PATHOPHYSIOLOGY OF PSEUDOHYPOPARATHYROIDISM
- Definition
- Pseudohypoparathyroidism (PHP) = end-organ resistance to parathyroid hormone (PTH).
- Laboratory fi ndings: hypocalcemia, hyperphosphatemia, and increased blood PTH (secondary hyperparathyroidism).
- Main Types
- PHP Type 1
- PHP Type 2
PSEUDOHYPOPARATHYROIDISM TYPE 1
- Overview
- Characterized by decreased renal cAMP production in response to exogenous PTH.
- Caused by mutations in the GNAS gene (encodes the α-subunit of the stimulatory G protein, Gsα).
- Result: lack of adenyl cyclase activation when PTH binds its receptor → PTH effect is lost.
- Maternal Imprinting
- GNAS expression in kidney, pituitary, gonads, thyroid is primarily from the maternal allele.
- Tissue-specific imprinting leads to three PHP-1 subtypes.
1. PHP Type 1a (Albright Hereditary Osteodystrophy)
- Inheritance: Autosomal dominant, maternally transmitted GNAS inactivating mutation.
- Biochemical: Hypocalcemia, hyperphosphatemia, high PTH (secondary hyperparathyroidism).
- Physical Phenotype (Albright hereditary osteodystrophy):
- Short stature, rounded face, short neck, obesity.
- Ocular abnormalities.
- Shortened fourth and fi fth metacarpals (“knuckle, knuckle, dimple, dimple”).
- Dental hypoplasia, subcutaneous calcifications.
- Developmental delay, mental retardation, flattened nasal bridge.
- Additional Hormone Resistance
- Often have resistance to other G-protein–coupled hormones (e.g., TSH, gonadotropins).
- Clinical manifestations: hypothyroidism, delayed puberty, oligomenorrhea, infertility, growth hormone deficiency.
- Bone Changes
- PTH can be functional at the bone → potential for osteoclast overactivity, subperiosteal resorption, and osteitis fi brosa cystica changes.
2. Pseudopseudohypoparathyroidism
- Inheritance: Paternally transmitted GNAS mutation.
- Phenotype: Albright hereditary osteodystrophy without PTH resistance.
- Laboratory: Normal serum calcium, phosphate, and PTH.
- Notable Finding: May show excess dermal ossification (progressive osseous heteroplasia).
3. PHP Type 1b
- Cause: Maternal transmission of mutations in GNAS regulatory elements.
- Phenotype: No Albright hereditary osteodystrophy features.
- Main Feature: Renal PTH resistance → hypocalcemia, hyperphosphatemia, increased serum PTH.
4. PHP Type 1c
- Defect: Mutation affects coupling of G protein to the PTH receptor; adenyl cyclase itself is intact.
- Clinical: Albright hereditary osteodystrophy features + biochemical abnormalities (hypocalcemia, hyperphosphatemia, high PTH).
PSEUDOHYPOPARATHYROIDISM TYPE 2
- Overview
- Same laboratory fi ndings as PHP type 1: hypocalcemia, hyperphosphatemia, high PTH.
- No Albright hereditary osteodystrophy phenotype.
- Normal cAMP response to exogenous PTH.
- But no phosphaturia after PTH → suggests a defect beyond cAMP (e.g., at cAMP-dependent protein kinase A).
- Acquired (not familial), onset can be from infancy to older age.
CLINICAL MANIFESTATIONS OF PHP TYPE 1A
- Synonym: Albright hereditary osteodystrophy.
- Inheritance: Autosomal dominant, maternal GNAS mutation.
- Onset: Hypocalcemia usually noticed between ages 3 and 8 due to secondary hyperparathyroidism.
- Key Phenotype
- Short stature, round face, short neck, obesity, flattened nasal bridge.
- Short 4th and 5th metacarpals/metatarsals, causing the “knuckle, knuckle, dimple, dimple” sign.
- Ocular issues (microphthalmia, strabismus, hypertelorism, etc.).
- Dental hypoplasia.
- Developmental delay or mental retardation.
- Subcutaneous ossifications (osteoma cutis).
- Hormonal Resistance Beyond PTH
- TSH → hypothyroidism.
- Gonadotropins → delayed puberty, oligomenorrhea, infertility.
- Growth hormone → short stature, poor growth.
- Bone
- Some skeletons show changes of secondary hyperparathyroidism (bone resorption, cystic lesions).
- Variant: Pseudopseudohypoparathyroidism
- Paternal GNAS mutation → physical features of Albright hereditary osteodystrophy without PTH resistance.