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The Journal of Clinical Endocrinology & Metabolism 92(7):2624 –2631
Copyright © 2007 by The Endocrine Society
doi: 10.1210/jc.2007-0135
Endocrine Abnormalities in Patients with
Fanconi Anemia
Neelam Giri, Dalia L. Batista, Blanche P. Alter, and Constantine A. Stratakis
Clinical Genetics Branch (N.G., B.P.A.), Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville,
Maryland 20852; and Developmental Endocrinology Branch (D.L.B., C.A.S.), National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, Maryland 20892
Background: Fanconi anemia (FA) is an inherited disorder with
chromosomal instability, bone marrow failure, developmental defects, and a predisposition to cancer. Systematic and comprehensive
endocrine function data in FA are limited.
Objective: We studied a cohort of FA patients enrolled in the National Cancer Institute’s Inherited Bone Marrow Failure Syndrome
study.
Study Design and Patients: Retrospective review of the medical
records of 45 FA patients (ages 2– 49 yr), 23 of whom were intensively
evaluated at the National Institutes of Health. Anthropometric measurements, GH, IGF-I, IGF binding protein-3, thyroid, gonadal hormone, lipid levels, glucose homeostasis, brain imaging, and bone mineral density were obtained in these latter patients.
Results: Endocrine abnormalities were present in 73%, including
short stature and/or GH deficiency (51%), hypothyroidism (37%), mid-
F
ANCONI ANEMIA (FA) is a rare, genetically and phenotypically heterogeneous, autosomal (MIM no.
227650) or X-linked recessive (MIM no. 300515) (1) chromosome instability disorder characterized by multiple congenital anomalies, a high frequency of bone marrow failure
(BMF), and increased susceptibility to specific malignancies
(2). To date, 13 complementation groups (A, B, C, D1, D2, E,
F, G, I, J, L, M, and N) and FA-associated genes (FANCA,
FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE,
FANCF, FANCG, FANCJ/BRIP1/BACH1, FANCL, FANCM,
and FANCN) have been identified (3, 4).
The most common presentation of FA is progressive BMF,
which develops in 90% of patients (2). Other findings, including short stature, skin pigmentation abnormalities, and
characteristic malformations of upper extremities, head,
eyes, ears, kidneys, and genitals are widely recognized as
part of this rare syndrome (2). To a lesser extent, certain
endocrine abnormalities have been recognized as features of
FA, most notably GH deficiency (GHD), hypothyroidism,
First Published Online April 10, 2007
Abbreviations: BMD, Bone mineral density; BMF, bone marrow failure; BMI, body mass index; FA, Fanconi anemia; GHD, GH deficiency;
HDL, high-density lipoprotein; IBMFS, Inherited Bone Marrow Failure
Syndrome; IGFBP-3, IGF binding protein-3; LDL, low-density lipoprotein; MRI, magnetic resonance imaging; PSIS, pituitary stalk interruption
syndrome; SCT, stem cell transplantation; SDS, sd score.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
line brain abnormalities (17%) (these patients had very short stature
and 60% were GH-deficient); abnormal glucose/insulin metabolism
(39%); obesity (27%); dyslipidemia (55%); and metabolic syndrome
(21%). Patients with any endocrine abnormality were shorter than
those without; only GH deficiency correlated significantly with short
stature (P ⫽ 0.01). In addition, 65% of peripubertal or postpubertal
patients had gonadal dysfunction. Ninety-two percent of the patients
18 yr or older had osteopenia or osteoporosis.
Conclusions: Endocrine dysfunction is widespread in children and
adults with FA; we expand the FA phenotype to include early onset
osteopenia/osteoporosis and lipid abnormalities. Despite the reputation of FA as a progressive, lethal disease, proper management of the
full spectrum of FA-related endocrinopathy offers major opportunities
to reduce morbidity and improve quality of life. Our findings emphasize the need for comprehensive endocrine and metabolic evaluation
and long-term follow-up in patients with FA. (J Clin Endocrinol
Metab 92: 2624 –2631, 2007)
and hypogonadism (5–10). However, only one prior crosssectional study has assessed FA-related endocrine abnormalities (10), the frequency and variety of which are not
widely appreciated. Endocrinopathies may develop in utero
(11) or evolve over time, and may be influenced by treatments for FA, such as chronic red cell transfusions, androgen
therapy, and/or stem cell transplantation (SCT). The aim of
our study was to evaluate systematically endocrine function
in FA patients enrolled in the National Cancer Institute’s
Inherited Bone Marrow Failure Syndrome (IBMFS) study.
Subjects and Methods
Subjects
This report includes 45 patients with FA (Table 1). Twenty-three were
evaluated prospectively at the National Institutes of Health Clinical
Center (Group 1). Endocrine data were abstracted retrospectively from
the medical records of 22 patients who were not seen at the Clinical
Center (Group 2). All subjects were consenting participants in National
Cancer Institute Protocol 02-C-0052 (http://marrowfailure.cancer.gov).
There were 19 males and 26 females, with ages ranging from 2– 49 yr.
Twenty-eight patients were 18 yr of age or younger; 17 were older than
age 18. All patients demonstrated increased chromosomal aberrations in
blood lymphocytes (or skin fibroblasts, in those suspected to have hematopoietic somatic mosaicism) after culture with DNA cross-linking
agents (diepoxybutane and mitomycin C). The diagnosis was confirmed
in 80% of cases by complementation studies and/or mutation analysis.
Twenty-three of the 38 patients tested were FA-A, nine were FA-C, one
each was FA-D1 and FA-F, two were FA-J, and two did not belong to
any of the known FA complementation groups. Thirty-seven patients
had BMF with hypocellular marrow and presence of at least one: hemoglobin less than 9 g/dl, absolute neutrophil count less than 1500/␮l,
2624
Giri et al. • Endocrine Abnormalities in Fanconi Anemia
J Clin Endocrinol Metab, July 2007, 92(7):2624 –2631
2625
TABLE 1. Clinical characteristics of 45 FA patients
Patient characteristics
n
Male: Female
Median age in years (range)
Age ⱕ 18 yr
Age ⬎ 18 yr
No. with BMF (%)
No. with MDS (%)
No. treated with androgen
No. with hemosiderosis
Physical anomaliesa (%)
Total group
Group 1
Group 2
P value
45
19:26
16 (2– 49)
28 (62%)
17 (38%)
37 (82)
9/37 (38)
5
2
38 (84)
23
8:15
18 (6 – 43)
12
11
18 (78)
5/18 (28)
2
2
19 (83)
22
11:11
14 (2– 49)
16
6
19 (86)
4/19 (21)
3
0
19 (86)
0.4
0.08
0.2
0.1
0.7
0.7
0.7
0.5
0.5
Denominators indicate number in each cohort unless otherwise indicated. BMF, Bone marrow failure; MDS, myelodysplastic syndrome.
Physical anomalies include skin pigmentation, 82%; hearing deficits, 56%; microphthalmia, 56%; hypogenitalia in males, 53%; short stature,
51%; thumb anomalies, 51%; microcephaly, 47%; renal anomalies, 42%; and others, 27%.
a
or platelet count less than 140,000/␮l in 28 of 37, or myelodysplastic
syndrome in nine of 37. Five had been on androgens, two had transfusion-related hemosiderosis, and nine had undergone prior SCT. At the
time of evaluation, 84% had one or more malformations of the types
reported previously (2): 82% hyperpigmentation and/or hypopigmentation of the skin and/or café-au-lait spots, 56% hearing deficits, 56%
microphthalmia and/or microcornea, 53% (males) hypogenitalia, 51%
short stature (below ⫺2 sd), 51% thumb anomalies, 47% microcephaly,
42% renal malformations, 33% developmental delay, 27% skeletal abnormalities, and less than 20% cardiac or gastrointestinal malformations.
Groups 1 and 2 patients had similar phenotypic and hematological
profiles.
night fasting using clonidine (0.125 mg/m2 by mouth) and arginine (0.5
g/kg iv over 30 min). GHD was defined on the basis of peak serum GH
concentration less than 7 ␮g/liter after two GH stimulation tests (14).
Spontaneous GH secretion was measured every 20 min from 2000 –
0800 h; the mean, baseline, number of secretory peaks or bursts, and sum
of peaks were calculated.
Diurnal TSH variation was performed to diagnose central hypothyroidism as previously described (15): blood samples were drawn hourly
starting at 1400 h and ending at 1800 h, and again at 2100 h and ending
at 0200 h. Normal TSH surge was a 50% increase of mean TSH nighttime
above mean afternoon values.
Anthropometric measurements
Serial prolactin. Blood samples were drawn every 20 min for 1 h.
Oral glucose tolerance test was scheduled in the morning after a 12-h
overnight fast. An oral glucose load of 1.75 g/kg to a maximum of 75 g
(Glucola; Ames Laboratories, Elkhart, IN) was given. Blood samples
were obtained for glucose and insulin at 0 (fasting), 30, 60, and 120 min
after ingestion of the glucose load. The blood glucose was classified
according to American Diabetic Association recommendations: normal,
fasting plasma glucose 55–100 mg/dl (⬍5.6 mmol/liter); hyperglycemia
or impaired, fasting glucose greater than 100 –125 mg/dl (5.6 – 6.9
mmol/liter); and diabetes, fasting glucose 126 mg/dl or greater (ⱖ7.0
mmol/liter). Diagnostic threshold for diabetes for the oral glucose tolerance test were: 1) normal if plasma glucose was less than 140 mg/dl
(⬍7.8 mmol/liter); 2) impaired glucose tolerance at 140 –199 mg/dl
(7.8 –11 mmol/liter); and 3) diabetes at 200 mg/dl or greater (⬎11.1
mmol/liter) (16). Insulin resistance was measured by the homeostatic
model assessment, which uses the product of fasting insulin concentration (milliunits per liter) and the fasting glucose level (millimoles per
liter) divided by 22.5; insulin resistance was homeostatic model assessment greater than 2 (17).
Group 1 patients underwent a complete examination, including Tanner pubertal stage and testicular volume measurements in boys with a
Prader orchiometer (12). Weight (to the nearest 0.1 kg) was obtained
using a digital scale (Life Measurements Instruments, Concord, CA) and
height (in triplicate to the nearest 1 mm) using a Harpenden stadiometer
(Holtain Ltd., Crymych, UK) calibrated before each set of measurements.
Height was expressed as a sd score (SDS) specific for age and gender,
based on National Center for Health Statistics data. Short stature was
defined as height SDS below ⫺2.0 sd. Target height was calculated using
gender-corrected mid-parental height (13). Body mass index (BMI) was
calculated using the common formula (weight in kilograms divided by
the square of height in meters). BMI for age and gender in those 18 yr
or younger was judged based on National Center for Health Statistics
data: 1) underweight, BMI-for-age less than 5th percentile; 2) normal
weight, 5th percentile or greater to less than 85th percentile; 3) at risk of
overweight, 85th percentile or greater to less than 95th percentile; and
4) overweight, 95th percentile or greater. Among adults, patients were
classified as overweight if their BMI was 25–29.9, and obese if their BMI
was 30 or greater.
Biochemical testing
Blood samples were obtained between 0700 – 0800 h after overnight
fasting for blood cell counts, chemistry panels, insulin, hemoglobin A1C,
IGF-I, IGF binding protein-3 (IGFBP-3), 25-OH-vitamin-D and 1,25(OH)2-vitamin-D, intact PTH, ionized calcium, TSH, free T4, ACTH,
cortisol, estradiol, testosterone, LH, FSH, prolactin, and lipid profile
[triglycerides, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)]. Abnormal lipid profile was considered the
presence of one or more of total cholesterol more than 200 mg/dl, LDL
more than 129 mg/dl, triglycerides more than 150 mg/dl, or HDL less
than 40 mg/dl.
Serial testing
GH stimulation test. Indications for GH testing were: low IGF-I, low
IGFBP-3, or falling off the growth chart in children. Prepubertal patients
received sex hormone priming using ethynylestradiol (40 ␮g/m2/d
orally for 2 d) or testosterone enanthate (200 mg im 5–10 d before testing).
GH-stimulation testing was performed between 0700 – 0800 h after over-
ACTH stimulation test. Approximately 1 h after the insertion of an iv line,
baseline blood samples were obtained for cortisol and ACTH levels.
Subjects then received 0.15 ␮g/kg to a maximum dose of 250 ␮g iv push
of cosyntropin (ACTH 1–39). Blood was obtained for cortisol at 0, 30, and
60 min. Adrenal insufficiency was defined as a peak cortisol level less
than 18 ␮g/dl (500 nmol/liter) (18).
GnRH stimulation test. The gonadotropic axis was investigated by measuring LH and FSH levels at baseline and 0, 30, 60, 120, and 180 min after
a GnRH provocative test (500 ␮g sc leuprolide acetate or iv gonadorelin),
and by determining basal levels of total and free testosterone, and
estradiol (19, 20). Premature ovarian failure was diagnosed if women
less than 40 yr of age did not have menses for at least 4 months and had
menopausal serum FSH concentrations on at least two occasions (21).
Hypogonadism for postpubertal males was defined as a morning serum
total testosterone less than 200 ng/dl (6.4 nmol/liter). Testicular failure
was considered when testosterone was low, and FSH and LH were
elevated; central hypogonadism was defined as a decreased LH and FSH
response to the GnRH stimulation test. All hormone assays and blood
chemistries were performed by standard methods.
2626
J Clin Endocrinol Metab, July 2007, 92(7):2624 –2631
Giri et al. • Endocrine Abnormalities in Fanconi Anemia
Imaging studies
Bone age was determined by the method of Greulich and Pyle (22).
Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry scan (QDR-4500A; Hologic, Inc., Bedford, MA) at the following sites: one third proximal radius, anteroposterior lumbar spine at
L1–L4, femoral neck and total hip; correlated for body surface area; and
adjusted for age and sex. Magnetic resonance imaging (MRI) of the
pituitary gland was performed as previously described (23). Indications
for MRI were low IGF-I and/or IGFBP-3 levels, falling off the growth
chart in children, and/or GHD.
Statistical methods
Results are expressed as median, range, or mean ⫾ 1 sd. Analyses
were performed using Microsoft Excel (Microsoft Office Excel 2003;
Microsoft, Redmond, WA) and Stata9 (StataCorp Release 9, College
Station, TX). For Student’s t test, a P value of less than 0.05 was considered significant.
Results
Anthropometric measurements
Height. Median height SDS for the entire cohort was ⫺1.9
(range 0.8 to ⫺7.8; mean ⫺2.1 ⫾ 1.89). Fifty-one percent (23
of 45) were short, with a median height SDS of ⫺3.5 (range
⫺7.8 to ⫺2.0; mean ⫺3.8 ⫾ 1.5). Median predicted adult
height (target height) SDS for the 37 patients for whom parental heights were available was ⫺0.2 (range ⫺1.5 to 1.2;
mean ⫺0.2 ⫾ 0.8) (Fig. 1). In 86% (32 of 37) of patients, the
actual height SDS was much lower than the target height
SDS, and in 19 patients, this difference was more than 2 sd.
Patients with endocrine abnormalities (hypothyroidism,
GHD, abnormal glucose/insulin homeostasis) were significantly shorter than those without (Table 2): mean height SDS
⫺2.7 ⫾ 2.0 vs. ⫺1.3 ⫾ 1.4, respectively (P ⫽ 0.01).
Weight. BMI was normal for age in 51% (23 of 45), 22% (10 of
45) were underweight, and 27% (12 of 45) were overweight
or obese. There was a similar distribution of patients with
short stature or endocrinopathy in the underweight (five of
10), overweight (six of 12), or normal weight for age (12 of
23) groups (P ⫽ 0.5).
Endocrine testing
Several patients had multiple endocrine abnormalities (Table 3).
Growth hormone axis. Fifty percent of the 14 evaluated patients
were GH-deficient. Five of eight patients who underwent GH
stimulation tests were GH-deficient as were two of five who
underwent overnight spontaneous GH secretion study, with
low mean (0.3 and 1.6 ng/ml respectively), low baseline (0.1
and 3.3 ng/ml), low secretory bursts (0 and 2), or low sum
of peaks. GH-deficient patients were significantly shorter
than those without GHD: mean height SDS ⫺5.0 ⫾ 1.4 (median ⫺4.9, range ⫺7.8 to ⫺2.0) vs. ⫺2.9 ⫾ 1.4 (median ⫺2.7,
range ⫺4.9 to ⫺0.9) (P ⫽ 0.01) (Table 2). Four patients with
GHD who were on thyroid hormone replacement for a history of hypothyroidism were euthyroid when tested. IGF-I
and IGFBP-3 levels were available in nine of 14 patients who
underwent GH studies. IGF-I was low in six: four of four
patients with GHD vs. two of five without GHD (P ⫽ 0.2).
IGFBP-3 was low in three: three of four patients with GHD
vs. zero of five without GHD (P ⫽ 0.05).
Thyroid function. Thirty-seven percent (13 of 35) of the patients tested were hypothyroid; 20% (five of 20) of those 18
yr or younger and 53% (eight of 15) of those older than 18 yr.
Median TSH was 7.1 ␮IU/ml (range 4.5–14; normal 0.4 – 4.0
␮IU/ml). Fourteen percent (five of 35) had subclinical hypothyroidism: median TSH 7.12 ␮IU/ml (range 4.68 –7.97
␮IU/ml). T4 levels were normal with a median value 7.7
␮g/dl (range 7.0 –11.4; normal 4.5–12.5 ␮g/dl). Central hypothyroidism was diagnosed in one of four patients who
underwent overnight TSH studies. No patient had thyroid
antiperoxidase or antithyroglobulin antibodies. Median
height SDS of hypothyroid patients was lower (⫺2.9, range
3
Height SDS and Projected Height
2
1
Height SDS
0
Projected
height
-1
-2
-3
-4
-5
-6
-7
-8
-9
0
5
10
15
20
25
30
35
40
45
50
55
Age in ye a rs
FIG. 1. Actual height SDS (yellow square) at the time of study and target height SDS (blue triangle) of 37 patients in whom data on parental
heights were available.
Giri et al. • Endocrine Abnormalities in Fanconi Anemia
J Clin Endocrinol Metab, July 2007, 92(7):2624 –2631
2627
TABLE 2. Height SDS and endocrine abnormality
Parameter
Height SDSa
Endocrineb
GH
Thyroid
Glucose/insulinc
a
b
c
Normal group
Abnormal group
n
Mean height SDS
n
Mean height SDS
22
17
7
22
25
⫺0.1 ⫾ 0.85
⫺1.3 ⫾ 1.4
⫺2.9 ⫾ 1.4
⫺1.8 ⫾ 1.6
⫺2.1 ⫾ 2.0
23
25
7
13
16
⫺3.8 ⫾ 1.5
⫺2.7 ⫾ 2.0
⫺5.0 ⫾ 1.4
⫺2.9 ⫾ 2.3
⫺1.8 ⫾ 1.5
P value
⬍0.001
0.01
0.01
0.1
0.4
Normal within ⫺2 SD; abnormal less than ⫺2 SD.
Includes thyroid, GH, and glucose/insulin studies.
Abnormal is any of diabetes mellitus, hyperglycemia, glucose intolerance, or insulin resistance.
⫺7.8 to 0.8; mean ⫺2.9 ⫾ 2.3) than that of the euthyroid
patients (⫺1.3, range ⫺4.9 to ⫺0.1; mean ⫺1.8 ⫾ 1.6), a
difference that was not statistically significant (Table 2).
Gonadal function in males. Hypogenitalism with small testes
and phallus was diagnosed in 64% of the 14 males in whom
this examination was reported. Fertility was not routinely
evaluated; however, none of the eight adult males (median
age 19 yr; range 18 –33) has fathered a pregnancy.
Gonadal function in females. Seventeen females were pubertal
or postpubertal (median age 27 yr; range 14.5– 49). Menarche
occurred between ages 11.5–14 yr in 88% (15 of 17). Two
patients were diagnosed with primary amenorrhea at 15.7
and 15.4 yr. Both were on androgen therapy for BMF. Three
of the four females (27, 27, and 34 yr) who attempted pregnancy had primary infertility in their twenties. Nine patients
had premature menopause, at a median age of 29 yr (range
24 –36 yr). Six were on menopausal hormone therapy. In the
three patients (ages 27, 27 and 33) who were not on menopausal hormone therapy, FSH levels were elevated at 44, 48,
and 46 U/liter, and their corresponding LH levels were 30,
29, and 22 U/liter. One prepubertal female (9 yr old) with a
prior history of SCT had primary ovarian failure; her estradiol level was less than 20 pg/ml with FSH and LH levels 41
and 14 U/liter, respectively.
Metabolic abnormalities. Glucose and insulin abnormalities
were seen in 39% (16 of 41) of the patients, hyperglycemia
and/or glucose intolerance were seen in 24% (10 of 41),
diabetes mellitus was seen in 10% (four of 41), and insulin
resistance was seen in 42% (10 of 24) of the tested patients.
Fifty-five percent (16 of 29) had dyslipidemia: elevated LDL
in 21% (six of 29), low HDL in 31% (nine of 29), and elevated
triglycerides in 10% (three of 29).
Forty percent (four of 10) of patients with hyperglycemia,
40% (four of 10) with insulin resistance, 75% (three of four)
with diabetes, and 50% (eight of 16) with dyslipidemia were
at increased risk of being overweight or obese. Only patients
with diabetes tended to be overweight or obese (P ⫽ 0.06)
when compared with those without these metabolic abnormalities. Metabolic syndrome (overweight/obesity, dyslipidemia, and insulin resistance) was diagnosed in 21% (three
of 14) of the adults.
Twelve of 24 children tested had at least one metabolic
abnormality: four had insulin resistance, one had diabetes,
and seven had dyslipidemia. Five of 24 were at risk of overweight or were overweight: three of these five had abnormal
glucose/insulin metabolism, two of whom also had
dyslipidemia.
There were no abnormalities in ionized calcium, 25-OHvitamin-D and 1,25-(OH)2-vitamin-D, PTH, prolactin, and
morning ACTH and cortisol levels.
Imaging studies
Bone age. Bone age was delayed in two of 13 children (ⱕ18
yr) in whom it was measured: chronological age 4.9 vs. bone
age 2 yr; chronological age 6.0 vs. bone age 2.6 yr. Both had
GHD and were also receiving thyroid replacement for hypothyroidism. Bone age was advanced to 12 yr in a 9-yr-old
girl who had previously received androgens for BMF.
MRI of brain and pituitary gland. Five of 24 patients who
underwent imaging studies had an abnormal MRI. All five
had markedly short stature, and three were GH deficient.
Midline brain defects were found in four patients. Three had
partial or complete absence of the corpus callosum and/or
septum pellucidum; one had holoprosencephaly with pituitary stalk interruption syndrome (PSIS) and septo-optic dysplasia (Fig. 2); and the fifth patient had a thickened pituitary
stalk. Pituitary and brain MRI were normal in all other
patients.
Bone studies. BMD was studied in 13 patients (median age
27.5 yr; range 18 – 43). Ninety-two percent (12 of 13) had
osteopenia (three males, four females) or osteoporosis (one
male, four females). The only patient with a normal dualenergy x-ray absorptiometry scan was a 27-yr-old male.
Seven of the eight females with an abnormal BMD were
menopausal; one 20 yr old had no menstrual irregularities
and had not received any treatment for BMF. One of the four
males with an abnormal BMD had previously received androgen, one was post-SCT, and two had not received any
treatment.
Correlations between endocrine abnormalities such as hypothyroidism, GHD, and metabolic dysfunction with physical anomalies were not significant (data not shown). Patients
with hypothyroidism were more likely to have multiple
physical anomalies, a finding which approached but did not
reach statistical significance (P ⫽ 0.06). There was also no
association between FA complementation groups and endocrine abnormalities (data not shown).
Discussion
FA, the leading cause of inherited aplastic anemia, is associated with a high frequency of short stature and endocrine
Hypo
Hypo
N
N
N/A
Hypo
N
N/A
Hypo
N/A
N/A
Hypo
N
N/A
N/A
N/A
N/A
N
N
N
N
N/A
N/A
N
Hypo
Hypo
⫺0.29
⫺3.04
⫺2.47
⫺1.29
⫺4.9
⫺4.23
⫺2.34
⫺2.3
⫺7.78
⫺0.97
⫺2.0
⫺2.9
0.06
0.35
⫺5.31
⫺2.32
0.05
⫺4.76
⫺0.5
0.03
⫺0.97
⫺1.79
0.05
⫺2.32
⫺2.32
⫺1.46
33/F
35/F
39/F
43/F
2.2/M
3.2/F
4.7/M
3.9/M
4.9/M
6.4/F
6.8/M
8.6/F
10/M
11/M
13/F
16/F
16/F
16/M
18/M
18/M
19/M
21/F
24/F
29/F
35/F
49/F
20a
21a
22a
23a
Group 2
24a
25a
26a
27a
28a
29
30a
31a
32a
33
34a
35a
36a
37a
38
39
40
41
42
43a
44a
45a
N
N/A
N/A
N/A
N/A
N/A
Low
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Low
Low
N/A
Low
Low
Low
Low
Low
Low
N
Low
N
N
N
N
N
N
Low
Low
N
N
N
N
IGF-I
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N
N
N/A
N
Low
N
N
N
Low
N
N
N
N
N
N
N
N
Low
Low
N
N
N
N
IGFBP-3
N/A
N/A
N/A
N/A
N/A
N
N/A
N/A
N/A
N/A
GHD
GHD
N/A
N/A
N/A
N/A
N/A
N/A
GHD
N
N/A
N/A
N/A
N
N/A
GHD
GHD
N/A
N/A
GHD
N/A
N
N
N/A
N
N/A
N/A
N/A
GHD
N
N
N/A
N/A
GH
N/A
N
N
Absent CC,
SP
N
N/A
N/A
N/A
N/A
N/A
Vascular
abnormality
N
N/A
Absent CC,
SP
N/A
N/A
N/A
N/A
N
N/A
N/A
N/A
N
N
N
Intracranial
lipoma
Thick stalk
of pituitary
N/A
N
NA
N
N/A
N
N/A
N
N
N
N/A
N/A
N
SOD, PSIS
N
Absent SP
N
N/A
Brain image
N
N
N
N
N
DM
Hyperglycemia
N
DM
Glucose intolerance
N
N
N/A
N/A
N/A
Hyperglycemia
N
N/A
N
Glucose intolerance
N
N
N
N
N
IR, hyperglycemia
IR, DM
N
IR
N
N
N
N
IR, glucose intolerance
N
IR, hyperglycemia,
glucose intolerance
IR, hyperglycemia
IR
N
IR, DM
N
N
IR, glucose intolerance
N
IR, hyperglycemia
Glucose/insulin abnormal
N/A
Hypogonadism
N/A
N/A
N
N/A
POF
POF
Primary amenorrhea
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
POF
POF
POF
POF
Hypogonadism
N
POF
POF
POF
N
Primary amenorrhea
N
N
N
N
N
N
Hypogonadism
N/A
Primary ovarian failure
N
N
N
Gonadal function
Low HDL
Hypogenitalia
Low HDL
Obese, delayed puberty
Normal
High triglycerides
Overweight, low HDL, osteoporosis
Normal
Hypogenitalia, delayed bone age
No report
No report
No report
At risk for overweight
Overweight, no other report
At risk for overweight, no other
report
No other report
At risk for overweight, low HDL
Hypogenitalia
Hypogenitalia
No abnormality
Hypogenitalia
Hypogenitalia
High LDL, delayed bone age
Prepubertal, high LDL
No other abnormality
No abnormality
Overweight, low HDL, bone age
advanced
Normal endocrine
No abnormality
Hypogenitalia
Normal endocrine
Osteopenia
Low HDL, osteoporosis
High LDL
Osteopenia
Hypogenitalia, high triglycerides,
osteopenia
Low HDL
Obese, high LDL, osteopenia
Overweight, osteoporosis
Overweight, high LDL, low HDL,
osteopenia
Obese, high LDL, triglycerides,
hypogenitalia, osteopenia
Osteopenia
Osteoporosis
Overweight
Osteoporosis, low HDL
Other abnormalities
J Clin Endocrinol Metab, July 2007, 92(7):2624 –2631
Patients 4 and 29; 7, 34, and 42; 13 and 39; 15 and 35; 23 and 43 are siblings; patients 16 and 17 are identical twins. CC, Corpus callosum; DM, diabetes mellitus; IR, insulin
resistance; N, normal; N/A, not available; SP, septum pellucidum; SOD, septo-optic dysplasia; POF, premature ovarian failure.
a
Any endocrine abnormality and/or short stature.
N
⫺4.55
33/M
19a
Hypo
N
Hypo
Hypo
⫺2.93
⫺1.96
⫺2.8
⫺4.93
27/M
28/F
28/F
30/F
15a
16a
17a
18a
Hypo
N
N
N
N
Thyroid
N
N
Hypo
N
N
N
N
N
Hypo
14/M
15/F
16/M
16/F
18/M
18/M
18.5/M
21/F
22/M
6
7a
8a
9
10a
11
12a
13
14a
⫺5.24
⫺3.5
⫺2.64
⫺0.53
⫺0.73
Height
SDS
0.05
⫺2.09
⫺0.89
⫺0.71
⫺4.86
⫺1.2
⫺1.79
⫺0.99
0.78
6/F
9.3/F
9.7/F
9.8/F
9.9/F
Age(yr)/
Sex
Group 1
1a
2a
3a
4
5a
Patient no.
TABLE 3. Summary of endocrine and metabolic findings, brain imaging, and BMD
2628
Giri et al. • Endocrine Abnormalities in Fanconi Anemia
Giri et al. • Endocrine Abnormalities in Fanconi Anemia
J Clin Endocrinol Metab, July 2007, 92(7):2624 –2631
2629
FIG. 2. Brain MRI of a 6-yr-old girl (patient 1 in
Table 3). A, Coronal T1-weighted image showing
absent septum pellucidum and squaring of frontal
horns (shown by the arrows). B, Sagittal precontrast T1-weighted image of the pituitary: the distal segment of the pituitary stalk is missing (as
shown by the top arrow), the proximal segment of
the stalk is hyperintense due to ectopic location of
the posterior pituitary, and the pituitary gland is
small and atrophic (bottom arrow). Photograph
and legend provided by Nicholas Patronas, M.D.,
Diagnostic Radiology Department, National Institutes of Health.
dysfunction: we observed that 73% of the subjects in our
series of 45 FA patients had one or more endocrine abnormalities. Only one previous report has focused on FA-related
endocrine findings (10), and it yielded findings that were
complementary to ours. Our study, which was performed as
part of a comprehensive evaluation of FA patients, included
a larger proportion of patients older than age 16, and, therefore, the overall age (median ⫽ 16, mean 21.2) was higher
than that reported by Wajnrajch et al. (10) (median not available, mean ⫽ 8.6), who specifically recruited FA patients for
an endocrine-based clinical research protocol. We report, for
the first time, abnormalities in lipid profile and BMD in FA.
These findings are of particular importance because many of
these abnormalities are both potentially a source of substantial morbidity and a treatable opportunity to minimize a
significant component of FA-related illness, important aspects of this rare syndrome that are not widely appreciated.
In our study, 13 of 14 patients in whom GH was measured
were short, and the seven with confirmed GHD were significantly shorter than those with normal GH. Our results
differ from those of others, in which height SDS did not differ
between the GH-deficient and the GH-sufficient patients
(10). In general, the incidence of short stature in FA is estimated as more than 50% (2, 10), and several case reports have
specifically implicated GHD as the cause (5–7, 9, 24 –27). It
should be pointed out that, unlike in other studies, prepubertal patients in our cohort were primed with sex steroids,
and hypothyroidism was corrected before GH testing. IGFBP-3 was low in three of four patients with GHD, and none
of five with normal GH. IGF-I was less useful diagnostically;
it was low not only in four of four with GHD, but also in two
of five GH-sufficient patients.
Four of the seven patients in our cohort with GHD had
midline brain anomalies on MRI, only one of which was PSIS
(Fig. 2). Dupuis-Girod et al. (26) reported five patients with
FA and PSIS, and suggested that the latter is a diagnostic
marker of GHD and severe growth failure. Although a recent
study reported small pituitary in seven of 11 patients with FA
(28), we found a small pituitary in only one patient (with
PSIS); in all others the pituitary size was normal to
low-normal.
DNA repair abnormalities in FA may also contribute to
growth failure; most patients with FA have intrauterine
growth retardation (29 –31) and some patients do not respond to GH treatment as completely as one might expect (5,
9, 32). The use of steroids in FA patients potentially may
contribute to short stature, but none of our patients had
received prolonged courses of glucocorticoids.
Short stature may also be a consequence of hypothyroidism, which we observed in 37% of patients studied, a prevalence similar to that reported by Wajnrajch et al. (10); all but
one had elevated TSH and normal T4 or free T4 levels, suggesting subclinical primary hypothyroidism. One patient
had low T4 and normal TSH, implying a central defect.
We observed abnormal glucose homeostasis (insulin resistance, hyperglycemia, glucose intolerance, and diabetes
mellitus) in 39% of our patients. Several factors, including
androgen therapy, iron overload, and being overweight/
obese may play a role (33, 34). Indeed, 63% (10 of 16) of those
with abnormal glucose metabolism had one or more contributing factor, including androgen therapy (n ⫽ 5), hemosiderosis (n ⫽ 2), and overweight/obesity (n ⫽ 7). However,
in 37% (six of 16), no cause could be identified. Abnormal
glucose metabolism may be an intrinsic manifestation of FA
homozygosity or the heterozygous carrier state, possibly related to the underlying genetic abnormality (35, 36).
Hypogonadism and other reproductive abnormalities
were present in 65% of our patients, consistent with previous
data (8, 37, 38). Reduced fertility has been reported in FA
animal models, with female and male mice showing follicular loss and reduced spermatogenesis, respectively (39, 40).
The limited histological data available from the gonads of FA
patients (41) suggests the presence of both a primary gonadal
defect and hypothalamic/pituitary dysfunction as the basis
for reduced fertility.
The very high prevalence of osteopenia and osteoporosis
represents a unique finding in our series, because there are
no prior reports of diminished BMD in patients with FA. In
2630
J Clin Endocrinol Metab, July 2007, 92(7):2624 –2631
fact, one of our first FA patients (not included in this study)
had bilateral Colles fractures at age 32. To the best of our
knowledge, bone density has simply not been evaluated in
previous reports of the FA clinical phenotype. Hypogonadism, a known risk factor for diminished BMD, was present
in 75%. A recent report has suggested that chronic anemia in
the elderly is associated with osteopenia and osteoporosis,
perhaps on the basis of hypoxemia (42). Thus, the anemia of
FA may be an underappreciated contributing factor.
Our study was limited by its relatively small sample size,
the cross-sectional nature of the data, and the fact that information was collected retrospectively in approximately
half of the cohort. Had we been able to directly examine all
45 subjects, it is likely that additional subclinical abnormalities would have been detected. Thus, the true prevalence of
endocrine abnormalities may in fact have been underestimated. A larger cohort with prospective follow-up will be
required to more accurately estimate the frequency of the
various endocrine disorders reported herein. Nonetheless,
this is the first series that has comprehensively evaluated
multiple endocrine parameters in both pediatric and adult
patients with FA, and our study confirms that endocrine
dysfunction is highly prevalent when carefully sought. Many
of the endocrine disorders to which FA patients are susceptible (e.g. GHD, hypogonadism, glucose intolerance, hypothyroidism, dyslipidemia, osteopenia) have the potential for
causing significant morbidity, including a major adverse effect on quality of life, but effective treatment exists for each
of them. Our study emphasizes the importance of periodic,
meticulous endocrine evaluation for patients with FA, to
optimize preventive and therapeutic interventions.
Acknowledgments
We thank Nicholas Patronas, M.D., and John Butman, M.D. (National
Institutes of Health Clinical Center, Department of Diagnostic Radiology), for reviewing brain and pituitary/hypothalamic imaging; Mark H.
Greene, M.D., for helpful discussions and comments; Sara Khaghani for
assistance with Fig. 1; Lisa Leathwood (research nurse) and the Westat
Research Staff for their invaluable help in coordinating the IBMFS study;
and all the FA participants who made this work possible by enrolling
in the IBMFS study.
Received January 18, 2007. Accepted March 30, 2007.
Address all correspondence and requests for reprints to: Neelam Giri,
M.D., Clinical Genetics Branch, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, 6120 Executive Boulevard EPS/
7024, Rockville, Maryland 20852. E-mail: [email protected].
This research was supported by the Intramural Research Program of
the National Cancer Institute (to N.G. and B.P.A.) of the National Institutes of Health by Contract N02-CP-11019-50 with Westat, Incorporated, and in part, by the National Institute of Child Health and Human
Development (to D.L.B. and C.A.S.) and National Institutes of Health
intramural project Z01-HD-000642-04 to C.A.S.
Disclosure Statement: The authors have nothing to disclose.
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