What is Albright Hereditary Osteodystrophy?
Albright hereditary osteodystrophy (AHO) is a condition initially identified in 1942 by Fuller Albright. This condition includes various symptoms such as a round face, shorter height with a bulky body build, shorter-than-normal fingers, the formation of bony tissue beneath the skin, and abnormal teeth. Other signs that may be associated with AHO include learning delays, obesity from an early age, and a relatively larger head size.
What Causes Albright Hereditary Osteodystrophy?
The AHO phenotype, a certain set of physical traits, is usually found in people with pseudohypoparathyroidism (PHP) types 1A and 1C, and pseudo-pseudohypoparathyroidism (PPHP). It’s rarely seen in people with PHP type 1B and isn’t observed in PHP type 2.
PHP is caused by a mutation in the GNAS1 gene, which makes part of a stimulatory protein. This gene is on the end of the long arm of chromosome 20.
For PHP types 1A and 1C, a non-functional GNAS1 mutation is inherited from the mother. People with these conditions have the AHO phenotype and hormonal resistance. However, those who inherit non-functional GNAS1 mutations from their fathers present with just the AHO phenotype without hormonal resistance – this is PPHP.
PHP type 2B is caused by unusual methylation, a chemical process, of the GNAS gene.
Risk Factors and Frequency for Albright Hereditary Osteodystrophy
Information about how common Albright hereditary osteodystrophy is can be hard to find. However, there is data on a similar disease called PHP. PHP affects about 0.34 to 1.1 out of every 100,000 people. But, it’s estimated that about 1 in every 20,000 people may have PHP.
Signs and Symptoms of Albright Hereditary Osteodystrophy
Pseudohypoparathyroidism (PHP1A and PPHP) is typically recognized by certain characteristic signs. Most adults with this condition are shorter than average, with about 80% of people with PHP1A and 50% to 70% of people with PPHP having a shorter stature. This is typically identifiable from childhood and is usually noticeable when comparing the height of affected individuals to their unaffected siblings or parents. Some affected individuals may also have been small for their age at birth. Another early symptom that can occur is the onset of obesity before the age of 2, although this is less common. Additionally, individuals may develop hard lumps under the skin due to abnormal bone growth.
Other signs specific to this condition include short fourth and/or fifth finger bones, which result in dimples over the corresponding knuckles. When both of these finger bones are shortened, it forms a pattern described as knuckle, knuckle, dimple, dimple. Shortening of the last section of the thumb is also a common abnormality associated with this condition. These changes in hand shape may not be noticeable at birth but can develop as the person grows. Some patients may also have dental abnormalities such as teeth that don’t emerge when they should, short or blunted tooth roots, altered tooth pulps, too few teeth or thinner tooth enamel. Mild delays in development and cognitive impairment may also be present in some individuals.
People with this condition may also experience symptoms related to low calcium levels. Newborns can show jitteriness, seizures, and have a harsh, high-pitched cry, older children and adults may experience muscle cramps, numbness around the mouth, tingling sensations, and carpopedal spasm (a sudden, involuntary muscle contraction). Individuals with milder low calcium levels can experience similar symptoms).
- Short stature from childhood
- Onset of obesity before age 2
- Hard lumps under the skin from abnormal bone growth
- Short fourth and/or fifth finger bones
- Dimpling over knuckles due to short finger bones
- Shortened last section of the thumb
- Dental abnormalities
- Symptoms related to low calcium levels like muscle cramps and numbness around the mouth
Testing for Albright Hereditary Osteodystrophy
The primary tests for PTH resistance, a condition that affects the body’s response to the parathyroid hormone, involve checking the levels of serum calcium, serum albumin, and serum phosphorus in your body. If these tests show low calcium levels, high phosphorus levels, and increased PTH, all in the absence of Vitamin D or magnesium deficiency or kidney problems, then you might have PTH resistance.
In cases where the condition Albright’s hereditary osteodystrophy (AHO) is present, PTH resistance might still exist even if calcium levels appear normal. This could be the case if the PTH level is slightly above the normal range with Vitamin D levels within the normal range.
If PTH resistance is confirmed, further tests may be needed to check for resistance to other hormones. These tests might include checking the levels of thyroid-stimulating hormone and serum-free thyroxine. Usually, the thyroid-stimulating hormone level is slightly elevated in these cases.
All patients with PTH resistance should also undergo a check of their growth hormone-IGF1 axis, especially if they’re shorter than average. And any patients with delayed puberty should be tested for resistance to gonadotropin.
Doctors should also frequently monitor their patient’s bone growth with X-rays of their left hand. These X-rays can reveal potentially shortened metacarpals (bones in the hand), metatarsals (bones in the foot), or the distal phalanges of the thumbs. These images can also show advanced bone age and abnormal bone growth.
People with low calcium levels may also have prolonged QT times (a measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle) as shown by an electrocardiogram (ECG).
If the condition is severe, a CT scan of the brain may reveal calcification (or hardening) in the brain’s basal ganglia or more widespread calcification in the subcortical white matter, a condition known as Fahr syndrome.
Treatment Options for Albright Hereditary Osteodystrophy
People suffering from pseudohypoparathyroidism typically receive treatment through supplements of calcium that are taken orally, consumption of calcitriol, and limiting the intake of phosphate in their diet. If these patients also have a mild form of hypothyroidism, known as subclinical hypothyroidism, they might be prescribed a medication called levothyroxine.
A treatment involving growth hormones might be recommended for patients who are not making enough of it naturally, typically using the same dosage given to individuals who are smaller than average for their age. If a patient is experiencing delayed puberty due to a resistance to gonadotropin, a hormone involved in sexual development, they may be given replacement therapy for sex hormones.
What else can Albright Hereditary Osteodystrophy be?
The symptoms that define Albright hereditary osteodystrophy (AHO) are not exclusively seen in pseudohypoparathyroidism, but can be observed in other medical problems too. Here are some conditions that might seem like AHO but are not:
1. “Brachydactyly-mental retardation” syndrome or another AHO-type syndrome: This comes from a specific genetic mutation. Common signs like short fingers (Brachydactyly), gaining weight, developmental delays, learning disorders can be seen. Some mild resistance to parathyroid hormone can happen but there may be no additional bone growth.
2. “iPPSD4” or “Acro-dysostosis type 1”: An irregular facial structure and nasal shape, severe short fingers, and hormone resistance are some symptoms. Some people who have AHO and no genetic irregularities in a certain gene (GNAS1) were found to have a mutation in another gene (PRKRA1A).
3. “iPPSD5” or “Acro-dysostosis type 2”: This includes severe finger shortening, unusual facial structure and nasal shape, learning disorders, and certain mutations.
4. “iPPSD6”: This involves short height, shortened fingers, high blood pressure, and a specific pattern in a brain artery.
5. “Isolated brachydactyly E”: This involves a specific gene mutation responsible for a certain type of shortened fingers.
6. “Brachydactyly E with short stature, PTHLH type”: This disease involves dental problems, learning difficulties, and unusual facial features.
7. “Trichorhinophalangeal syndrome”: This typically involves less severe shortening of fingers, sparse hair, a bulbous nose, a thin upper lip, a growth hormone deficiency, and hip malformation.
8. “Turner syndrome”: This typically involves short height, unusually short fourth fingers, premature failure of the ovaries, unusual elbow shape, and wrist deformity.
What to expect with Albright Hereditary Osteodystrophy
There is not much information available about the long-term outlook of Albright hereditary osteodystrophy. However, it is typically seen that individuals with this condition usually have a normal life expectancy. That being said, those with Albright’s are more likely to suffer from severe obesity, and complications related to it. These include issues like sleep apnea, mental health disorders, seizures, and eye conditions like cataracts. It’s especially common in Albright’s cases associated with PHP1A.
Possible Complications When Diagnosed with Albright Hereditary Osteodystrophy
Patients with PTH resistance can suffer from long-term low calcium and high phosphate levels in the blood, leading to the hardening of vital parts of the brain. This circumstance can result in mental health disorders, movement issues, and Parkinson’s disease.
People with AHO, a type of hormonal disorder, tend to have a high likelihood of developing carpal tunnel syndrome, a condition that causes numbness and tingling in the hand and arm.
Children with PHP1A, a rare genetic disorder, have been found to be at a greater risk for sleep apnea, a potentially serious sleep disorder in which breathing repeatedly stops and starts.
Patients with PHP1A also have a lower sensitivity to insulin, which increases their risk of developing impaired glucose tolerance, a pre-diabetic state of hyperglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology.
Spinal stenosis, a narrowing of spaces in the spine, is a common condition reported in AHO patients and can lead to weakness and numbness in the legs and feet.
Rarely, misplaced bone growth in or around the joints can lead to limited joint movements.
Preventing Albright Hereditary Osteodystrophy
Albright hereditary osteodystrophy is a disease that’s passed down through families. Once it starts, it can’t be cured. However, frequent check-ups can help spot related health problems early, even if no symptoms are showing yet. This allows early start of treatment. Also, patients who want to have children can undergo testing for GNAS1 mutations. This helps them understand if they have a risk of passing the disease to their kids. Children whose fathers have the disease usually only develop bone problems. But if their mother has the disease, they can also develop hormone problems.
