Management of Pediatric Fibrous Dysplasia/McCune-Albright Syndrome

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1 Management of Pediatric Fibrous Dysplasia/McCune-Albright Syndrome Alison Boyce, MD 3 rd Meeting of the FD/MAS International Consortium Leiden University Medical Center, Leiden, The Netherlands

2 Fibrous Dysplasia/McCune-Albright syndrome: A complex bone and endocrine disorder fibrous dysplasia rickets GH excess precocious puberty Cushing s syndrome hyperthyroidism Bone, pituitary, gonads, thyroid, adrenal, other

3 Onset of manifestations of affected tissues Fibrous dysplasia Café-au-lait Precocious Pub. Thyroid Phosphate Growth hormone Cushing s subclinical clinically evident spontaneous resolution possible Age Most affected and unaffected tissues can be identified in childhood

4 Precocious Puberty in MAS Cyst Ovary ovarian cysts Recurrent ovarian cysts Breast development, growth acceleration Vaginal bleeding when cysts resolve

5 Precocious Puberty in MAS Estrogen causes early closure of growth plates Treatment is needed to: Prevent disabling short stature in adulthood Prevent psychosocial consequences of early sexual maturation AVOID SURGERY

6 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

7 S u b j e c t s B o n e A g e ( y e a r s ) / C h r o n o l o g i c A g e ( y e a r s ) Extended efficacy of letrozole in NIH cohort length of treatment bone age advancement 3 n = 22 mean Tx = 4.3y 2 p < S t a r t E n d Y e a r s O n L e t r o z o l e P o s t L e t r o z o l e Estrada et al, EJE 2016

8 MAS Testicular Disease Leydig cell hyperplasia Leydig cell hyperplasia with Sertoli component Testicular lesions in ~85% Precocious puberty in ~15% Treatment: Spironolactone + letrozole NO SURGERY! Cancer has been rarely reported Ongoing monitoring

9 Thyroid Disease in MAS US abnormalities in ~66%; hyperthyroidism in ~30% T3 overproduction; increased T3/T4 ratio (>20) Kids with US abnormalities may develop hyperthyroidism later goiter characteristic ultrasound Collins JCEM 2003, Celi JCEM 2008

10 Thyroid Disease in MAS Management Short-term: methimazole Long-term: Surgery prefer high-volume center May regrow Radioactive iodine cancer reported Collins JCEM 2003, Celi JCEM 2008

11 Growth Hormone Excess GH & PP PP ~15% of patients Growth acceleration may be subtle, confounded by FD & endocrinopathies

12 GH excess: deformity and vision loss macrocephaly FD patent obliterated FD optic canal sphenoid bone optic foramen blind Prophylactic optic nerve decompression is not indicated Lee, NEJM, 2002 (n=38) Watchful waiting is superior to surgery (meta-analysis) Amit, PLos ONE 2011 GH excess is a risk factors for vision loss Cutler, Neurosurgery, 2006 Early GH excess treatment prevents morbidity Boyce Collins, JCEM 2013 (n=129)

13 GH excess management issues: macrocephaly, vision & hearing loss macrocephaly Otic canal compression Treatment: medication (octreotide, lanretotide, pegvisomant) surgery (hypophosectomy, always difficult) radiation (cancer risk)

14 Cushing s syndrome Presents age <1 year Early recognition is essential! Adrenalectomy if possible Caveat: spontaneous resolution in ~1/3 Neurodevelopmental sequelae Brown et al, JCEM, 2010

15 Phosphate Wasting in FD Low Blood Phosphorus FD + rickets Osteomalacia, Bone Pain b o renal phosphate wasting b o = osteoid o b = bone

16 FGF-23 (RU/ml) FGF23 is a Hormone that Causes Phosphate Wasting in FD FGF23 is made by FD cells More FD = More FGF23 r=0.55, p<0.001 FD cells Skeletal Burden of FD May show up during times of rapid growth (ex: infancy, puberty) May resolve in adulthood

17 Fracture rate (# fractures/patient/year) Hypophosphatemia Increases Fractures 0,5 0,45 0,4 0,35 0,3 hypophosphatema normal phosphorus 0,25 0,2 0,15 0,1 0, Age (years) (Leet,JBMR, 2004)

18 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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