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Management of Pediatric Fibrous Dysplasia/McCune-Albright
SyndromeAlison Boyce, MD
3rd Meeting of the FD/MAS International ConsortiumLeiden University Medical Center, Leiden, The
Netherlands
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Fibrous Dysplasia/McCune-Albright syndrome:
A complex bone and endocrine disorder
Bone, pituitary, gonads, thyroid, adrenal, other
GH excess precociouspuberty
hyperthyroidismCushing’s syndrome
fibrous dysplasiarickets
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Fibrous dysplasia
Café-au-lait
Precocious Pub.
Thyroid
Phosphate
Growth hormone
Cushing’s
0 5 10 15 20 30 50→
Age
Onset of manifestations of affected tissues
subclinical
clinically evident
spontaneous resolution possible
Most affected and unaffected tissues can be identified in childhood
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Precocious Puberty in MAS
Ovary
Cyst
• Recurrent ovarian cysts
• Breast development, growth acceleration
• Vaginal bleeding when cysts resolve
ovarian cysts
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Precocious Puberty in MAS
Treatment is needed to:
• Prevent disabling short stature in adulthood
• Prevent psychosocial consequences of early sexual maturation
AVOID SURGERY
Estrogen causes early closure of growth plates
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Current Treatment Options
Tamoxifen (Eugster et al, 2003)• Alters estrogen receptor activity• 12 month prospective trial, 25 girls with MAS
Decreased: linear growth, bone age advancement and vaginal bleeding
increased: uterine volume
Letrozole (Feuillan et al, 2007)• Prevent estrogen production• 36 month pilot study, 9 girls with MAS
decrease: growth rate, bone age advancement and vaginal bleeding
one case of ovarian torsion
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0 3 6 9 1 2
Y e a r s
Su
bje
cts
O n L e t r o z o l e P o s t L e t r o z o l e
S t a r t E n d
0
1
2
3
Bo
ne
Ag
e (
ye
ar
s)
/
Ch
ro
no
log
ic A
ge
(y
ea
rs
)
p < 0 . 0 0 0 1
Extended efficacy of letrozole in NIH cohort
n = 22mean Tx = 4.3y
length of treatment bone age advancement
Estrada et al, EJE 2016
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Leydig cell hyperplasia
MAS Testicular Disease
Testicular lesions in ~85% Precocious puberty in ~15% Treatment: Spironolactone + letrozole
NO SURGERY!
Cancer has been rarely reported Ongoing monitoring
Leydig cell hyperplasia with Sertoli component
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Collins JCEM 2003, Celi JCEM 2008
Thyroid Disease in MAS
goiter characteristic ultrasound
• US abnormalities in ~66%;
hyperthyroidism in ~30%
• T3 overproduction;
increased T3/T4 ratio (>20)
• Kids with US abnormalities
may develop
hyperthyroidism later
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Collins JCEM 2003, Celi JCEM 2008
Thyroid Disease in MAS
Management
•Short-term: methimazole
• Long-term:
Surgery
prefer high-volume center
May regrow
Radioactive iodine
cancer reported
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Growth Hormone Excess
• ~15% of patients
• Growth acceleration may be subtle, confounded by FD & endocrinopathies
GH & PP
PP
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Lee, NEJM, 2002 (n=38) Prophylactic optic nerve decompression is not indicated
GH excess is a risk factors for vision lossCutler, Neurosurgery, 2006
Watchful waiting is superior to surgery (meta-analysis)Amit, PLos ONE 2011
FD patent obliteratedFD
GH excess: deformity and vision loss
optic canal
optic foramen blind
sphenoid bone
macrocephaly
Early GH excess treatment prevents morbidityBoyce…Collins, JCEM 2013 (n=129)
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GH excess management issues: macrocephaly, vision & hearing loss
Treatment:•medication (octreotide, lanretotide, pegvisomant)• surgery (hypophosectomy, always difficult)•radiation (cancer risk)
macrocephalyOtic canal compression
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•Presents age <1 year
•Early recognition is essential!
• Adrenalectomy if possible
• Caveat: spontaneous resolution in ~1/3
• Neurodevelopmental sequelae
Brown et al, JCEM, 2010
Cushing’s syndrome
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Low Blood Phosphorus
renal phosphatewasting
FD + rickets Osteomalacia, Bone Pain
o
o
b
b
o = osteoid b = bone
Phosphate Wasting in FD
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FD cells
FGF23 is made by FD cells
0
50
100
150
200
250
300
350
400
0 20 40 60 80
FG
F-2
3 (
RU
/m
l)
Skeletal Burden of FD
r=0.55, p<0.001
FGF23 is a Hormone that Causes Phosphate Wasting in FD
May show up during times of rapid growth (ex: infancy, puberty)May resolve in adulthood
More FD = More FGF23
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0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
0,45
0,5
0-5 6-10 11-15 16-20 21-25 26-30 31-35 36-50
Fra
ctu
re r
ate
(#
fra
ctu
res
/pa
tie
nt/
ye
ar)
Age (years)(Leet ,JBMR, 2004)
hypophosphatema
normal phosphorus
Hypophosphatemia Increases Fractures
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Hypophosphatemia: Treatment
1. Phosphorus Supplements
– Pills, powder, or liquid
– Short-acting, must give 3-5 times a day
– Diarrhea, GI discomfort
2. Calcitriol
– Prevents hyperparathyroidism (major side effect of Phosphorus supplements)
– May increase urine calcium
• Monitor urines and kidney ultrasounds
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Questions?