Albright's hereditary osteodystrophy

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 This article is about the subtype of pseudohypoparathyroidism known as Albright's hereditary osteodystrophy.
   For the genetically-related condition, see McCune–Albright syndrome.

Albright's hereditary osteodystrophy
Synonyms	Acrodysostosis with hormone resistance, AHO
Pronounce	N/A
Field	Endocrinology, Medical genetics
Symptoms	Short stature, round facies, brachydactyly, choroid plexus calcification, dental enamel hypoplasia, intellectual disability
Complications	Hypocalcemia, secondary hyperparathyroidism, tetany
Onset	Childhood
Duration	Lifelong condition
Types	N/A
Causes	Mutations in the GNAS gene
Risks	Family history of the condition
Diagnosis	Genetic testing, blood tests (serum calcium, PTH), urine tests, MRI
Differential diagnosis	Pseudopseudohypoparathyroidism, hypoparathyroidism, McCune–Albright syndrome
Prevention	None
Treatment	Calcium and vitamin D supplementation, phosphate binders
Medication	Cholecalciferol, calcitriol
Prognosis	Good with treatment
Frequency	Rare
Deaths	Rare due to complications from untreated hypocalcemia

Albright's hereditary osteodystrophy (AHO) is a rare inherited disorder that affects bone development, endocrine function, and certain metabolic pathways. It is most commonly associated with pseudohypoparathyroidism type 1A, a condition in which the body exhibits resistance to parathyroid hormone (PTH). The phenotype includes a constellation of physical abnormalities and hormone resistance syndromes.

Overview

AHO is characterized by a distinct clinical presentation involving skeletal abnormalities, subcutaneous ossifications, and resistance to multiple hormones that signal via Gs alpha protein-coupled receptors, particularly parathyroid hormone. It is caused by mutations in the GNAS gene, which encodes the G protein alpha subunit (Gsα), critical for signal transduction in endocrine tissues.

Signs and Symptoms

Choroid plexus (bottom left), a site of pathological calcification in AHO.

Patients with AHO often display:

• Short stature
• Brachydactyly (shortening of the fourth and fifth metacarpals)
• Rounded facies
• Dental enamel hypoplasia
• Choroid plexus calcifications
• Subcutaneous calcifications
• Intellectual disability (mild to moderate)
• Hypocalcemic tetany
• Hypogonadism
• Obesity (variable)

These features may overlap with other disorders, making genetic testing important for confirmation.

Genetics

AHO is typically inherited in an autosomal dominant fashion and is caused by mutations in the maternal allele of the GNAS gene due to the phenomenon of genomic imprinting. The gene product, Gsα, is critical for activating adenylate cyclase and cyclic AMP (cAMP) signaling in response to several hormones.

In cases where the mutation is inherited from the father, individuals may display the phenotype without hormone resistance—a condition known as pseudopseudohypoparathyroidism.

Pathophysiology

The hallmark of AHO is end-organ resistance to parathyroid hormone. Although PTH levels are elevated due to low serum calcium and high phosphate, the kidneys fail to respond, leading to hypocalcemia and hyperphosphatemia.

This resistance is due to defective Gsα protein activity in tissues where the maternal allele is the only active copy—such as the renal tubules and the thyroid gland—explaining the tissue-specific hormone resistance.

Diagnosis

Diagnosis is clinical and biochemical, confirmed by molecular genetic testing:

• Complete blood count (CBC)
• Serum calcium: ↓
• Serum phosphate: ↑
• Serum parathyroid hormone (PTH): ↑
• Genetic testing for GNAS mutations
• Imaging: MRI or CT scan to assess choroid plexus calcifications and skeletal anomalies

Treatment

Management aims to normalize calcium and phosphate levels:

• Calcium supplementation
• Vitamin D analogs (e.g., calcitriol)
• Phosphate binders
• Monitoring for associated hormone deficiencies (e.g., thyroid-stimulating hormone, gonadotropins)

Early treatment improves outcomes and reduces the risk of tetany, seizures, and long-term skeletal complications.

Prognosis

With appropriate medical management, patients with AHO can lead normal or near-normal lives. Hormone resistance, if not recognized and treated early, can lead to complications, but the structural anomalies remain lifelong.

History

The condition was first described by Fuller Albright in 1942. Albright observed a unique syndrome combining skeletal malformations with signs of parathyroid hormone resistance, laying the foundation for understanding pseudohypoparathyroidism.

Related Disorders

• Pseudopseudohypoparathyroidism: Shares the AHO phenotype but lacks hormone resistance
• McCune–Albright syndrome: Caused by mosaic GNAS mutations but presents with endocrine hyperfunction rather than resistance

See Also

• Parathyroid hormone
• Pseudohypoparathyroidism
• Endocrine system
• Gs alpha subunit
• Signal transduction
• Genomic imprinting

External Links

• NIH Rare Diseases Information
• OMIM Entry on AHO – 103580

NIH genetic and rare disease info

• NIH info on Albright's hereditary osteodystrophy

Albright's hereditary osteodystrophy is a rare disease.