Albright’s Hereditary Osteodystrophy (AHO) is a rare genetic disorder affecting how the body develops bones and regulates hormones. It presents with a wide array of physical and metabolic symptoms that can vary significantly among affected individuals.
Key Characteristics and Signs
Individuals with AHO often display distinctive skeletal abnormalities. Short stature is a common finding, with many individuals presenting with reduced height in adulthood. A rounded face and obesity are also frequently observed.
A hallmark skeletal feature is brachydactyly, which involves the shortening of bones in the hands and feet, particularly affecting the fourth and fifth fingers and toes. This can manifest as dimpling over the knuckles, sometimes referred to as ‘Archibald sign’. Subcutaneous ossifications, or the formation of bone under the skin, are another physical manifestation.
Beyond physical traits, AHO is often linked with endocrine issues, primarily pseudohypoparathyroidism type 1a (PHP1a). This condition means the body resists parathyroid hormone (PTH), even though the parathyroid glands produce normal or elevated amounts of it. This resistance leads to low blood calcium levels, known as hypocalcemia, and high blood phosphate levels, called hyperphosphatemia.
Symptoms of hypocalcemia can include tingling sensations, muscle cramps, and in some instances, seizures. Resistance to other hormones, such as thyroid-stimulating hormone (TSH) and gonadotropins, can also occur, potentially leading to subclinical hypothyroidism or delayed puberty.
Underlying Genetic Cause
AHO is caused by genetic changes in the GNAS gene, located on chromosome 20q13.3. This gene provides instructions for making the alpha subunit of the stimulatory G protein (Gsα), a protein involved in cellular signaling. Gsα is involved in the body’s response to various hormones, including parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), and gonadotropins.
Mutations in the GNAS gene lead to a reduction in the activity of the Gsα protein, affecting how cells respond to these hormonal signals. The inheritance pattern of AHO is autosomal dominant, but the expression of symptoms is influenced by genomic imprinting. Genomic imprinting is an epigenetic process where the expression of a gene depends on whether it was inherited from the mother or the father.
If the mutated GNAS gene is inherited from the mother, individuals typically present with both the physical features of AHO and the hormonal resistance of pseudohypoparathyroidism type 1a (PHP1a). However, if the same mutation is inherited from the father, individuals usually exhibit the physical characteristics of AHO but without the associated hormone resistance, a condition sometimes referred to as pseudopseudohypoparathyroidism (PPHP). The parental origin of the mutated gene largely determines the specific combination of symptoms.
Diagnosis and Treatment Approaches
Diagnosing AHO typically involves a combination of clinical observations, laboratory tests, and genetic confirmation. Healthcare providers assess physical signs, such as short stature, a round face, and brachydactyly, which often suggest the condition. Blood and urine tests are performed to evaluate hormone levels and mineral balance.
These laboratory tests specifically measure calcium, phosphate, and parathyroid hormone (PTH) levels to identify pseudohypoparathyroidism (PHP). Genetic testing confirms the diagnosis by identifying mutations in the GNAS gene.
Managing AHO involves a multidisciplinary approach focused on addressing its diverse manifestations. For endocrine complications like hypocalcemia, treatment often includes oral calcium and vitamin D supplementation to help maintain appropriate blood calcium levels. For hyperphosphatemia, dietary phosphate restriction and the use of phosphate binders may be recommended.
Subclinical hypothyroidism, if present, can be managed with levothyroxine replacement therapy. Growth hormone treatment may be considered for patients with documented growth hormone deficiency, particularly to address short stature. Other supportive treatments, such as those for dental abnormalities or developmental delays, are tailored to the individual’s specific needs.
Long-Term Outlook
Albright’s Hereditary Osteodystrophy is a chronic condition that requires ongoing medical management throughout an individual’s life. While there is no cure, regular monitoring and tailored treatments can help manage symptoms and improve quality of life. The long-term outlook varies depending on the severity of symptoms and the presence of associated hormonal resistance.
Individuals with AHO may face potential long-term complications. These can include dental problems such as delayed tooth eruption, short roots, or enamel hypoplasia. Some individuals may experience developmental delays or cognitive impairment. Obesity is also a common feature that can lead to related health issues, including obstructive sleep apnea.
Associated hormonal resistance can lead to other issues, such as cataracts, neuropsychiatric disturbances, and movement disorders like parkinsonism, often linked to calcifications in brain regions. A coordinated care team, typically including endocrinologists, geneticists, and orthopedic specialists, is beneficial for optimizing patient care. Regular monitoring of calcium and phosphate levels and addressing other hormonal imbalances are important to prevent complications.