Pseudohypoparathyroidism (Albright Hereditary Osteodystrophy)

The target cannot hear the hormone. PTH normally binds its receptor and, through Gs-alpha (encoded by GNAS), activates adenylate cyclase and cAMP to raise calcium and excrete phosphate. In pseudohypoparathyroidism a Gs-alpha defect leaves the kidney and bone resistant to PTH, so calcium falls and phosphate rises. The parathyroids respond by secreting more PTH, hence the paradoxical high PTH with low calcium.

Parent of origin. GNAS is imprinted, expressed differently from the maternal and paternal alleles in some tissues, so the parent of origin of the mutation shapes the phenotype. A maternal defect (PHP type 1a) causes both AHO and hormone resistance. A paternal defect (pseudo-pseudohypoparathyroidism, PPHP) causes the AHO physical phenotype without hormone resistance.

The AHO phenotype. Albright hereditary osteodystrophy comprises:

• Short stature
• A round or moon face
• Obesity
• Brachydactyly with short 4th and 5th metacarpals and metatarsals
• Subcutaneous ossifications or calcifications
• Variable developmental delay or intellectual impairment

The metacarpal sign. With the 4th and 5th metacarpals shortened, the affected knuckles form dimples instead of prominences when the patient clenches a fist. This is the positive metacarpal sign, remembered as "knuckle-knuckle-dimple-dimple".

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The biochemistry. PHP 1a and 1b give low calcium, high phosphate and high PTH, with a low or normal 1,25-vitamin D. The high PTH is what distinguishes it from hypoparathyroidism, where PTH is low. PPHP has the AHO look with normal calcium and PTH.

Presentation. Clinical signs of hypocalcaemia may be the presentation: Chvostek and Trousseau signs, tetany, seizures or cataracts.

Imaging. Hand and foot radiographs show the short 4th and 5th metacarpals and metatarsals and the positive metacarpal sign. The subcutaneous ossifications and intracranial (basal-ganglia) calcification may also be present.

Genetics. GNAS sequencing and methylation analysis (for the PHP1b imprinting defects) confirm the diagnosis and clarify the subtype. The work-up should also screen for associated hormone resistance, for example TSH resistance with hypothyroidism.

PHP is most often contrasted with hypoparathyroidism, but the examinable skill is the biochemical-pattern differential that places it among the causes of hypocalcaemia.

Each of these is developed separately in hypoparathyroidism, vitamin D deficiency, osteomalacia and renal osteodystrophy.

Correcting the calcium. Treat the hypocalcaemia with oral calcium plus active vitamin D (calcitriol or alfacalcidol). PTH resistance impairs renal 1-alpha-hydroxylation, so ordinary vitamin D is insufficient. Titrate to a low-normal calcium and a falling PTH, and monitor for hypercalciuria and nephrocalcinosis.

The other resistances. Give levothyroxine for TSH resistance and hypothyroidism, and address gonadotropin resistance and growth as needed.

Genetic counselling. The family needs GNAS imprinting explained, with the parent-of-origin risk to offspring.

The orthopaedic role. The brachydactyly and short stature seldom require surgery. Manage symptomatic subcutaneous ossifications, address any functional problems, and coordinate care with endocrinology.

The test. In the Ellsworth-Howard test, exogenous PTH is infused and the urinary cAMP and urinary phosphate (phosphaturic) responses are measured. The pattern defines the functional subtypes:

• Normal, or true hypoparathyroidism. Both the urinary cAMP and the phosphaturic responses rise, because the target responds normally.
• PHP type 1 (the GNAS/Gs-alpha group: 1a, 1b and 1c). Both responses are blunted, because the lesion is at or proximal to cAMP generation, the receptor-Gs-alpha-adenylate-cyclase step.
• PHP type 2 (rare, and not a GNAS-imprinting disorder). The urinary cAMP response is normal but the phosphaturic response is blunted, so the defect lies distal to cAMP generation.