What is Pseudohypoparathyroidism?

Pseudohypoparathyroidism (PHP) is a rare genetic disorder where the body is resistant to parathyroid hormone (PTH). The parathyroid glands produce PTH normally, but the target organs (bones and kidneys) don't respond to it properly. This leads to low calcium, high phosphorus, and elevated PTH—similar lab findings to hypoparathyroidism, but the PTH is HIGH instead of low.

Cause:

PHP is caused by mutations in the GNAS gene, which codes for a protein (Gsα) involved in PTH signaling. When this protein is defective, PTH cannot activate its receptor properly.

Types of PHP:

Type 1a (PHP1a) – Most Common:

• Also called Albright Hereditary Osteodystrophy (AHO)
• Maternal inheritance (imprinting disorder)
• PTH resistance + distinctive physical features (see below)
• May also have resistance to other hormones (TSH, FSH/LH, GHRH)

Type 1b (PHP1b):

• PTH resistance only (no AHO physical features)
• Usually isolated to kidney PTH resistance
• Milder symptoms

Type 1c (PHP1c):

• PTH resistance + AHO features
• Similar to PHP1a but different genetic mechanism

Type 2 (PHP2):

• Very rare; downstream signaling defect
• PTH resistance without typical Gsα defect

Albright Hereditary Osteodystrophy (AHO) Features:

Physical characteristics seen in PHP1a (and pseudopseudohypoparathyroidism—see below):

• Short Stature
• Round Face
• Obesity (Truncal)
• Brachydactyly: Short fingers and toes, especially 4th and 5th metacarpals (shortened knuckles—"knuckle-knuckle-dimple-dimple" sign when making a fist)
• Subcutaneous Ossifications: Bone formation in soft tissues
• Dental Abnormalities: Enamel hypoplasia, delayed eruption
• Developmental Delay/Intellectual Disability: Mild to moderate (variable)

Pseudopseudohypoparathyroidism (PPHP):

• Individuals with AHO physical features but NORMAL calcium, phosphorus, and PTH
• No hormone resistance
• Occurs when GNAS mutation is inherited from father (paternal inheritance)
• Essentially "looks like PHP1a but normal labs"

Symptoms:

Symptoms are due to hypocalcemia (low calcium):

• Neuromuscular: Muscle cramps, tetany, paresthesias (tingling), seizures
• Neuropsychiatric: Cognitive impairment, anxiety, depression
• Fatigue, Weakness
• Cataracts
• Basal Ganglia Calcifications: Can cause movement disorders
• Dental Problems

In PHP1a, additional symptoms from resistance to other hormones:

• Hypothyroidism: TSH resistance (elevated TSH, low T4)
• Hypogonadism: Delayed or absent puberty from FSH/LH resistance

Diagnosis:

Labs:

• Low Serum Calcium
• High Phosphorus
• HIGH PTH: This is the KEY difference from true hypoparathyroidism (where PTH is low)
• Low or Normal Vitamin D
• TSH: May be elevated (subclinical or overt hypothyroidism)

Imaging:

• Hand X-rays: Shortened 4th/5th metacarpals
• X-rays: Subcutaneous ossifications
• Brain CT/MRI: Basal ganglia calcifications

Genetic Testing:

• Confirms GNAS mutation
• Helps distinguish PHP1a from PHP1b or PPHP

Treatment:

Same as Hypoparathyroidism (Calcium + Active Vitamin D):

• Calcium Supplementation: 1500-3000 mg/day
• Active Vitamin D (Calcitriol): 0.25-2 mcg/day
• Goal: Maintain calcium in low-normal range (8.0-9.0 mg/dL) to avoid hypercalciuria

Treat Other Hormone Resistances:

• Hypothyroidism: Levothyroxine if TSH elevated and T4 low
• Hypogonadism: Hormone replacement (estrogen/testosterone) if needed
• Growth Hormone: Rarely considered if severe short stature

Supportive Care:

• Educational support for developmental delays
• Physical/occupational therapy
• Weight management

Monitoring:

• Calcium, Phosphorus, PTH: Every 3-6 months
• TSH, Free T4: Annually (or as needed)
• Kidney Function: Creatinine annually
• 24-Hour Urine Calcium: Monitor for hypercalciuria
• Renal Ultrasound: Check for kidney stones/nephrocalcinosis
• Growth and Development: Pediatric patients

Prognosis:

• With proper treatment, most patients can maintain normal calcium levels and avoid acute complications
• Intellectual disability and developmental delays are variable (mild to moderate in PHP1a)
• Physical features (AHO) persist throughout life
• Risk of complications (kidney stones, cataracts, basal ganglia calcifications) same as hypoparathyroidism