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
    1. PHP Type 1
    2. 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.

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