summary Pseudohypoparathyroidism is a rare genetic metabolic bone disease caused by a defect in the GNAS1 protein that leads to a decreased response to PTH. Patients present with characteristic findings of short 4th and 5th metacarpals, round facies, short stature, and symptoms of hypocalcemia. Diagnosis is made based on physical examination findings, serum labs, and results of the Ellsworth-Howard test. Treatment is medical management with oral calcium and 1alpha-hydroxylated vitamin D metabolites. Etiology 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 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 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 Labs Type Appearance PTH Calcium Phos Vitamin 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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