Welcome to the Endocrine Society's fellow training series Rare Bone Disease Module. In this section we'll be talking about McCoon-Albright syndrome. The objectives will be for you to diagnose and treat this condition. We will start with a case. Shannon brings you her two-year-old daughter because she found blood in her diaper for the past few days. She has not yet discussed this with her new boyfriend. Please pause the video and come up with your differential diagnosis. Some conditions to consider are child abuse, GI bleeds, hematuria, and precocious puberty. Shannon later tells you that the blood in the diaper has been happening for about one week every month. Physical exam shows a happy baby with no signs of trauma to the vagina or rectum. Skin exam shows cafe au lait spots that do not cross the midline and have jagged borders. You diagnose McCoon-Albright syndrome based on these characteristic skin findings and precocious puberty. In McCoon-Albright syndrome, cafe au lait spots do not correlate with disease severity or location of bony involvement. Laser treatment can help cosmetically. There are two ways to diagnose McCoon-Albright syndrome. The patient has at least two of the following. Cafe au lait spots, polyostatic fibrous dysplasia, this means bony involvement of more than one bone, and a primary endocrinopathy, which is typically precocious puberty. So two out of those three. The alternative way to diagnose McCoon-Albright syndrome is if the patient has a monostatic fibrous dysplasia, so just one bone involvement, but tests positive for a GNAS mutation. Primary endocrinopathies associated with McCoon-Albright syndrome include precocious puberty, hyperthyroidism, primary hyperparathyroidism, hyperprolactinemia, hypophosphatemia from renal phosphate wasting, growth hormone excess, and Cushing syndrome. The new genetic mutation in McCoon-Albright syndrome is unique. It is a postzygotic somatic activating mutation of GNAS. This means it's a gain-of-function mutation that occurs after the embryo has already started to form. It later develops the mutation and doesn't inherit the mutation from the parent. This has clinical implications for the patient's family because the risk of McCoon-Albright syndrome is thus the same as the general population. Mutations early in embryogenesis cause widespread disease and mutations later in embryogenesis cause more limited disease. The phenotype can vary from asymptomatic to lethal. Shannon is now happy with her new boyfriend and plans to marry him. She wants to know what the risk of her future children is of having McCoon-Albright syndrome. What do you tell her? Please pause the video and come up with your thoughts. McCoon-Albright syndrome comes from a postzygotic mutation, which means it is not inherited. The patient's family thus has the same risk as the general population, which is about 1 in 100,000 to 1 in a million. Significant morbidity of McCoon-Albright syndrome comes from fibrous dysplasia. This is where fibrous connective tissue and poorly formed trabecular bone replaced regular bone. In the picture, you can see how normal bone on the left and fibrous dysplasia on the right is present. Most clinically significant bone lesions are present by age 10. Fibrous dysplasia becomes less active in adulthood. However, bone pain often starts in adolescence and progresses into adulthood. Craniofacial fibrous dysplasia can cause facial asymmetry. Fractures and progressive deformity from fibrous dysplasia in other areas can cause trouble with mobility. There are currently no available treatments to alter the disease course. Encourage physical therapy to optimize function. Refer to orthopedic surgery to repair fractures, prevent and correct deformities. Shannon wants to know if her daughter has fibrous dysplasia. What are some ways that you can do to assess this? Please pause the video and come up with your ideas. Start with a total body bone scan like you would see in this picture. The arrow marks the affected bone of the skull, spine, and foot. After that, check x-rays or CT scans of the affected area on bone scan to better characterize the bony involvement. If your patient has craniofacial fibrous dysplasia, then get vision and hearing exams. Vertebral fibrous dysplasia may result in scoliosis. This can compromise breathing and be lethal. If scoliosis becomes more severe, then patients need surgical fusions to stabilize their spine. Picture A on the left shows a spine with extensive scoliosis. Picture B on the right shows the same patient after spinal fusion. IV bisphosphonates can relieve bone pain. This graph shows pain intensity at baseline in white on the left, after six months of IV bisphosphonate therapy in light gray in the middle, and after study completion in dark gray all the way to the right. You can see that pain intensity decreases with therapy. Base the dosing of bisphosphonates on symptoms, not on a scheduled time or bone turnover markers. Oral bisphosphonates can also be effective, but are less so than IV bisphosphonates. Question, which manifestation of McCune-Albright syndrome would you most likely refer for surgery? Please pause the video to make your selection. The best answer choice is A, thyroidectomy for hyperthyroidism. Malignant transformation is possible with I-131, so avoid that therapy. You can however consider methimazole. For precocious puberty, try to slow bone age to allow full adult height. Treat boys with androgen receptor blockers like spironolactone or flutamide. Alternatively, select inhibitors of sex steroid synthesis like letrozole. Treat girls with letrozole or receptor modulators of estrogen like tamoctifen. You can add luprolide to boys or girls. Prophylactic ovarian cystectomy in girls may decrease their fertility, so try to use medical therapy. Treat growth hormone excess with octreotide or pegzizumab before considering surgery. Surgery may be difficult from craniofacial fibrous dysplasia. Additionally, the diffuse pituitary infiltration requires total hypothecetomy, which would cause hypopituitarism. Growth hormone excess and radiation may increase the risk of malignant transformation. Prophylactic optic nerve decompression increases the risk of vision loss. In a study of this procedure, there was stable vision in 31 patients, which was 75% of the participants. Without prophylactic optic nerve decompression, there was stable vision in 229, which was 95% of participants. In summary, McCoon-Albright syndrome develops from a postzygotic activating mutation of GNAS. The most classic presentation is jagged cafe au lait spots that don't cross the midline, fibrous dysplasia, and precocious puberty. Treat the gonads by trying to delay puberty. Treat the bones with IV bisphosphonates for pain, also with physical therapy and surgery.

McCoon-Albright syndrome

cafe au lait spots

precocious puberty

GNAS mutation

fibrous dysplasia