Article

Optic Neuropathy in McCune-Albright Syndrome: Effects of Early Diagnosis and Treatment of Growth Hormone Excess

Department of Radiology (M.G.), Massachusetts General Hospital, Boston, Massachusetts 02114
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 10/2012; 98(1). DOI: 10.1210/jc.2012-2111
Source: PubMed
ABSTRACT
Context:GH excess is a serious complication of McCune-Albright syndrome (MAS) and has been associated with craniofacial morbidity.Objective:The aim of the study was to determine whether early diagnosis and treatment of MAS-associated GH excess prevents optic neuropathy and hearing impairment, the major morbidities associated with GH excess.Design and Setting:A retrospective cross-sectional analysis was conducted at a clinical research center.Patients:Twenty-two subjects with MAS-associated GH excess and 21 control MAS subjects without GH excess were included in the study.Intervention:Biochemical testing included random GH, nadir GH after glucose load, nadir GH on frequent sampling, and IGF-I Z-score. Subjects underwent imaging, ophthalmological, audiological, and otolaryngological assessment. Treatment included octreotide, pegvisomant, transphenoidal surgery, and/or radiotherapy as indicated.Main Outcome Measure:Association of optic neuropathy and hearing impairment to age at GH excess diagnosis/treatment was measured.Results:Of 129 MAS subjects, 26 (20%) were diagnosed with GH excess based on elevation of two measures of GH function. Of these, 22 subjects were candidates for pharmacological intervention. Optic neuropathy was significantly correlated with intervention status, with no cases in the early intervention group (diagnosed/treated before age 18) or the control group, and four of seven (57%) in the late intervention group (diagnosed/treated after age 18) (Fisher's exact test; odds ratio, 0.027; P = 0.0058). Early diagnosis/intervention was not associated with reduction in hearing deficits (odds ratio, 1.25; P = 1.00). Mean head circumference sd score was significantly higher in the late (6.08; range, 2.70 to 22.56) than the early intervention (2.67; range, -0.65 to 6.72) or control groups (2.13; range, -2.06 to 7.79) (P = 0.003).Conclusions:Early diagnosis/treatment of GH excess in MAS is important to prevent optic neuropathy and craniofacial expansion. The relationship between hearing deficits and GH excess remains less clear and requires further study.

Full-text

Available from: Alison M Boyce, Nov 10, 2014
Optic Neuropathy in McCune-Albright Syndrome:
Effects of Early Diagnosis and Treatment of Growth
Hormone Excess
Alison M. Boyce,* McKinley Glover,* Marilyn H. Kelly, Beth A. Brillante,
John A. Butman, Edmond J. Fitzgibbon, Carmen C. Brewer,
Christopher K. Zalewski, Carolee M. Cutler Peck, H. Jeffrey Kim,
and Michael T. Collins
Context: GH excess is a serious complication of McCune-Albright syndrome (MAS) and has been
associated with craniofacial morbidity.
Objective: The aim of the study was to determine whether early diagnosis and treatment of
MAS-associated GH excess prevents optic neuropathy and hearing impairment, the major mor-
bidities associated with GH excess.
Design and Setting: A retrospective cross-sectional analysis was conducted at a clinical research
center.
Patients: Twenty-two subjects with MAS-associated GH excess and 21 control MAS subjects without
GH excess were included in the study.
Intervention: Biochemical testing included random GH, nadir GH after glucose load, nadir GH on
frequent sampling, and IGF-I Z-score. Subjects underwent imaging, ophthalmological, audiolog-
ical, and otolaryngological assessment. Treatment included octreotide, pegvisomant, transphe-
noidal surgery, and/or radiotherapy as indicated.
Main Outcome Measure: Association of optic neuropathy and hearing impairment to age at GH
excess diagnosis/treatment was measured.
Results: Of 129 MAS subjects, 26 (20%) were diagnosed with GH excess based on elevation of two
measures of GH function. Of these, 22 subjects were candidates for pharmacological intervention.
Optic neuropathy was significantly correlated with intervention status, with no cases in the early
intervention group (diagnosed/treated before age 18) or the control group, and four of seven
(57%) in the late intervention group (diagnosed/treated after age 18) (Fisher’s exact test; odds
ratio, 0.027; P 0.0058). Early diagnosis/intervention was not associated with reduction in hearing
deficits (odds ratio, 1.25; P 1.00). Mean head circumference
SD score was significantly higher in
the late (6.08; range, 2.70 to 22.56) than the early intervention (2.67; range, 0.65 to 6.72) or
control groups (2.13; range, 2.06 to 7.79) (P 0.003).
Conclusions: Early diagnosis/treatment of GH excess in MAS is important to prevent optic neurop-
athy and craniofacial expansion. The relationship between hearing deficits and GH excess remains
less clear and requires further study. (J Clin Endocrinol Metab 98: E126–E134, 2013)
M
cCune-Albright syndrome (MAS) is a combination
of polyostotic fibrous dysplasia (FD), cafe´-au-lait
skin pigmentation, and hyperfunctioning endocrinopa-
thies (1–5). FD/MAS results from postzygotic mutations in
the
-subunit of the G
s
stimulatory protein (G
s
), leading
to constitutive receptor activation and inappropriate
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2013 by The Endocrine Society
doi: 10.1210/jc.2012-2111 Received May 1, 2012. Accepted September 25, 2012.
First Published Online October 23, 2012
* A.M.B. and M.G. contributed equally to the manuscript.
Author affiliations are shown at the bottom of the next page.
Abbreviations: BSS, Bone scan score; CT, computed tomography; FD, fibrous dysplasia;
G
s
,G
s
stimulatory protein; MAS, McCune-Albright syndrome; MRI, magnetic resonance
imaging; SDS,
SD score.
JCEM ONLINE
Advances in Genetics—Endocrine Research
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Page 1
cAMP production (3, 4). Disease burden is determined by
the embryonic stage during which the mutation occurs,
and the locations to which mutated progenitors subse-
quently migrate (6, 7). The resulting phenotype is mosaic
with a high degree of clinical variability.
GH excess affects approximately 20% of patients with
MAS (8) and has been associated with craniofacial mor-
bidity, including vision and hearing impairment (8 –12).
Treatment options include medical management, surgery,
and radiotherapy. Patients with craniofacial FD often
present a surgical challenge due to skull base thickening
and obliteration of the sphenoid sinus (13). Additionally,
pituitary adenomectomy is frequently ineffective due to
diffuse somatolactotroph hyperplasia in MAS-associated
GH excess (14, 15). Radiotherapy is controversial because
activating G
s
mutations may act as oncogenes, and ma
-
lignant transformation is likely increased by radiation ex-
posure (16–18). The mainstay of treatment is thus lifelong
medical therapy with somatostatin analogs and the GH
receptor antagonist pegvisomant, used alone or in com-
bination (10, 19).
Medical management is frequently effective in normal-
izing IGF-I levels (8, 10, 19). However, despite a strong
association between GH excess and craniofacial morbid-
ity, no clear effects on craniofacial FD have been demon-
strated with treatment. To determine the impact of GH
excess treatment on progression of craniofacial morbidity,
we performed a retrospective cross-sectional analysis of a
large cohort of patients with MAS-associated GH excess,
correlating clinical, biochemical, and radiographic fea-
tures with therapeutic history and outcomes. We hypoth-
esized that duration of untreated MAS-associated GH ex-
cess would correlate with a higher risk of craniofacial
morbidity.
Patients and Methods
All 129 subjects with MAS in the NIH cohort were evaluated.
Subjects underwent physical examination, biochemical testing,
and imaging.
Biochemical
Testing included GH, IGF-I, GH suppression test, and frequent
overnight GH sampling. GH and IGF-I levels were drawn fasting at
0800 h on 2 consecutive days and averaged. GH levels were ob-
tained by chemiluminescence immunoassay (Immulite 2000 ana-
lyzer; Siemens Medical Solutions Diagnostics, Deerfield, IL); values
greater than 5.0 ng/ml were considered consistent with GH excess.
IGF-I levels were measured by chemiluminescence immunoassay
(before the year 2000, Nichols Advantage Specialty System; Nich-
ols Institute Diagnostics, San Juan Capistrano, CA; and after 2000,
Immulite 2500 analyzer; Siemens Medical Solutions Diagnostics).
For IGF-I, values were converted to Z-scores using reference ranges
for age and gender. Z-scores greater than 2.0 were considered ele-
vated. GH suppression testing included administration of oral glu-
cose 75 g and measurement of GH levels at 0, 30, 60, 120, and 180
min. Lack of GH suppression below 1 ng/ml at 60 min was con-
sidered elevated. Frequent overnight GH sampling involved col-
lecting samples every 20 min from 2000 to 0800 h. A lack of nadir
below 1.0 ng/ml was considered elevated.
Imaging
Subjects underwent head computed tomography (CT), pitu-
itary magnetic resonance imaging (MRI), and radio-labeled
99
Tc-methylene diphosphonate bone scintigraphy. FD burden
was quantified by bone scan score (BSS) determined from scin-
tigraphy using a validated scoring system (20). Head CT was
used to determine optic nerve encasement, head circumference,
and sphenoid sinus opacification. Head circumference was de-
termined radiographically using previously described method-
ology (21), and macrocephaly was defined as greater than 2
SD
for age and gender. Sphenoid sinus opacification was classified
as below 50%, 50 –75%, or above 75%. Baseline optic nerve
encasement was classified as below 50%, 50–75%, or above
75% using previously described methodology (11).
Audiology/otolaryngology
Baseline audiometric evaluations were conducted, and fol-
low-up evaluations were performed at each visit, usually annu-
ally. A four- frequency (0.5/1/2/4 kHz) pure tone average greater
than 20 dB hearing level was used as a marker for clinically
significant hearing loss in this cohort. Conductive hearing loss
was present when the air conduction pure tone average was
worse than the normal bone conduction pure tone average by
greater than 10 dB. Otolaryngology evaluations were performed
by a single physician (H.J.K.) for microscopic ear examination.
Analyses were performed from clinical data obtained at di-
agnosis and before initiation of GH excess treatment. Compar-
isons were performed between groups of subjects with MAS-
associated GH excess and a group of control subjects with FD/
MAS without GH excess. Control subjects were matched for age,
gender, and degree of craniofacial FD using skull BSS (20).
Neuro-ophthalmology
Subjects were assessed for optic neuropathy and/or visual
field deficits by a single neuro-ophthalmologist (E.J.F.). Vari-
ables included: 1) best corrected visual acuity; 2) visual fields; 3)
Skeletal Clinical Studies Unit (A.M.B., M.G., M.H.K., B.A.B., C.M.C.P., M.T.C.), Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes
of Health (NIH), Bethesda, Maryland 20892; Program in Developmental Endocrinology and Genetics (A.M.B.), National Institute of Child Health and Human Development, NIH, Bethesda, Maryland
20892; Bone Health Program (A.M.B.), Division of Orthopaedics and Sports Medicine, Children’s National Medical Center, Washington, D.C. 20010; Duke University School of Medicine (M.G.),
Durham, North Carolina 27710; Department of Radiology (M.G.), Massachusetts General Hospital, Boston, Massachusetts 02114; Department of Diagnostic Radiology (J.A.B.), Mark O. Hatfield
Clinical Research Center, National Institutes of Health, Bethesda, Maryland 20892; National Eye Institute (E.J.F.), NIH, Bethesda, Maryland 20892; Audiology Unit (C.C.B., C.K.Z.), Otolaryngology
Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892; University of Tennessee Health Science Center (C.M.C.P.), Hamilton Eye Institute,
Memphis, Tennessee 38163; Office of the Clinical Director (H.J.K.), National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892; and Department of
Otolaryngology (H.J.K.), Head and Neck Surgery, Georgetown University Hospital, Washington, D.C. 20007
J Clin Endocrinol Metab, January 2013, 98(1):E126–E134 jcem.endojournals.org E127
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Page 2
contrast vision; 4) color vision; and 5) fundoscopic examination.
Using previously described methodology (9), optic neuropathy
was diagnosed in individuals with abnormal visual fields or an
abnormality of at least two of the three other variables.
Intervention status
Subjects with GH excess were classified based on intervention
status. Early and late intervention were defined as initiation of
pharmacotherapy before or after age 18, respectively.
Intervention and efficacy
Clinical management was determined individually, taking
into consideration predicted height, pubertal status, biochemical
measures, and craniofacial morbidity. Treatment efficacy for
children and adults was defined by an on-treatment IGF-I Z-
score between 2 to 1, and 2 or less, respectively.
Subjects determined appropriate for pharmacotherapy were ini-
tiated on monthly octreotide, with dose escalation until the goal
IGF-I Z-score was obtained or the maximum dose (30 mg/month)
was reached. Subjects without appropriate IGF-I Z-score reduction
on maximal dose octreotide were initiated on pegvisomant. Trans-
phenoidal pituitary surgery and external beam irradiation were
considered to be the final recourse in subjects
with significant morbidity who failed to meet
IGF-I efficacy criteria with maximal doses of
both octreotide and pegvisomant.
Analyses
Descriptive statistics were used to char-
acterize baseline demographic, radiologi-
cal, and laboratory values. Depending on
the analysis, comparisons were performed
between all groups or only early and late
intervention groups. For continuous data,
one-way ANOVA analyses assessed differ-
ences between multiple groups, whereas t
test comparisons were performed between
two groups. Depending on the analysis,
groups were compared using a nonparamet-
ric Wilcoxon or Dunn’s multiple compari-
son test. Association between treatment and
morbidity was analyzed using Fisher’s exact
test. Analyses were performed using Graph-
Pad Prism Version 5 (GraphPad Software
Inc., San Diego, CA).
Study approval
The study was approved by the Institu-
tional Review Board of the National Insti-
tute of Dental and Craniofacial Research.
Subjects and/or their guardians provided in-
formed consent/assent.
Results
Study population and natural
history of MAS-associated GH
excess
Twenty-six subjects (20%) with GH
excess were identified. Females constituted 46% of sub-
jects with GH excess and 56% of the total cohort. Fifteen
subjects were placed in the early intervention group and
seven in the late intervention group. Four subjects had
only slight GH excess not requiring medical intervention
and were excluded from the analyses. Twenty-one control
subjects with FD/MAS without GH excess matched for
age, gender, and skull BSS were placed in the control
group.
There was a significant difference in age at enrollment
between groups, with subjects in the early intervention
group younger on average than those in the late interven-
tion group (median 7.5 yr, 25–75%, 5.6 –11.3 for the early
group vs. median 26.2 yr, 25–75%, 18.9 –34.5 for the late
group; P 0.0003) (Fig. 1A). The control group con-
tained subjects age-matched with both intervention
groups, with a median age at enrollment of 11.0 yr, 25–
75%, 9.9–16.2 (Fig. 1A). There was no significant differ-
ence between mean length of follow-up in the early, late,
Enrollment Age
Length of Follow Up
Enrollment
Age
Late Intervention
Early Intervention
A
Length
of
Follow
Up
Late Intervention
Early Intervention
B
0 10 20 30 40 50
Controls
Age (years)
p = 0.0003
0 10 20 30
Controls
Years
p = 0.609
Random Growth Hormone
C
IGF-1 Z-Score
D
Controls
Late Intervention
Early Intervention
Late Intervention
Early Intervention
0 20 40 60
Controls
Growth Hormone (ng/mL)
p = 0.29
-10 0 10 20 30 40
Controls
IGF-1 Z-score
p = 0.08
60 min on OGTT
E
Serial GH Sampling Nadir
F
Late Intervention
Early Intervention
Late Intervention
Early Intervention
Growth Hormone (ng/mL)
0 20 40 60 80
p = 0.26
0 20 40 60
Growth Hormone (ng/mL)
p = 0.11
FIG. 1. Baseline demographics, follow-up, and measures of GH excess. A and B,
Comparisons of enrollment age and length of follow-up, respectively, for each group. Panels
C–F depict various measures of GH excess for each group: C, random GH; D, IGF-I Z-score; E,
GH at 60 min on standard oral glucose tolerance test (OGTT); F, GH nadir on frequent
overnight GH sampling. Error bars represent the mean and 1 SD. P values represent the results
of comparison differences between the three groups (A, B, C, and D, ANOVA), or two groups
(E and F, t test).
E128 Boyce et al. Optic Neuropathy in MAS-Associated GH Excess J Clin Endocrinol Metab, January 2013, 98(1):E126–E134
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Page 3
and control groups [4.5, 6.9, and 5.4 yr, respectively (P
0.61) (Fig. 1B)] or in the length of follow-up between the
early and late intervention groups (P 0.34). In combi-
nation, subjects in the early and late intervention groups
were followed on pharmacological treatment for a total of
115 patient-years.
Baseline biochemical data
There was no significant difference between the early
and late intervention groups in random GH levels (14.8
and 26.3 ng/ml for the early and late groups, respec-
tively; P 0.29) or IGF-I Z-scores (3.5 and 10.6 for the
early and late groups, respectively; P 0.08) (Fig. 1C).
The mean nadir GH values on serial overnight sampling
were 7.1 and 19.1 for the early and late intervention
groups (P 0.11). Mean GH values 60 min after oral
glucose load were 6.7 and 14.3 in the early and late
intervention groups (P 0.26).
Control subjects had a mean random GH level of 1.2
ng/ml and mean IGF-I Z-score of 1.1. No additional
testing of the GH axis was performed in these subjects.
Characterization of radiographic findings at
baseline
All subjects had some level of craniofacial FD. Mean
skull BSS were 3.2, 3.7, and 3.3 for the early, late and
control groups, respectively (0 no involvement; 4
100% involvement) (Table 1). There were no differences
between any groups or subgroups.
All groups had similar prevalence of sphenoid sinus
opacification (73, 71, and 76% in the early, late and con-
trol groups, respectively) (Table 1). The prevalence of
more than 75% optic nerve encasement on CT was 73%
(22 of 30) of all eyes in the early intervention group,
100% (14 of 14) in the late intervention group, and
90% (19 of 21) in the control group. ANOVA compar-
ison for all three groups showed no difference between
the means (P 0.81). Mean head circumference
SD
scores (SDS) were significantly higher in the late inter-
vention group (6.08; range, 2.70–22.56) than the early
(2.67; range, 0.65 to 6.72) or control groups (2.13;
range 2.06 to 7.79) (P 0.003).
Pituitary MRI was performed on subjects in the
early and late intervention groups, and findings varied
widely between subjects. Approximately one third of
the early and late intervention groups had normal MRIs
[four of 14 (29%) and two of seven (29%) of the early
and late groups, respectively] (Table 1). Other findings
included micro- and macroadenomas [eight of 14 (57%)
and six of seven (86%) in the early and late intervention
groups, respectively] and abnormal enhancement of the
TABLE 1. Radiographic findings
Early intervention Late intervention Controls P value
n15721
Sphenoid sinus opacification NS
50% 2 (13%) 2 (29%) 2 (10%)
50–75% 2 (13%) 0% 3 (14%)
75% 11 (73%) 5 (71%) 16 (76%)
Optic nerve encasement (total eyes) NS
50% 5 (17%) 0% 0
50–75% 3 (10%) 0% 2 (10%)
75% 22 (73%) 14 (100%) 19 (90%)
Head circumference
a
0.01
SDS, median (range) 2.67 (0.65 to 6.72) 6.08 (2.70 to 22.56) 3.09 (1.35 to 7.18)
2 SDS 9 (64%) 7 (100%) 2 (50%)
Skull bone scan score (% involvement)
b
NS
1 (0–5%) 0 0 0
2 (5–25%) 3 (21%) 0 3 (14%)
3 (25–50%) 5 (37%) 2 (29%) 7 (33%)
4(50%) 6 (43%) 5 (71%) 11 (52%)
Pituitary/sella MRI
c
Normal 4 (29%) 2 (29%) N/A NS
Microadenoma 7 (50%) 2 (29%) N/A
Macroadenoma 1 (7%) 4 (57%)
d
N/A
Diffuse enhancement 2 (14%) 0% N/A
Extension beyond sella 6 (43%) 5 (71%) N/A
N/A, Not available; NS, not significant.
a
One subject in the early intervention group did not have a head CT done.
b
One subject in the early intervention group did not have a bone scan done.
c
One subject in the early intervention group and all subjects in the control group did not have an MRI done.
d
One subject in the late intervention group had both a micro- and a macroadenoma.
J Clin Endocrinol Metab, January 2013, 98(1):E126–E134 jcem.endojournals.org E129
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Page 4
pituitary without discrete adenoma [two of 14 (14%) in
the early intervention group, none in the late intervention
group]. Representative MRI images are shown in Fig. 2.
Representative CT images of subjects in the early and late
intervention groups are compared, demonstrating differ-
ences in craniofacial morbidity and optic canal narrowing
(Fig. 3).
Baseline morbidity
One subject in the early intervention group (one of 15)
and one subject in the control group (one of 21) developed
optic neuropathy after prophylactic optic nerve decom-
pression performed before enrollment, and despite normal
preoperative neuro-ophthalmological findings. These
subjects were excluded from analyses involving optic neu-
ropathy because visual deficits were considered a surgical
complication. In the late intervention group four of seven
(57%) subjects had optic neuropathy. Optic neuropathy
developed at a relatively young age in these subjects (12,
14, 16, and 23 yr). Baseline audiological evaluations
showed that five of 15 (33%) of the early intervention
subjects had conductive hearing loss, compared with one
of seven (14%) in the late intervention and two of 20
(10%) in the control group. There was accumulation of mid-
dle ear fluid on baseline otolaryngology assessment in four of
five subjects with hearing deficits in the early intervention
group, the one subject with hearing deficits in the late in-
tervention group, and one of two subjects with hearing
deficits in the control group. One subject in the control
group had a unilateral high-frequency
sensorineural hearing loss.
Treatment outcomes
Figure 4 outlines the treatment and
outcomes paradigm. Candidates for
pharmacotherapy (n 22) were initi-
ated on long-acting octreotide (san-
dostatin LAR) monotherapy. Treat-
ment was effective in 11 of 19 (58%)
compliant subjects.
In five of eight subjects in whom oc-
treotide was ineffective, pegvisomant
was added to the regimen. The combi-
nation was effective in reducing the
IGI-I Z-score into the normal range in
four of five subjects and decreased but
did not normalize the IGF-I in the fifth.
Two subjects were considered candi-
dates for transphenoidal surgery after
failing pharmacotherapy. One subject
underwent transphenoidal adenomec-
tomy, which was ineffective in reducing
IGF-I Z-score into the normal range.
Another subject underwent transphenoidal total hypoph-
ysectomy. Postoperatively, there was a reduction in IGF-I
Z-score to efficacy criterion; however, the subject unfor-
tunately died from a postoperative hemorrhage. One sub-
ject was initiated on pegvisomant monotherapy after fail-
ing octreotide monotherapy, did not tolerate the regimen,
and had focused irradiation to the sella. At 4 yr after ra-
diotherapy, she achieved an IGF-I decline that did not meet
efficacy criterion. Overall, pharmacotherapy (octreotide
alone or with pegvisomant combination) was effective in
achieving the treatment goal in 79% (15 of 19) of subjects
compliant with the regimen.
Pre- and posttreatment IGF-I Z-scores are presented in
Fig. 5. Paired t tests for the early intervention group re-
vealed a significant reduction in mean IGF-I Z-score from
2.7 to 0.3 (P 0.0004). A similar result was seen in the
late intervention group, with a reduction of IGF-I Z-score
from 4.3 to 0.3 (P 0.007).
Morbidity at follow-up
There were no new cases of optic neuropathy in any
groups at follow-up. One subject in the late intervention
group with neuropathy at baseline required optic nerve
decompression during the follow-up period after devel-
oping amaurosis, considered progression/worsening of
optic neuropathy.
Audiological evaluation revealed one new case of con-
ductive hearing loss at follow-up in the control group (one
FIG. 2. Representative sphenoid sinus and pituitary images. A, CT demonstrating FD of the skull
and relatively normal sphenoid sinus anatomy, highlighted by the asterisk. B, CT showing
craniofacial FD leading to partial sphenoid sinus opacification, highlighted by the asterisk.C,
Subject with complete opacification of the sphenoid sinus secondary to severe craniofacial FD. D,
MRI from the subject in panel A demonstrates normal appearance of the pituitary despite clinically
significant GH excess. E, MRI from the subject in panel B shows diffuse pituitary enlargement with
abnormal enhancement. F, MRI from the subject in panel C demonstrates diffuse gland
enlargement and a right-sided pituitary macroadenoma (arrow).
E130 Boyce et al. Optic Neuropathy in MAS-Associated GH Excess J Clin Endocrinol Metab, January 2013, 98(1):E126–E134
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Page 5
of 20; 4.8%), associated with middle ear effusion. Two
subjects in the early intervention group and one subject in
the control group with baseline conductive hearing loss
had resolution of middle ear fluid at follow-up. Five sub-
jects did not have follow-up audiology evaluations (two in
the early group, two in the late group, and one control),
including three with baseline hearing deficits, and thus
cannot be characterized.
Impact of pharmacotherapy on morbidity
Analysis by intervention status revealed that at base-
line, early intervention was associated with decreased
odds of optic neuropathy. In the late intervention group,
four of seven had optic neuropathy at baseline compared
with none of the 14 in the early intervention group and
none of the 20 in the control group (odds ratio 0.027,
P 0.0058, early vs. late; odds ratio 52.7, P 0.002,
late vs. controls). Early intervention was not associated
with reduced odds of hearing deficits (Fisher’s exact test,
OR 1.25, P 1.00, early vs. late; OR 2.83, P 0.25,
early vs. controls; OR 2.27, P 0.58, late vs. controls).
Discussion
GH excess and craniofacial
morbidity
In this cohort, diagnosis and treat-
ment of GH excess before age 18 was
associated with decreased odds of optic
neuropathy. This study represents an
extension of previous work, which
demonstrated an association between
GH excess and vision and hearing im-
pairment, generating the hypothesis
that GH excess leads to progression of
craniofacial FD (8 –12). This hypothe-
sis is supported by findings here,
wherein early diagnosis and treatment
of GH excess appeared to prevent one
of the most clinically significant FD-re-
lated morbidities.
The mechanism by which MAS-as-
sociated GH excess results in optic neu-
ropathy is not established but is likely
secondary to optic nerve traction from
craniofacial deformity and/or optic
nerve canal compression (9, 11). In our
cohort, craniofacial deformity was as-
sessed by a combination of skull BSS
and head circumference. BSS quantifies
the percentage of the skull affected by
FD and confirmed that all groups had
similar levels of craniofacial FD in-
volvement. BSS does not assess qualitative features of FD;
therefore, to evaluate craniofacial expansion we com-
pared head circumference Z-scores between groups.
Scores were significantly higher in the late intervention
compared with the early intervention and control groups,
consistent with greater expansion of craniofacial FD.
Taken together, these findings support our hypothesis that
untreated GH excess leads to expansion of craniofacial
FD, and that increased optic neuropathy in the setting of
GH excess may arise from optic nerve traction and/or op-
tic nerve compression related to expansion and deformity
of the skull (9 –11).
Deformity and functional impairment resulting from
craniofacial expansion are known FD-related morbidities.
The pathogenesis of FD expansion has not been well-es-
tablished but is likely related to stromal cell proliferation
and osteoclast invasion of normal areas of bone. The
mechanism by which GH excess contributes to expansion
of craniofacial FD has not been thoroughly investi-
gated. In patients without FD, GH excess leads to linear
growth acceleration and expansion of multiple skeletal
FIG. 3. Representative skull FD and optic canal images. A–C, CT images from a 28-yr-old
woman from the early intervention group who was successfully treated for GH excess from
the age of 9 yr with octreotide. Pretreatment and on-treatment IGF-I Z-scores were above 5
and 0, respectively. D–F, CT images from a 26-yr-old man from the late intervention group
who did not present until the age of 18. Pretreatment and on-treatment IGF-I Z-scores were
above 5 and 2.5, respectively. A and D, Three-dimensional reconstructed anterior-posterior
CT images; B and E, lateral images with the soft tissues overlaid in translucent blue. Note the
greater severity of mandibular macrognathia and acromegalic features (frontal bossing) in the
late intervention subject (D and E), despite the fact that the subject had had several cranial
reduction operations. C and F, Effect of untreated GH excess on the optic nerve (asterisk) and
optic canals (outlined by arrows). The late treatment subject has canals that are significantly
narrower, with the left canal completely occluded (double asterisk), leaving the subject blind
in the left eye.
J Clin Endocrinol Metab, January 2013, 98(1):E126–E134 jcem.endojournals.org E131
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Page 6
areas, including the craniofacial region (22). These ef-
fects have been postulated to occur through effects of
IGF-I overproduction on bone-forming cells (23, 24).
Expansion of craniofacial FD in MAS-associated GH
excess thus likely arises from a combination of G
s
-
mediated stromal cell pathology and downstream ef-
fects of IGF-I overproduction.
In contrast to its significant association with optic neu-
ropathy, GH excess was not associated with increased
odds of hearing deficits. This suggests that FD-associated
hearing loss may arise from GH-independent effects. Sub-
jects with transient conductive hearing loss secondary to
middle ear effusion improved after clearance of the
middle ear fluid. This suggests that hearing impairment in
FD/MAS may be at least partially related to
alterations in middle ear and Eustachian tube
dynamics. Adenoid and tonsillar hypertro-
phy with associated Eustachian tube dys-
function have been reported in patients with
acromegaly and with exogenous GH admin-
istration (25).
Characterization of GH excess
GH excess was diagnosed based on eleva-
tion of at least two indices of GH function, one
of which was frequent GH sampling. Frequent
sampling has been established as an accurate
tool to detect abnormal GH production and
secretion dynamics in acromegalic adults (26
28). In children, frequent sampling has been
studied in short stature associated with GH
neurosecretory dysfunction (29, 30); however,
there are few reports of its use in children with
GH excess. In our series, frequent overnight
GH sampling was elevated in 22 of 24 subjects,
including 16 of 17 children. These results sug-
gest that frequent sampling is a sensitive tool
for diagnosing GH excess in both adults and
children.
Treatment effects
In this cohort, pharmacotherapy was effective in re-
ducing IGF-I values in most subjects, consistent with pre-
vious reports that octreotide alone (31) or in combination
with pegvisomant is effective treatment for MAS-associ-
ated GH excess (10, 32, 33). All subjects under age 18 who
were compliant with the prescribed regimen achieved the
desired reduction in IGF-I Z-score. Somatostatin analogs
with or without pegvisomant thus remain an effective
first-line treatment for MAS-associated GH excess.
Surgery is technically difficult because FD of the skull base
(seen in virtually all patients with GH excess) as well as sphe-
noid sinus opacification often preclude the standard trans-
phenoidal approach. Because the pitu-
itary gland is diffusely involved with
somatolactotroph hyperplasia (14, 15),
effective surgical treatment typically ne-
cessitates total hypophysectomy. This is
illustrated in the two subjects referred for
surgery, one of whom had a transphenoi-
dal adenomectomy, which was ineffec-
tive in decreasing IGF-I levels, and the
other who underwent total hypophy-
sectomy, which effectively reduced
markers of GH excess but unfortu-
nately resulted in death from late
Screened for MAS/GH Excess
N = 129
MAS/FD without GH Excess
N = 103
MAS and
GH
Octreotide alone
a
N=22
xcess
N = 26
No pharmacotherapy
N = 4
N
=
22
Octreotide alone:
Effective: 11 / 21
Octreotide alone
Ineffective: 8 / 21
Non-compliant
2 / 21
Octreotide + Pegvisomant
Effective: 4 / 5
Octreotide + Surgery
c
Effective: 1 / 2
Pegvisomant alone
b
Effective: 0 / 1
Radiation
d
Effective: 0 / 1
FIG. 4. Treatment paradigm and outcomes. Flow diagram summarizing treatment
and outcomes of MAS-associated GH excess. a, One subject was placed on
octreotide and then lost to follow-up. b, Pegvisomant alone was attempted due to
subject preference. c, Transphenoidal hypophysectomy effectively reduced IGF-I
values postoperatively, but the subject died due to postoperative complications; one
subject underwent pituitary adenomectomy, which was ineffective. d, Focused
irradiation to the sella turcica led to reduction in IGF-I values that did not meet
criteria for efficacy.
Early Intervention
4
6
re
Late Intervention
4
6
re
-2
0
2
IGF-1 Z scor
-2
0
2
IGF-1 Z scor
Baseline
Follow Up
-4
Baseline Follow Up
-4
2
p = 0.0004
p
=
0.007
B
A
FIG. 5. Baseline and follow-up IGF-I Z-scores. A and B, Pretreatment and posttreatment IGF-I
Z-scores for the early and late intervention groups, respectively.
E132 Boyce et al. Optic Neuropathy in MAS-Associated GH Excess J Clin Endocrinol Metab, January 2013, 98(1):E126–E134
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Page 7
postoperative hemorrhage. The combination of a diffi-
cult surgical approach and requisite postoperative hy-
popituitarism makes surgical treatment of MAS-asso-
ciated GH excess problematic, and it should be reserved
for patients with intractable disease not responsive to
pharmacotherapy.
Radiation is another option for patients with GH ex-
cess who fail medical management. Radiotherapy in FD/
MAS is controversial because the risk of sarcomatous
transformation of FD is potentially increased by radiation
exposure (16), and there are reports of individuals with
FD/MAS who developed fatal sarcomas after radiother-
apy for pituitary adenomas (17, 18). Additionally, there is
little evidence that radiotherapy is effective in MAS-asso-
ciated GH excess. Our subject who underwent radiation
had a reduction in IGF-I; however, Z-scores remained el-
evated at greater than 2
SD after 4 yr of follow-up. A series
of five patients with MAS-associated GH excess who un-
derwent pituitary radiation likewise failed to achieve nor-
malization of IGF-I after a median follow-up of 5 yr,
whereas two patients subsequently placed on pegvisomant
showed rapid normalization (19). Radiotherapy should
thus be reserved as a final recourse for patients with ex-
tremely severe GH excess who are resistant to pharmaco-
therapy and are not candidates for surgery.
Study limitations and potential biases
This study is limited by the inherent deficits of retro-
spective analyses. Although a randomized control trial
comparing treated and untreated subjects is optimal, given
the established association between GH excess and optic
neuropathy, it is clinically and ethically inappropriate.
Lead time bias is also an important consideration. The
younger age of the early intervention group is a reflection
of a shift in practice that arose out of the identification of
an association between GH excess and optic neuropathy.
This bias is potentially controlled for by the following
points: 1) the late treatment group developed vision loss at
relatively young ages (12, 14, 16, 23); 2) at present the
mean age of most subjects in the early intervention group
is almost equal to the ages at which vision was lost in
subjects who developed optic neuropathy [16.3 (
SD 4.7) vs.
15.2 (
SD 5.6) yr]; 3) the subjects in the early treatment
group who had more severe GH excess and who were
treated early, and thus had the longest follow-up on treat-
ment, did not develop vision loss during many years of
treatment and follow-up; and 4) no subject in either group
has developed vision loss since treatment was initiated
(115 patient-years). Subjects will be followed as part of an
ongoing natural history study, with planned longitudinal
analyses to characterize treatment effects and morbidity
over time.
Small sample size is another limitation, particularly of
the late intervention group. This is a common limitation in
studies of FD/MAS due to the rarity of the condition. De-
spite its relatively small sample size, this is the largest re-
ported cohort of subjects with MAS-associated GH ex-
cess, and significant differences were achieved between
treatment groups in parameters of interest.
Referral bias may affect our cohort. As a tertiary refer-
ral center, these subjects may be more severely affected,
thus diminishing potential generalizability of the data.
However, greater severity will select for greater morbidity,
thus allowing for the occurrence of morbidity endpoints.
Conclusion and future directions
The results of these analyses support the hypothesis
that early diagnosis and treatment of GH excess in MAS
prevents optic neuropathy. The relationship between
hearing loss and GH excess remains less clear and requires
further study. In this cohort that was largely pediatric at
presentation, frequent overnight sampling was a useful
tool to diagnose GH excess. Medical treatment with oc-
treotide with or without pegvisomant was effective in nor-
malizing IGF-I in most subjects. Surgery and radiotherapy
remain controversial and should be reserved for final re-
course in patients with severe disease resistant to maximal
medical therapy.
Acknowledgments
Address all correspondence and requests for reprints to: Ali-
son M. Boyce, M.D., Bone Health Program, Division of Or-
thopaedics and Sports Medicine, Children’s National Medical
Center, 111 Michigan Avenue NW, Washington, D.C. 20010.
E-mail: aboyce@childrensnational.org. Or, Michael T. Col-
lins, M.D., Craniofacial and Skeletal Diseases Branch, Na-
tional Institute of Dental and Craniofacial Research, National
Institutes of Health, 30 Convent Drive, Building 30, Room
228, MSC 4320, Bethesda, Maryland 20892-4320. E-mail:
mcollins@mail.nih.gov.
This work was supported by the Division of Intramural Re-
search, National Institute of Dental and Craniofacial Research,
National Institute of Child Health and Human Development,
National Institute on Deafness and Other Communication Dis-
orders, and the National Eye Institute, National Institutes of
Health, Department of Health and Human Services, and in part
by the Clinical Research Training Program, a public-private
partnership supported by the NIH, and a grant to the Foundation
for the NIH from Pfizer Pharmaceutical Group (to M.G.).
Disclosure Summary: The authors have no conflicts of
interest.
J Clin Endocrinol Metab, January 2013, 98(1):E126–E134 jcem.endojournals.org E133
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Page 8
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E134 Boyce et al. Optic Neuropathy in MAS-Associated GH Excess J Clin Endocrinol Metab, January 2013, 98(1):E126–E134
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Page 9
  • Source
    • "Untreated growth hormone excess is associated with expansion of craniofacial fibrous dysplasia, leading to macrocephaly and increased risk of vision loss [Boyce et al 2013] (Figure 2B). "
    [Show abstract] [Hide abstract] ABSTRACT: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS), the result of an early embryonic postzygotic somatic activating mutation of GNAS (encoding the cAMP pathway-associated G-protein, Gsα), is characterized by involvement of the skin, skeleton, and certain endocrine organs. However, because Gsα signaling is ubiquitous additional tissues may be affected. Café-au-lait skin macules are common and are usually the first manifestation of the disease, apparent at or shortly after birth. Fibrous dysplasia (FD), which can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton, can range from an isolated, asymptomatic monostotic lesion discovered incidentally to a severe disabling polyostotic disease involving practically the entire skeleton and leading to progressive scoliosis, facial deformity, and loss of mobility, vision, and/or hearing. Endocrinopathies include: Gonadotropin-independent precocious puberty resulting from recurrent ovarian cysts in girls and autonomous testosterone production in boys; Testicular lesions with or without associated gonadotropin-independent precocious puberty; Thyroid lesions with or without non-autoimmune hyperthyroidism; Growth hormone excess; FGF23-mediated phosphate wasting with or without hypophosphatemia in association with fibrous dysplasia; and Neonatal hypercortisolism. The prognosis for individuals with FD/MAS is based on disease location and severity. In most individuals the diagnosis of FD/MAS is based on the finding of two or more typical clinical features. In individuals whose only clinical finding is monostotic fibrous dysplasia, identification of a somatic activating mutation of GNAS is required to establish the diagnosis. Mutation detection depends on the level of mosaicism in the tissue and the sensitivity of the technique. Treatment of manifestations: Management is most effectively accomplished by a multidisciplinary team of specialists. FD. No medical therapies are available; management focuses on optimizing function and minimizing morbidity related to fractures and deformity (including scoliosis). Precocious puberty. Treatment prevents bone age advancement and compromise of adult height. For girls, options include the aromatase inhibitor letrozole and/or the estrogen receptor modulator tamoxifen; for boys, treatment options are less well established. Thyroid disease. Methimazole effectively manages hyperthyroidism; however, because hyperthyroidism is persistent, thyroidectomy is common. Growth hormone excess. Medical therapy is the preferred first-line treatment; options include (alone or in combination) octreotide and the growth hormone receptor antagonist pegvisomant. Hypercortisolism. Treatment varies by the presentation of neonatal Cushing syndrome. Surveillance: In all persons with FD/MAS, monitor: Infants for clinical signs of hypercortisolism; Children for growth acceleration and other clinical signs of precocious puberty and/or growth hormone excess; thyroid function tests routinely in children age <5 years; Males for testicular lesions with physical examination and testicular ultrasound. In persons with FD, periodic radiographs to monitor existing FD and development of new lesions; phosphorus levels to monitor for the development of hypophosphatemia. Craniofacial FD: yearly vision and hearing evaluations; periodic skull CT. Spine FD: close monitoring for progressive scoliosis. In children with thyroid abnormalities on ultrasound examination but normal thyroid function, monitor thyroid function periodically. Agents/circumstances to avoid: Contact sports and other high-risk activities (when skeletal involvement is significant); prophylactic optic nerve decompression (in patients with craniofacial FD); surgical removal of ovarian cysts; radiation therapy for treatment of FD; risk factors for malignancy (e.g., radiation exposure). FD/MAS is not inherited. No parent of a child with FD/MAS has been demonstrated to have any significant, distinctive manifestations of the disorder. The risk to sibs is expected to be the same as in the general population. There are no verified instances of vertical transmission of FD/MAS. Copyright © 1993-2015, University of Washington, Seattle. All rights reserved.
    Full-text · Article ·
  • No preview · Article · Nov 1975 · The Journal of legal medicine
  • Source
    [Show abstract] [Hide abstract] ABSTRACT: Fibrous dysplasia (FD) is a skeletal disorder caused by activating mutations in Gsα that result in elevations in cAMP. A feature of FD is elevated blood levels of the bone cell-derived phosphaturic hormone, fibroblast growth factor-23 (FGF23). FGF23 regulates serum phosphorus and active vitamin D levels by action on proximal renal tubule cells. An essential step in the production of biologically active FGF23 is glycosylation by the UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyl transferase (ppGalNAc-T3). In the absence of glycosylation, FGF23 is processed into inactive N- and C-terminal proteins by a subtilisin proprotein convertase, probably furin. Normally, most if not all circulating FGF23 is intact. In FD, C-terminal levels are elevated, suggesting altered FGF23 processing. Altered processing in FD is the result of a cAMP-dependent, coordinated decrease in ppGalNAc-T3 and an increase in furin enzyme activity. These findings, and emerging data from other diseases, suggest regulation of FGF23 processing may be a physiologically important process.
    Full-text · Article · Mar 2013 · Current Osteoporosis Reports
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