4/23/2015. Insights into McCune Albright Syndrome: A Complex, Rare Disease with Individual Presentations. Conflict of Interest Disclosure

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1 Insights into McCune Albright Syndrome: A Complex, Rare Disease with Individual Presentations Lori Guthrie RN C, BSN, CCRC Beth Brillante RN, BSN, MBA PENS 2015 National Conference Conflict of Interest Disclosure Conflicts of Interest None Lori Guthrie Beth Brillante The National Institutes of Health (NIH) is the nation s largest hospital devoted entirely to clinical research. We are located in Bethesda, Maryland, just a few miles north of Washington, DC. 1

2 We are Research Nurse Specialists who coordinate research studies for children and adults with rare bone and endocrine conditions, one of which is McCune Albright Syndrome. Beth Brillante We work on a team that is comprised of: Adult and Pediatric Endocrinologists Endocrine Fellows Dental/Craniofacial Surgeon Lab Technician Research Nurses McCune Albright Syndrome Research Study at NIH Prospective Cohort Study investigate cause of disease and health outcomes Largest cohort of McCune Albright Syndrome patients in the world, >215 Range from <1 to 98 years of age Current study: 1998 to present Prior studies: mid 1980s

3 Objectives 1. Name the gene mutation associated with McCune Albright Syndrome. 2. List the three body systems most commonly affected by McCune Albright Syndrome. 3. Discuss the current medical management and medications used to manage fibrous dysplasia and McCune Albright Syndrome. 4. Identify two psychosocial aspects related to the challenges of living with McCune Albright Syndrome. 5. Discussion/Questions. McCune Albright Syndrome Differential Diagnosis These depend on presentation and may include: Neurofibromatosis Osteofibrous dysplasia Non ossifying fibromas Idiopathic central precocious puberty Milder form of osteogenesis imperfecta Ovarian neoplasm McCune Albright Syndrome first descriptions Dr. Donovan McCune Dr. Fuller Albright 3

4 What is McCune Albright Syndrome (MAS)? Rare genetic disorder Affects 1 in 100,000 to 1 in 1,000,000 people worldwide No known cause for the mutation The mutation did not come from either parent and will not be passed to children MAS Gene Mutation GNAS (guanine nucleotide binding protein, alpha stimulating activity polypeptide 1) Spontaneous mutation: long arm (q) arm of chromosome 20 at position 13.3 Mutates cells within variously affected tissues Highly variable presentations depends on specific tissues involved and extent of involvement G s α is the on and off switch for many cells Skin Ovary Bone Thyroid Pituitary Café au lait fibrous dysplasia growth hormone excess precocious puberty hyperthyroidism 4

5 How MAS Happens Stem Cell Mutation occurs by chance Mutation in the gene GNAS GNAS codes for the protein, Gsα Migrates & expands as embryo is formed Skin Thyroid Bone How MAS Happens Stem Cell Mutation occurs by chance Mutated cell proliferates Mutation is now in cells that will later give rise to different tissues: skin, bone, ovaries, etc. Migrates & expands as embryo is formed Skin Thyroid Bone How MAS Happens Stem Cell Mutation occurs by chance Mutated cell proliferates Mutated cells migrate & expands as embryo is formed Skin Thyroid Bone 5

6 How MAS Happens Stem Cell Mutation occurs by chance Mutated cell proliferates Mutated cells migrate & expands as embryo is formed Where and when the mutation occurs determines what manifestations the person will and won t have Diagnosis Diagnosis most often occurs in early childhood May be diagnosed: at birth presence of café au lait spots early childhood in cases with severe polyostotic fibrous dysplasia or development of precocious puberty adulthood incidental finding on imaging Clinical Manifestations in MAS Skin ectoderm Bone mesoderm Endocrine endoderm 6

7 Skin café au lait spots Light brown patches of skin, often present at birth Irregular edges are often compared to a map of the coast of Maine Not specific for MAS 10% of healthy population have café au lait spots Spectrum of café au lait spots first sign of MAS coast of Maine appearance Spectrum of café au lait spots Often starts or ends near the midline NO correlation with location or extent of bone disease 7

8 Clinical Manifestations in MAS Skin ectoderm Bone mesoderm endocrine endoderm Abnormal scar like (fibrous) tissue in bones. Ground glass appearance. Fibrous Dysplasia (FD) Monostotic affecting one bone Polyostotic affecting multiple bones No medical treatments known to alter the course of FD Surgery correct deformity and repair fractures Physical therapy and occupational therapy optimize mobility and function Fibrous Dysplasia Deformity, Pain, Limp, Fractures, Disability Wind swept deformity Shepherd s crook deformity Fragility fractures 8

9 Fibrous Dysplasia Virtually any bone in the body may be affected. Most common are: facial and skull bones pelvis femur tibia humerus ribs small bones in hands and feet FD variations in severity Nuclear Medicine: Technetium 99m Bone Scan FD in the spine: scoliosis bone scan MRI X ray Scoliosis is common; may be progressive. Scoliosis occurs at sites of FD Progression can be stopped by rods 9

10 FD Craniofacial In the craniofacial area (bones of the skull and face), most complications are related to FD expansion. This may lead to facial asymmetry, and very rarely, loss of vision and hearing. Craniofacial fibrous dysplasia: progression ½

11 Fibrous Dysplasia and Pain Common; can occur in any FD location FD pain may be due to fracture or hypophosphatemia, or it may be related to the FD itself Treatment: 1. Over the counter medications (such as acetaminophen, ibuprofen, and naproxen) mild to moderate pain 2. Intravenous bisphosphonates (such as pamidronate or zoledronic acid) 3. Narcotic medications last resort Clinical Manifestations in MAS Skin ectoderm Bone mesoderm Endocrine endoderm McCune-Albright Syndrome Precocious Puberty Café-au-lait Fibrous Dysplasia Growth Hormone Excess Hyperthyroid Cushings Syndrome Phosphate Wasting 11

12 EA([2 Peripheral Precocious Puberty in Girls arises from early activation of ovaries Recurrent ovarian cysts Breast development Vaginal bleeding Increased growth velocity Bone age advancement Some teens/women have menstrual irregularities Women with MAS are often able to become pregnant and have healthy children Reduced final adult height Ovary Pelvic Ultrasound Peripheral Precocious Puberty in Boys arises from early activation of testicles Less common in boys, than girls Increased growth velocity Bone age advancement Reduced final adult height Pubic and axillary hair Increased growth of testicles/penis Early sexual behavior/aggression Leydig or Sertoli cell hyperplasia in testicles PP: 18 yo, 4 feet, 11 inch Precocious Puberty Treatment Peripheral Precocious Puberty: Commonly used medication is letrozole, which blocks the formation of estrogen. Boys may be treated with a combination of letrozole and spironolactone, which blocks the action of testosterone. Central Precocious Puberty: Occurs when a child who was previously well controlled on medications, presents with signs of breakthrough puberty. Occurs when the pituitary gland turns on too early. Treated with an injectable medication called leuprolide, which suppresses the pituitary gland. 12

13 Slide 34 EA([2 Find photo ofadult female standing Estrada, Andrea (NIH/NICHD) [E], 2/25/2015

14 Growth Hormone (GH) Excess Production of high levels of growth hormone from the pituitary gland Gigantism due to GH excess Short stature due to precocious puberty Main symptom accelerated growth rate GH excess may cause FD to expand Untreated GH excess higher risk of vision loss in patients with skull disease Treatments: Octreotide is a drug that prevents the release of growth hormone from the pituitary Pegvisomant is a medication that blocks the action of growth hormone on its receptor Pituitary surgery or radiation used rarely Hyperthyroid Production of excess thyroid hormone, resulting in hyperthyroidism Other thyroid abnormalities: goiter, cysts, and nodules Treatment: Methimazole drug that blocks thyroid hormone production. Most patients with MAS and hyperthyroidism will eventually have a thyroidectomy. After thyroidectomy patients will need standard thyroid hormone replacement. Very slight increased risk of thyroid cancer Cushing Syndrome Excess cortisol production, a rare complication Presents during infancy or the first few years of toddlerhood Symptoms vary: low birth weight and abnormal weight gain, especially in the face and trunk Can become severely ill, and in rare cases death In a few cases, Cushing syndrome in MAS has resolved on its own Treatment: Depends on the age of the child, the severity of illness Drugs which may be used to block cortisol production Surgery to remove the adrenal glands 13

15 Phosphate Wasting Hypophosphatemia: low levels of phosphorus in the blood Causes bone pain, muscles weakness, increased fractures Occurs when fibrous dysplasia bones produce excess amounts of FGF23, a hormone which causes the kidneys to lose phosphorus in the urine Treatment: a combination of oral phosphate supplements and vitamin D Map of Tissues is established in utero and manifests at an early age Fibrous dysplasia Café au lait Precocious Pub. Thyroid Phosphate Growth hormone Cushings subclinical clinically evident spontaneous resolution possible Age > Complete staging after age 5 allows for determination of affected and unaffected tissues NIH MAS cohort Findings Prevalence (%) Fibrous dysplasia 99 Café au lait 89 Gonads male 77 female (PP) 78 Thyroid 69 Phosphate wasting 48 requiring treatment 17 Growth hormone excess 18 Cushings 7 14

16 Psychosocial Considerations Related to MAS/FD Impaired physical function may = physical limitations Self Esteem/mental health impact Parental/Family Dynamics Quality of life in children with FD/MAS * = p < 0.05 MAS vs US Kelly, Bone, 2005 Quality of life in adults with FD/MAS Adults * = p < 0.05 MAS vs US norms Kelly, Bone,

17 Physical Function Impaired, HRQOL Preserved Impaired physical function may = physical limitations low risk activities to avoid fracture/injuries to bone (swimming); Adaptations if necessary wheelchair Self esteem/mental health impact MAS/FD population perceptions similar to general population Parental/Family Dynamics education support groups Magic Foundation, Fibrous Dysplasia Foundation Resources for Patients and Families Comprehensive NIH CC Clinical Evaluation skeletal survey 99 Tc MDP bone scan DEXA bone density dental CT & MRI ultrasound thyroid/gonads otolaryngology photos additional testing as needed Mon Tues Wed Thur Fri serum and urine endocrine and bone markers rehabilitation medicine pain service bone biopsy GYN/Urology ophthalmology histopathology molecular analyses cell biology NIH Natural History Study of FD/MAS 16

18 NIH Research Related to FD/MAS: Present and Future Pancreatic collaboration with Johns Hopkins University prospective research, part of NIH natural study, to determine incidence of pancreatic neoplasm (intraductal papillary mucinous neoplasm (IPMN) in high risk subjects of the NIH FD/MAS population Dental collaboration with University of Pennsylvania retrospective study to determine dental outcomes in NIH FD/MAS pediatric population Neurological study to be developed to examine neurological/neuropsychological effects, if any, of FD/MAS Novel Therapies denosumab (for bone pain) high throughput screening for molecular targeting test up to 300,000 chemicals for activity designer drug: inhibits mutated G s, but not normal G s Selected References 1. McCune DJ. Osteitis fibrosa cystica: the case of a nine year old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am J Dis Child. 1936;52: Albright F, Butler AM, Hampton AO, Smith P. Syndrome characterized by osteitis fibrosa disseminata, areas, of pigmentation, and endocrine dysfunction, with precocious puberty in females: report of 5 cases. N Engl J Med. 1937;216: Collins MT. Spectrum and natural history of fibrous dysplasia of bone. J Bone Miner Res. 2006;21:P99 P104. doi: /jbmr.06s Collins MT, Bianco P. Fibrous dysplasia. In: Favus MJ, editor. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Washington, D.C.: American Society for Bone and Mineral Research; pp Collins MT, Shenker A. McCune Albright syndrome: new insights. Curr Opin in Endocrinol and Diabetes. 1999;6: doi: / Hart ES, Kelly MH, Brillante B, Chen CC, Ziran N, Lee JS, Feuillan P, Leet AI, Kushner H, Robey PG, Collins MT. Onset, progression, and plateau of skeletal lesions in fibrous dysplasia and the relationship to functional outcome. J Bone Miner Res. 2007;22: doi: /jbmr Kelly MH, Brillante B, Collins MT. Pain in fibrous dysplasia of bone: age related changes and the anatomical distribution of skeletal lesions. Osteoporos Int Glorieux FH, Rauch F. Medical therapy of children with fibrous dysplasia. J Bone Miner Res. 2006;21:P doi: /jbmr.06s Stanton RP. Surgery for fibrous dysplasia. J Bone Miner Res. 2006;21:P doi: /jbmr.06s Leet AI, Magur E, Lee JS, Wientroub S, Robey PG, Collins MT. Fibrous dysplasia in the spine: prevalence of lesions and association with scoliosis. J Bone Joint Surg Am. 2004;86 A: Feuillan P, Calis K, Hill S, Shawker T, Robey PG, Collins MT. Letrozole Treatment of Precocious Puberty in Girls with the McCune Albright Syndrome: A Pilot Study. J Clin Endocrinol Metab. 2007;92: doi: /jc [ 12. Congedo V, Celi FS. Thyroid disease in patients with McCune Albright syndrome. Pediatr Endocrinol Rev. 2007;4: Chanson P, Salenave S, Orcel P. McCune Albright syndrome in adulthood. Pediatr Endocrinol Rev. 2007;4: Feuillan PP. McCune Albright syndrome. Curr Ther Endocrinol Metab. 1997;6: Questions? 17