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4/23/2015
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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.
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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 ‐ 1998
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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 SyndromeDifferential 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
Dr. Donovan McCune
Dr. Fuller Albright
McCune‐Albright Syndrome –first descriptions
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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
Gsα is the “on and off switch” for many cells
Skin
Café‐au‐lait
Ovary Bone Thyroid Pituitary
precocious puberty hyperthyroidism
fibrous dysplasia growth hormone excess
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SkinThyroidBone
How MAS Happens
Migrates &expands asembryois formed
Mutation occurs by chance
Stem Cell
Mutation in the gene GNAS
GNAS codes for the protein, Gsα
SkinThyroidBone
How MAS Happens
Mutation occurs by chance
Mutated cell proliferatesMigrates &expands asembryois formed
• Mutation is now in cellsthat will later give rise to differenttissues: skin, bone, ovaries, etc.
Stem Cell
SkinThyroidBone
How MAS Happens
Mutation occurs by chance
Mutated cell proliferates
Mutated cells migrate & expands as embryo
is formed
Stem Cell
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Where and when the mutationoccurs determines what manifestations the person
will and won’t have
How MAS Happens
Mutation occurs by chance
Mutated cell proliferates
Mutated cells migrate & expands as embryo
is formed
Stem Cell
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
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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
• NO correlation with locationor extent of bone disease
• Often starts or ends near the midline
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Clinical Manifestations in MAS
Skin – ectoderm Bone – mesoderm endocrine‐ endoderm
Fibrous Dysplasia (FD)• Abnormal scar‐like (fibrous) tissue in bones. “Ground glass” appearance.
• 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 DysplasiaDeformity, Pain, Limp, Fractures, Disability
Shepherd’s crookdeformity
Wind‐swept deformity
Fragility fractures
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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
• Scoliosis is common; may be progressive.
• Scoliosis occurs at sites of FD
• Progression can be stopped by rods
FD in the spine: scoliosisbone scan MRI X‐ray
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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
200216.13 11
96 .31.
16
3 ½ 7 11 12
14 16 18 3030
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• 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
Fibrous Dysplasia and Pain
Clinical Manifestations in MAS
Skin – ectoderm Bone – mesoderm Endocrine‐ endoderm
McCune-Albright Syndrome
Café-au-lait
Fibrous Dysplasia
PrecociousPuberty
Growth Hormone Excess
Hyperthyroid
Cushings Syndrome
Phosphate Wasting
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Peripheral Precocious Puberty in Girlsarises from early activation of ovaries
• Recurrent ovarian cysts
• Breast development
• Vaginal bleeding
• Increased growth velocity
• Bone age advancement
• Reduced final adult height
• Some teens/women have menstrual irregularities
• Women with MAS are often able to become pregnant and have healthy children
Pelvic UltrasoundOvary
EA([2
Peripheral Precocious Puberty in Boysarises 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.
Slide 34
EA([2 Find photo ofadult female standing Estrada, Andrea (NIH/NICHD) [E], 2/25/2015
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Growth Hormone (GH) Excess• Production of high levels of growth hormone from the pituitary gland
• 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
Gigantism dueto GH excess
Short stature due to precocious puberty
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
• 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
Cushing Syndrome
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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
Fibrous dysplasia
Café‐au‐lait
Precocious Pub.
Thyroid
Phosphate
Growth hormone
Cushings
0 5 10 15 20 30 50→
Age
“Map” of Tissues is established in utero and manifests at an early age
subclinical
clinically evident
spontaneous resolution possible
‐> Complete staging after age 5 allows for determination of affected and unaffected tissues
Findings Prevalence (%)
Fibrous dysplasia 99Café‐au‐lait 89Gonads
male 77female (PP) 78
Thyroid 69Phosphate wasting 48
requiring treatment 17Growth hormone excess 18Cushings 7
NIH MAS cohort
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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, 2005
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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
http://www.magicfoundation.org/www
http://fibrousdysplasia.org/
Resources for Patients and Families
skeletal survey
Mon Tues Wed Thur Fri
serum and urineendocrine and bone markers
99Tc‐MDP bone scanDEXA bone density
ultrasound thyroid/gonads
rehabilitation medicine
pain service
GYN/Urology
additionaltesting
as needed
ophthalmology
CT & MRI
dentalphotos
otolaryngology
bone biopsy
histopathologymolecular analyses cell biology
Comprehensive NIH CC Clinical Evaluation
NIH Natural History Study of FD/MAS
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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 Gs, but not normal Gs
Selected References1. 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;52:743–744.
2. 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;216:727–746.
3. Collins MT. Spectrum and natural history of fibrous dysplasia of bone. J Bone Miner Res. 2006;21:P99–P104. doi: 10.1359/jbmr.06s219.
4. 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; 2006. pp. 415–418.
5. Collins MT, Shenker A. McCune‐Albright syndrome: new insights. Curr Opin in Endocrinol and Diabetes. 1999;6:119–125. doi: 10.1097/00060793‐199904000‐00006.
6. 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;22:1468–1474. doi: 10.1359/jbmr.070511.
7. Kelly MH, Brillante B, Collins MT. Pain in fibrous dysplasia of bone: age‐related changes and the anatomical distribution of skeletal lesions. Osteoporos Int. 2007
8. Glorieux FH, Rauch F. Medical therapy of children with fibrous dysplasia. J Bone Miner Res. 2006;21:P110–113. doi: 10.1359/jbmr.06s221.
9. Stanton RP. Surgery for fibrous dysplasia. J Bone Miner Res. 2006;21:P105–109. doi: 10.1359/jbmr.06s220
10. 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:531–537
11. Feuillan P, Calis K, Hill S, Shawker T, Robey PG, Collins MT. Letrozole Treatment of Precocious Puberty in Girls with the McCune‐AlbrightSyndrome: A Pilot Study. J Clin Endocrinol Metab. 2007;92:2100–2106. doi: 10.1210/jc.2006‐2350.[
12. Congedo V, Celi FS. Thyroid disease in patients with McCune‐Albright syndrome. Pediatr Endocrinol Rev. 2007;4:429–433
13. Chanson P, Salenave S, Orcel P. McCune‐Albright syndrome in adulthood. Pediatr Endocrinol Rev. 2007;4:453–462.
14. Feuillan PP. McCune‐Albright syndrome. Curr Ther Endocrinol Metab. 1997;6:235–239.
Questions?