Welcome to this section on Albright's Hereditary Osteodystrophy. This condition involves short bones, obesity, and ectopic ossifications as you can see in these pictures. The objectives are for you to identify concerning exam findings for Albright's Hereditary Osteodystrophy, describe how the inheritance pattern affects phenotype, and select the most appropriate management. Diagnosis begins with the physical exam, which can show brachydactyly. This means bone shortening and typically occurs in the metacarpals and metatarsals, but spares the phalanges. These pictures show shortening of the fourth metacarpal and metatarsal. The short bones are not present at birth, but result from premature closure of epiphyses. Thus, Albright's Hereditary Osteodystrophy is more obvious in childhood than it is in infancy. The main treatment is occupational therapy to enhance function. This picture shows a mother on the right and her daughter on the left with Albright's Hereditary Osteodystrophy. It demonstrates that these patients often have early-onset obesity with a stocky build, short stature, and round faces. Obesity typically becomes less pronounced in adulthood. Their resting energy expenditure is lower than BMI-matched controls, but their hyperphagia is similar. Dietary counseling should take this into account. Extraskeletal osteoblasts form islands of ectopic bone in the dermis and subcutaneous fat. These photographs show subcutaneous calcifications in the right neck. The X-ray shows calcifications of the right cheek. The 3D CT shows lattice-like calcifications extending downward from the zygomatic bone as well as inferior and lateral to the mandible. The main treatment options are physical therapy to preserve movement and meticulous skin care to prevent cutaneous breakdown. Consider surgical excision of demarcated superficial lesions with pain or movement impairment. Avoid immobilization as it can cause joint stiffness. Other abnormalities may benefit from surgery including skeletal deformities, carpal tunnel, and recurrent otitis media. The main cause of Albright's hereditary osteodystrophy are inactivating GNAS mutations. They can be sporadic or inherited in an autosomal dominant fashion. The mutations impair hormonal signaling via receptors that are coupled through the stimulatory G-protein alpha to activation of adenylate cyclase which would normally otherwise lead to CMP synthesis and gene transcription. Pseudohypoparathyroidism involves not only Albright's hereditary osteodystrophy but also PTH resistance. It results from GMAS mutations from the mother. Lab abnormalities are similar to hypoparathyroidism with high phosphorus and low calcium levels. However, PTH is high because of the resistance. It is important to ensure that vitamin D, magnesium, and renal function are normal when making the biochemical diagnosis to avoid confounding factors. Deranged mineral metabolism from PTH resistance can cause seizures. In contrast, pseudohypoparathyroidism involves Albright's hereditary osteodystrophy but without hormonal issues and patients inherited from their fathers. Babies can be small for gestational age with this condition. If you find someone with Albright's hereditary osteodystrophy, consider genetic testing of the patient and their parents. Please monitor PTH, calcium, phosphorus, and 250H vitamin D annually. Consider checking them more frequently for acute illness, pregnancy, lactation, or changes in vitamin D requirements. Treat hypocalcemia with calcitriol and oral calcium supplements. Normalize the 250H vitamin D level. Lower the PTH into the normal ranges but avoid suppressing it which can be associated with hypercalceria and renal calcifications. It is okay to target a normal serum calcium because patients typically have preserved sensitivity in the distal convoluted tubules which is protective against hypercalceria. Calcium and calcitriol requirements decline after puberty so adjust doses accordingly. PTH analogs are not helpful. A 19-year-old man presents for difficulty opening his mouth which has been present since childhood but now limits his ability to eat. Physical exam shows hard areas in the cheek and neck. Ring fingers are shorter than pinky fingers. He is 62 inches tall and weighs 164 pounds giving him a BMI of 30. Serum PTH, chemistry, and vitamin D levels are normal. What is the most likely etiology? Is it A. An activating calcium-sensing receptor mutation, B. An inactivating calcium-sensing receptor mutation, C. An inactivating GNAS mutation from the mother, or D. An inactivating GNAS mutation from the father? Please pause the video if you need more time. The best answer is D because there is no PTH resistant by the labs. If he had PTH resistance, the best answer would have been C. Answer A causes hypoparathyroidism and B causes familial hypocalceric hypercalcemia. It is important to screen for nephrocalcinosis with imaging. The x-ray on the left shows severe nephrocalcinosis. Consider head imaging for patients with neurological symptoms. The CT on the right shows bilateral calcifications of the globus pallidus in a child with pseudo-hypoparathyroidism and mild intellectual disability. It is also important to screen for other common comorbidities. Check thyroid function for TSH resistance. It presents with elevated TSH and low or normal free T4 levels. Treatment unfortunately does not prevent motor or cognitive delays in infants. Check IGF-1 starting at age 3 to 6 because patients can become resistant to GHRH. This fortunately responds to exogenous growth hormone therapy. Screen for hypogonadism and cryptorchism, treating if present. Screen for type 2 diabetes, sleep apnea, hyperlipidemia, and hypertension as they are very common comorbidities. Interestingly, patients are at a 4.4 fold increased risk of sleep apnea. Encourage eye exams to assess for cataracts and dental exams. These x-rays show uninterrupted teeth, blunted roof, and thin enamel. Patients may also have developmental delays and need help in school. Question. Which treatment is best for patients with Albright's hereditary osteodystrophy? Is it A. Braces for subcutaneous ossifications over joints. B. Calcium and calcitriol targeting normal serum calcium levels. C. Higher caloric intake than BMI matched controls. Or D. PTH analogs targeting low normal serum calcium levels. Please pause the video if you need more time. The best answer is B because it is okay to target normal serum calcium levels. Low normal serum calcium goals are not required like they are in hypoparathyroidism. A is not a good choice because immobilization can cause joint stiffness. C is incorrect. Patients generally require less food because their resting energy expenditure is lower than BMI matched controls. D is incorrect. PTH analogs are not helpful because of PTH resistance. In summary, Albright's hereditary osteodystrophy involves subcutaneous ossifications, obesity, and short bones from sporadic or autosomal dominant genus mutations. If genetic mutation is from the mother, patients also get PTH resistance. Treatment is with calcium and activated vitamin D supplements to target normal serum calcium, PTH, and vitamin D levels.

Albright's Hereditary Osteodystrophy

brachydactyly

genetic testing

calcitriol

normal serum calcium levels