMP and phosphate
      • Type 2
        • will show increased excretion of urinary cAMP and phosphate
Differential
  • Causes of hypocalcemia
    • renal osteodystrophy (low Ca, high PTH, high phosphate, high ALP)
    • hypoparathyrodism (low Ca, low PTH, high phosphate)
    • pseudopseuodohypoparathyroidism
      • mechanism
        • no PTH resistance
        • normal target cell response to PTH 
      • genetics
        • defect in GNAS1 (Gsα protein)
        • defective gene from father
      • skeletal defects
        • also has short 4th metacarpal and metatarsal 
        • metastatic calcification  
      • laboratory
        • normal PTH
        • normal calcium
        • normal phosphate
        • normal vit D
    • decreased vitamin D3
Type
Appearance
PTH
Calcium Phos Vit D Response to PTH administration Genetics
Hypoparathyroidism Normal
- -
Pseudohypoparathyroidism Type 1a
Skeletal defects
no increase in urinary cAMP or phosphate

GNAS1 (maternal defect, upstream)

Pseudohypoparathyroidism Type 1b Normal
  GNAS1 and STX16
Pseudohypoparathyroidism Type 2 Normal
increased urinary cAMP and phosphate GNAS1 (downstream)
Pseudopseudohypoparathyroidism Skeletal defects
N
N
N
N
  GNAS1 (paternal defect)
 
Treatment
  •  Nonoperative
    • oral calcium and 1alpha-hydroxylated vitamin D metabolites
      • indications
        • all patient with pseudohypoparathyroidism
    • IV calcium replacement
      • indications
        • patients with severe symptoms of hypocalcemia

 

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