What is Albright Hereditary Osteodystrophy?

Albright Hereditary Osteodystrophy (AHO) is a rare genetic disorder characterized by a distinct set of physical features caused by mutations in the GNAS gene. AHO is the physical phenotype seen in Pseudohypoparathyroidism Type 1a (PHP1a) and Pseudopseudohypoparathyroidism (PPHP).

Genetic Background:

• Caused by mutations in the GNAS gene, which codes for the Gsα protein involved in hormone signaling
• Inheritance: Autosomal dominant with genomic imprinting (expression depends on which parent passes the mutation)
• Maternal Inheritance: PHP1a (AHO features + hormone resistance—low calcium, high PTH)
• Paternal Inheritance: Pseudopseudohypoparathyroidism (PPHP) (AHO features but NORMAL calcium, PTH—no hormone resistance)

Key Difference:

• PHP1a (AHO + Hormone Resistance): AHO physical features + hypocalcemia, high PTH, possible hypothyroidism
• PPHP (AHO without Hormone Resistance): AHO physical features but normal calcium, PTH, thyroid function

Classic Physical Features of AHO:

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

Hormonal Features (PHP1a Only):

If AHO is associated with PHP1a (maternal inheritance), patients have resistance to multiple hormones:

• PTH Resistance: High PTH, low calcium, high phosphorus (pseudohypoparathyroidism)
• TSH Resistance: Subclinical or overt hypothyroidism (high TSH, low/normal T4)
• FSH/LH Resistance: Delayed or absent puberty, infertility
• GHRH Resistance: Growth hormone deficiency → short stature

Symptoms:

Physical/Skeletal:

• Short stature, round face, obesity
• Short fingers/toes
• Hard lumps under skin (ossifications)
• Dental problems

If PHP1a (Hormone Resistance Present):

• Hypocalcemia Symptoms: Muscle cramps, tetany, tingling, seizures
• Hypothyroidism Symptoms: Fatigue, weight gain, constipation
• Delayed Puberty or Infertility
• Developmental Delays, Cognitive Impairment

Diagnosis:

Clinical Diagnosis (Based on Physical Features):

• Combination of short stature, round face, brachydactyly, subcutaneous ossifications

Labs (for PHP1a):

• Low Calcium, High Phosphorus
• High PTH (despite low calcium—resistance to PTH)
• TSH: Elevated (if TSH resistance present)
• Free T4: Low or normal

For PPHP:

• Calcium, PTH, thyroid function ALL NORMAL (no hormone resistance)

Imaging:

• Hand X-rays: Shortened 4th and 5th metacarpals (diagnostic)
• X-rays of Soft Tissues: Subcutaneous ossifications
• Brain MRI/CT: Basal ganglia calcifications (common in PHP1a)

Genetic Testing:

• Confirms GNAS mutation
• Determines PHP1a vs. PPHP (based on parent of origin)

Treatment:

For PHP1a (with Hormone Resistance):

• Hypocalcemia/Hyperphosphatemia:
  • Calcium supplementation (1500-3000 mg/day)
  • Active Vitamin D (Calcitriol 0.25-2 mcg/day)
  • Low-phosphorus diet
• Hypothyroidism:
  • Levothyroxine (thyroid hormone replacement)
• Hypogonadism:
  • Hormone replacement (estrogen/testosterone) if delayed puberty or infertility
• Growth Hormone Deficiency:
  • Growth hormone therapy (if documented deficiency)

For PPHP (No Hormone Resistance):

• No specific hormonal treatment needed (calcium/PTH/thyroid normal)
• Supportive care for physical features

Supportive Care (Both PHP1a and PPHP):

• Obesity Management: Diet, exercise, weight management programs
• Developmental Support: Early intervention, special education, occupational therapy
• Dental Care: Regular dental visits
• Pain Management: For subcutaneous ossifications (if symptomatic)
• Surgical Excision: Of symptomatic ossifications (though they may recur)

Monitoring:

• PHP1a Patients:
  • Calcium, phosphorus, PTH: Every 3-6 months
  • TSH, Free T4: Annually
  • Growth charts, bone age
  • Kidney function, urine calcium (to prevent kidney stones from treatment)
• PPHP Patients:
  • Monitor for development of hormone resistance (can occur over time, though rare)
  • Growth, development

Prognosis:

• Life expectancy generally normal with appropriate treatment
• Intellectual disability and developmental delays are variable (mild to moderate)
• Physical features (AHO) persist throughout life
• Hormone abnormalities (PHP1a) are lifelong and require ongoing management