Management of Pediatric Fibrous Dysplasia/McCune-Albright

SyndromeAlison Boyce, MD

3rd Meeting of the FD/MAS International ConsortiumLeiden University Medical Center, Leiden, The

Netherlands

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

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

Precocious Puberty in MAS

Ovary

Cyst

• Recurrent ovarian cysts

• Breast development, growth acceleration

• Vaginal bleeding when cysts resolve

ovarian cysts

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

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

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

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

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

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

Growth Hormone Excess

• ~15% of patients

• Growth acceleration may be subtle, confounded by FD & endocrinopathies

GH & PP

PP

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)

GH excess management issues: macrocephaly, vision & hearing loss

Treatment:•medication (octreotide, lanretotide, pegvisomant)• surgery (hypophosectomy, always difficult)•radiation (cancer risk)

macrocephalyOtic canal compression

•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

Low Blood Phosphorus

renal phosphatewasting

FD + rickets Osteomalacia, Bone Pain

o

o

b

b

o = osteoid b = bone

Phosphate Wasting in FD

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

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

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

Questions?