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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-0135
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2624-2631
Copyright © 2007 by The Endocrine Society

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

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: girin{at}mail.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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%), midline 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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
FANCONI 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, and hypogonadism (5, 6, 7, 8, 9, 10). However, only one prior cross-sectional 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
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

This report includes 45 patients with FA (Table 1Go). 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/µl, or platelet count less than 140,000/µl 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.


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  		TABLE 1. Clinical characteristics of 45 FA patients

 
Anthropometric measurements

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 µg/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 overnight 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 µg/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.

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 (≥7.0 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).

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 µg/kg to a maximum dose of 250 µg 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 µg/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 µg 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.

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
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
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. 1Go). 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 2Go): mean height SDS –2.7 ± 2.0 vs. –1.3 ± 1.4, respectively (P = 0.01).


Figure 1
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  		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.

 

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  		TABLE 2. Height SDS and endocrine abnormality

 
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 3Go).


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  		TABLE 3. Summary of endocrine and metabolic findings, brain imaging, and BMD

 
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 2Go). 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 µIU/ml (range 4.5–14; normal 0.4–4.0 µIU/ml). Fourteen percent (five of 35) had subclinical hypothyroidism: median TSH 7.12 µIU/ml (range 4.68–7.97 µIU/ml). T4 levels were normal with a median value 7.7 µg/dl (range 7.0–11.4; normal 4.5–12.5 µg/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 –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 2Go).

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-OH-vitamin-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 (≤18 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. 2Go); and the fifth patient had a thickened pituitary stalk. Pituitary and brain MRI were normal in all other patients.


Figure 2
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  		FIG. 2. Brain MRI of a 6-yr-old girl (patient 1 in Table 3Go). 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.

 
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 dual-energy 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
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
FA, the leading cause of inherited aplastic anemia, is associated with a high frequency of short stature and endocrine 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, 6, 7, 9, 24, 25, 26, 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. 2Go). 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, 30, 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 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. 1Go; 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.


   Footnotes
 
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.

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.

Received January 18, 2007.

Accepted March 30, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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