EVALUATION OF GROWTH

Growth should be closely followed in children with Fanconi anemia (FA) and nutritional and/or medical causes for poor growth should be identified as early as possible. Height should be measured with a stadiometer and tracked using a growth chart. Children with FA who consistently track low on the growth chart compared with the average in the general population, or whose height gradually falls to a lower percentage, indicating a decline in annual growth velocity, should be evaluated by a pediatric endocrinologist. Endocrine evaluation should include a full assessment of growth and thyroid hormones, as well as pubertal status (Table 1). Recently published disease-specific FA growth charts can be used to monitor linear growth in cFA [11]. However, these growth charts have not yet been validated for monitoring of longitudinal growth in cfA. These growth charts demonstrate that growth failure is present early in the postnatal period [11] and some children with FA will be growing below what is normal for the general population (see also below).

Short Stature

Short stature is a common characteristic of patients with FA. More than half (60%) of patients with FA are shorter than all but 2.5% of their healthy peers. In scientific terms, this means the average person with FA is two standard deviation (SD) units, or -2 SD, shorter than the average person in the general population [7]. The average height of adult female patients with FA is about 150-153 cm (4 feet, 11 inches – 5 feet), while the average adult male patient with FA is 161 – 164 cm (5 feet, 3.5 inches – 5 feet, 4.5 inches) [11]. In children considered “short” by FA standards (at least shorter than 2 SD below the average in the general population, or < -2 SD), body heights ranged from 7.8 SD to 2 SD shorter than the average in their healthy peers (median, about -3.4 SD) [4, 7, 10]. However, there are individuals with FA who have a height in the normal range, and about 1 of every 10 patients is taller than the average in the general population depending on their genetic predisposition [7]. It should be noted that although height is an inherited trait, using parental height to predict adult height of children with FA may not be helpful because their stature is influenced by their disease and associated treatments [7].

 

Endocrine Abnormalities and Short Stature

Patients with FA who have hormone deficiencies tend to be shorter than patients with FA who have normal hormone levels [7, 10]. Adult patients with FA may be even shorter if they were not treated for growth hormone (GH) deficiency or hypothyroidism as children. One study described a patient with FA who had a genetic defect in the growth hormone receptor-signaling pathway that led to low insulin-like growth factor 1 (IGF-1) and primary IGF-1 deficiency, suggesting primary IGF-1 deficiency should be ruled out if clinical features are suggestive [1]. However, it is important to note that endocrine defects are not the only possible reason for short stature. Even FA patients with healthy hormone levels tend to be shorter than average for the general population, with only about half being within the height range considered normal. As a result, hormonal replacement therapy does not always result in normal growth. This suggests that there is a skeletal component to short stature in FA. Lack of DNA repair in FA accelerates cellular senescence [12]. It is likely that accelerated chondrocyte senescence contributes to impaired growth [13]. Indeed, the skeleton may be affected early in development  like in other conditions associated with DNA repair defects [14].

Fanconi Anemia Variants and Short Stature

Certain genetic mutations are strong predictors of short stature in patients with FA, independent of hormone levels. For example, a subset of patients with the IVS4 A to T variant of the FANCC gene have an average height of 4.3 SD less than average for the general population; these patients are significantly shorter than patients with FA who have other variants [10]. In contrast, patients with variants in the FANCA gene are of similar height to patients with other FA variants [7].

Birth Size and Short Stature

Average birth weight in infants with FA is at the lower end of the normal range, typically about 1.8 SD less than average for the general population. Approximately half of all children with FA are considered small for gestational age (SGA) at birth, with length or weight about 2 SD less than average [7]. In the general population, about 90% of children who are considered SGA at birth catch up to the normal range for height. In contrast, only about 25% of FA children who are considered SGA at birth catch up to the normal range [7]. In one series, the median height of children considered SGA at birth was -2.6 SD, while the median height of children considered appropriate for gestational age at birth was -2 SD [7].

Poor Nutrition and Short Stature

Being underweight is linked with short stature in patients with FA [7]. Suboptimal nutrition may predispose children to stunted growth, or growth failure; therefore, dietary changes may be indicated for maintaining optimal growth (see Chapter 9). However, based upon condition-specific FA growth curves [11] it is normal for cFA to have low weight and BMI. Therefore, while it is important to verify adequate caloric intake and exclude malabsorption, excess calories are unlikely necessary to improve linear growth. In addition, overnutrition in an attempt to improve linear growth and weight gain may lead to excessive weight gain and elevate cardiovascular risk.

Hematopoietic Cell Transplantation and Short Stature

It remains unclear whether hematopoietic cell transplantation (HCT) directly affects growth. However, medications used to treat patients with FA, such as androgens and corticosteroids, may negatively affect growth and bone maturation, and impair adult height. Some medications or radiation used during HCT may affect thyroid or gonadal function, which in turn negatively impacts growth and adult height. In addition, total body, abdominal, or thoracic radiation used in preparation for HCT may directly influence growth of the spinal vertebrae. A limitation of condition-specific FA growth charts is that 71% of the cohort used to develop the curves had received HCT [11].

Targeted Testing for Short Stature

Determining the patient’s bone age (BA) is part of a standard endocrine evaluation for short stature and involves a radiograph of the left hand and wrist. Bone age may need to be reassessed every 1-2 years in children with FA who have short stature. The results of BA assessments are sometimes used in height prediction algorithms, wherein if BA appears younger than the patient’s actual age, then the height prediction algorithm may suggest that normal adult height will be attained over time. This prediction assumes that the child will continue to experience healthy growth, optimal nutrition, normal hormone secretion, and normal timing of puberty. However, these assumptions are not necessarily correct in FA patients. The BA X-ray is a measure of growth plate senescence and is delayed in conditions that delay senescence [13]. Accelerated cell senescence in iFA may impact the utility of BA in cFA [12]. Androgen therapy may accelerate BA, while hypothyroidism, GH deficiency, hypogonadism, and corticosteroid therapy may delay BA. Therefore, estimates of adult height based on BA may lead to over-optimistic height predictions in patients with FA. Adult height predictions should be re-evaluated after a decrease in the growth velocity or following initiation of androgen therapy and after HCT [15].

In addition to tracking the patient’s BA, GH secretion can be indirectly evaluated by measuring IGF-1 and IGF-binding protein 3 (IGFBP-3) levels. Levels of these proteins may be used to screen patients with short stature or growth failure. A thorough evaluation for GH deficiency by stimulation testing and magnetic resonance imaging (MRI) of the pituitary gland may be performed, along with consultation with a pediatric endocrinologist. MRI is an important consideration since the incidence of anatomic abnormalities of the pituitary (ectopic pituitary, pituitary stalk interruption) is increased in iFA [16, 17].

WEIGHT ABNORMALITIES IN PATIENTS WITH FANCONI ANEMIA

Approximately half of children with Fanconi anemia (FA) are born small for gestational age (SGA) [7]. In one series, infants with FA who were considered SGA were not only shorter but also were thinner than infants considered to fall within normal parameters at birth. Specifically, the average body mass index (BMI) was -1.3 SD in infants considered SGA, compared with -0.5 SD in infants considered to fall in the average range [7].

The BMIs of children and adults with FA generally are similar to those of the non-FA population, with average BMIs of -0.2 SD in children and -0.95 SD in adults. One study suggested a lower average BMI of -1.3 +/-0.2 SD in children and in a few adults with FA [10]. Other studies reported that about 25-33% of all patients with FA are thin or underweight, while a few are overweight [4, 7, 11]. The frequency of overweight in children with FA is similar to that in the general population, with a range of 11-27% depending on the group of patients studied [4, 7, 11].

In some cases, being underweight may stem from the nutritional and gastroenterological problems common in patients with FA. Some children may have less than the expected appetite; others have trouble absorbing nutrients from food (see Chapter 9). In addition, illnesses that affect FA patients can raise caloric requirements. However, as documented by condition-specific FA growth charts, low weight is an intrinsic component of FA [11]. Glucose intolerance and insulin deficiency also may contribute to poor weight gain. Excess weight gain, on the other hand, may reflect lifestyle factors and a genetic predisposition to obesity.

Evaluation of Body Weight

Body weight of FA patients should be assessed at least annually, and more frequently if there is concern about failure to thrive or excessive weight gain relative to standard norms. Recently published condition-specific FA growth charts can be used to monitor weight gain in cFA [11]. If there are concerns related to body weight, a registered dietitian should assess the patient’s nutritional intake. In addition, the primary care provider should thoroughly evaluate the patient for underlying medical conditions, concurrent medications, specific hormone-related conditions, and related co-morbidities.

Dietary Intervention for Weight Abnormalities

Healthy dietary intake should be encouraged, including sufficient calcium and vitamin D from foods or supplements. Input from a registered dietician may be needed. The underlying causes of under- or overweight should be addressed, including treatment of endocrine or gastrointestinal disorders (see Chapter 9). Since low weight is an intrinsic feature of FA, it is important to verify adequate caloric intake and exclude malabsorption but recognize that excess calories are unlikely beneficial. Related co-morbidities due to obesity should be prevented and treated, as discussed later in this chapter in the sections on abnormal glucose metabolism, lipid abnormalities, and metabolic syndrome.

ABNORMAL GLUCOSE OR INSULIN METABOLISM

Diabetes mellitus occurs more commonly in patients with FA than in the general population [18]; moreover, patients with FA have a relatively high incidence of high blood sugars without meeting criteria for diabetes, also known as impaired glucose tolerance. Studies have shown that diabetes was detected in 5-10% of patients with FA, while an additional 24-68% of these patients had impaired glucose tolerance [2, 4, 6, 7, 10]. As many as 34-72% of patients with FA had elevated insulin levels 1-2 hours after eating. Interestingly, in other studies, insulin levels in patients with FA were low 10-45 minutes after an oral glucose test, suggesting slow initial insulin secretion, but became elevated 60-120 minutes after the test [2, 6]. Although the elevated levels suggest that insulin resistance may contribute to diabetes in patients with FA and markers of insulin resistance have been demonstrated in some cohorts [4, 10], these findings also support the possibility that insulin-producing β-cells do not function properly in patients with FA, which could impair first-phase insulin secretion [2, 6]; therefore, the diabetes observed in FA is not typical for either Type 1 or Type 2 diabetes.

The cause of impaired first phase insulin secretion in patients with FA is unknown but could stem from possible damage inflicted by enhanced reactive oxygen species (ROS) on the β-cells that secrete insulin or, alternatively, from iron overload in heavily transfused patients. Insulin resistance also appears to be related to ferritin levels and oxidative stress from iron overload in FA patients [19].

Several medications used in the treatment of FA, particularly androgens and corticosteroids, are known to alter glucose metabolism. Androgen treatment can significantly elevate both blood sugar and insulin levels [10]. Chronic steroid therapy also predisposes patients to insulin resistance and hyperglycemia [20, 21, 22]. The guidelines regarding glucocorticoid use in FA patients should be the same as in any other subject: Use the lowest possible dose of medication.

Screening for Abnormal Glucose and Insulin Metabolism

All patients should be screened for abnormalities related to glucose and insulin homeostasis upon diagnosis with FA and, if possible, every year thereafter (Table 1). Patients can be screened for glucose tolerance by measuring blood sugar and insulin concentrations after fasting for 8 hours, and by measuring post-prandial blood sugar and insulin concentrations two hours after a meal. The danger of measuring only serum glucose values, or relying solely on fasting values, is that some patients may be overlooked—particularly those with impaired glucose tolerance whose blood sugar and insulin levels are normal after fasting but elevated two hours after a meal. Glycosylated hemoglobin (HbA1c) and fructosamine levels may be deceptively normal, presumably due to impaired glycosylation or elevated levels of fetal hemoglobin in patients with bone marrow failure [7].Therefore, HbA1c scores may provide more useful information after HCT compared to before HCT.

In FA patients who have suspected endocrine abnormalities and possess risk factors such as overweight/obesity or hyperlipidemia, a more detailed evaluation is needed in consultation with an endocrinologist. This evaluation should include a two-hour oral glucose tolerance test (OGTT, 1.75 g glucose/kg body weight, maximum dose 75 g glucose). Some clinical centers obtain serum samples to measure blood sugar and insulin levels every 30 minutes during a two-hour OGTT. Patients with abnormal OGTTs must be followed at least annually with repeat testing. The prevalence of diabetes mellitus in patients with FA increases with age and disease progression, and the majority of FA patients may be at risk.

Table 1. Endocrine screening recommendations for patients with Fanconi anemia.

DYSLIPIDEMIA AND OBESITY

Patients with FA are at risk for lipid abnormalities, obesity and metabolic syndrome. Unhealthy levels of cholesterol and triglycerides, a condition known as dyslipidemia based on standard diagnostic criteria, were reported in 38% of 80 FA patients (median age 18.36 years, range 5.76-42.59 years) in the National Cancer Institute cohort [26]. In another study of 29 patients with FA, over half (55%) had dyslipidemia. Of these patients, 21% had elevated levels of low-density lipoprotein (LDL), 31% had low levels of high-density lipoprotein (HDL), and 10% had elevated triglycerides TG [4]. Another study found 17% of pediatric and adult patients with FA had high cholesterol [7]. An abnormal lipid profile was observed in 40% of patients with hyperglycemia or insulin resistance. Of the patients with FA and diabetes, 75% were overweight or obese. Adults with FA and diabetes tended to be overweight or obese, compared with those without these metabolic abnormalities. About 1 in 5 (21%) adults with FA were diagnosed with meta­bolic syndrome, a condition in which patients are overweight/obese, have dyslipidemia, and develop resistance to the effects of insulin. Half of the 24 children tested had at least one metabolic abnormality, including 4 children with insulin resistance, 1 with diabetes, and 7 with dyslipidemia [7]. Healthy diet, a regular exercise regimen, and careful screening for blood pressure and lipid abnormalities are recommended to reduce the risk for metabolic syndrome.

Lipid abnormalities in FA patients treated with anabolic steroids have not been systematically studied but anabolic steroids are known to develop an atherogenic lipid and lipoprotein profile with markedly decreased HDL levels and increased LDL characterized by atherogenic small LDL [27]. Advanced lipoprotein particle analysis looking at the individual lipoprotein particles was applied for the first time in this study and found considerable variability with LDL size at 21.1 nm (19.3-21-5 nm) and LDL particle number was elevated (median 1265 nmol/L, range673-2449 nmol/L) suggestive of future atherosclerosis. Eighteen FA patients with a median age of 18 years on no treatment who served as a control group in this study had a median total cholesterol 166 mg/dL, LDL 95 mg/dL, HDL 49 mg/dL, and TG 62 mg/dL. Future studies are also needed to show the lipid response to HCT which likely will have abnormal lipid profiles depending on the post immunologic treatment.

BONE MINERAL DENSITY

Poor bone health in Fanconi Anemia is largely characterized by low bone mineral density (BMD) on dual energy X-ray absorptiometry (DXA) imaging. Although a late finding of poor bone health, there is no significant evidence of an increased fracture rate (long bone or vertebral) in this population.

It remains unclear whether poor bone health/low bone mineral density is inherent to Fanconi Anemia or largely due to its associated therapies such as HCT, chemotherapy, or irradiation associated with transplant, and/or prolonged corticosteroid use.

While DXA imaging is used to screen for poor bone health, it can underestimate BMD in those with short stature, which is common in children/adolescents with Fanconi Anemia. To address this problem, it is recommended that the BMD of children with FA be adjusted for height and that Z-scores be calculated. An online calculator may be used to calculate the height-adjusted Z-score in children with FA [28].

Studies have shown variable results even after adjustment of bone mineral density for height, likely given variable medical history and exposure to different therapies. In 34 children and 3 adults with FA (including roughly equal numbers of patients with prior HCT and no HCT), lumbar spine BMD Z-scores adjusted for height age were in the normal range. However, while BMD remained within normal limits, the average height-adjusted lumbar BMD Z-score was lower in patients who had undergone prior HCT (-0.9) compared with those who had not had prior HCT (-0.3) [8]. Similar to the above study, in a larger group of 78 children (43 females, 17 HCT), BMD also continued to be normal when adjusted for height age [7]. However, in a smaller group, 3 of 9 children and adolescents <20 years with FA (33%) who were followed at the National Institutes of Health (NIH) had low height-adjusted BMD Z-scores (two of whom had undergone HCT) [21]. These children were older (13-18 years) and had normal height-adjusted BMD Z-score at the lumbar spine, but low values at the femoral neck; one child had vertebral compression fractures.

Bone mineral density may decrease after HCT in many patients, including those with FA, but the underlying reasons for this remain unclear [22, 23]. In a study of 49 children, including 12 with FA, BMD decreased during the first year after HCT, with the most significant bone loss occurring by six months [24]. The effects of HCT on BMD in children with FA were similar to those in children without FA. Similarly, in another study comparing bone health of 20 FA patients who underwent HCT to 13 cancer patients who also underwent HCT, the authors also did not find any significant difference in totalBMD or lumbar BMD z-scores. The reduction in lumbar BMD at six months correlated with the cumulative dose of glucocorticoids [23]. In contrast to the two prior studies, another study comparing 44 patients with FA after HCT to 74 patients who received HCT for hematologic malignancies and with 275 healthy controls found that reduced total body BMD was more prevalent in patients with FA compared to patients with hematologic malignancies [22].

While long-term prospective studies are needed to more extensively examine the mechanisms underlying decreased BMD following HCT in FA children, risk of hypogonadism and GH deficiency is high after HCT and can contribute to poor bone health. In a retrospective review of 45 patients with FA who underwent HCT, 92% of the patients 18 years and older had osteopenia/osteoporosis and 75% of them also had hypogonadism [4]. Additionally, in adults, HCT is associated with decreased bone formation and increased resorption, and similar mechanisms may apply in children [29]. Medications used during HCT, such as glucocorticoid therapy, also may contribute to low BMD. Long-term prospective studies should explore whether BMD declines further or recovers over time after HCT.

Screening for Bone Health

Dual energy absorptiometry (DXA) should be used to evaluate BMD in FA patients before HCT and every two years after HCT [30]. The first DXA evaluation may be performed at about age 14 if the patient has not undergone HCT, and follow-up scans should be dictated by the patient’s risk factors. Patients with FA who have hypogonadism and growth hormone deficiency should be evaluated for low BMD and treated as necessary. Levels of serum calcium, phosphorous, magnesium, and 25-OH vitamin D levels should be measured in HCT recipients and in patients with low BMD [31]. Once patients have low BMD on DXA scans, spine imaging should be obtained to evaluate for vertebral compression fractures.

Patients exposed to prolonged or high doses of corticosteroids, or who have a history of fractures, immobility, hypogonadism, or hormone deficiencies should be referred to an endocrinologist.

THERAPIES FOR BONE HEALTH

Among other dietary recommendations, it is important to maintain adequate dietary intake of calcium and vitamin D to provide the opportunity for normal bone growth and mineralization. Supplementation should meet standard recommended dietary requirements. Vitamin D levels should be targeted to achieve sufficient concentrations (>30 ng/mL) [32]. Treatment of hormone deficiency—specifically treatment of pubertal delay, hypogonadism, and GHD—is beneficial for bone mineralization.

Bisphosphonates are effective in preventing bone loss after HCT in adults and may be effective in improving the BMD in HCT-recipient children as well, but more studies are needed before a routine recommendation can be made regarding their use for the treatment of low BMD [33]. Experienced endocrinologists or nephrologists may consider treatment with bisphosphonates in children with FA who, sustain two or more low-impact long bone or one vertebral fractures and have height-adjusted BMD Z-scores lower than -2 SD. Oral bisphosphonates are not typically used in children/adolescents. The risk/benefit ratio of this treatment must be evaluated by a specialist prior to treatment.

HYPOTHYROIDISM

Many children with FA (from 30-60%, depending on thyrotropin or thyroid stimulating hormone (TSH) cut off values) have mildly abnormal levels of serum thyroid hormones, including borderline low levels of thyroxine (T4) or Free T4 (FT4), or borderline high levels of TSH [3, 4, 7, 10]. Mild hypothyroidism can occur either because the thyroid gland is abnormal and cannot make enough T4 hormone (known as primary hypothyroidism) or because the thyroid gland is normal, but the pituitary gland does not make enough TSH to stimulate the thyroid (known as central hypothyroidism).

In one study looking at 120 children with FA (78 children), 61% of children and 37% of adults had thyroid abnormalities. The authors also found that after HCT, children were more likely to have mild elevations in TSH (53% vs. 48%) [7]. Another study that looked at 44 patients who received HCT for FA found that younger age at HCT was a risk factor for thyroid dysfunction, which developed in 57% of patients [22].

The mechanism causing hypothyroidism in FA patients remains unclear, but there is no indication that the primary hypothyroidism stems from an autoimmune process, in which the body mounts an immune attack against itself. Therefore, the thyroid appears to fail for other reasons in patients with FA. Hypothetically, some thyroid cells may die because of unrepaired DNA damage stemming from oxidative injury. Additionally, primary and central hypothyroidism can be due to the negative effects of radiation and chemotherapy on the thyroid,  hypothalamus and/or pituitary gland.

Thyroid Evaluation

Thyroid function should be evaluated by obtaining an early morning (e.g., 8:00 am) blood sample and measuring FT4 and TSH levels. All FA patients should undergo screening for hypothyroidism once a year; or more often if clinically indicated. One example would be if the patient shows signs of growth failure (Table 1). Central hypothyroidism is suggested by low levels of FT4 and by a TSH ratio of less than 1.3 at 8:00 am compared to afternoon TSH [23]. Patients who are diagnosed with central hypothyroidism should undergo evaluation for other pituitary hormone deficiencies; specifically, the physician should rule out central adrenal insufficiency and consider ordering a pituitary MRI.

TREATMENT OF HYPOTHYROIDISM

Hypothyroidism should be treated promptly, particularly in children younger than 3 years of age. Thyroid hormone therapy should strive to reduce TSH levels to the range of 0.5-2 mU/L in patients with primary hypothyroidism. In central hypothyroidism, therapy should aim to raise FT4 levels to just above the middle of the normal range.

There is ongoing controversy about the use of TSH levels greater than 3 mU/L as a threshold for the treatment of mild primary hypothyroidism [23]. Some endocrinologists may use a TSH level of 3 mU/L, or even 4.5-5 mU/L, as the upper limit of a normal TSH level in healthy individuals. However, treatment, especially in adults, is often not considered necessary unless TSH levels are persistently 10 mU/L or higher, or unless FT4 levels are low [34, 35, 36]. Among pediatric endocrinologists, some use the above approach, while others prefer to treat mildly elevated TSH levels in the hopes of improving their patients’ growth [23].

In one study of 45 children with Fanconi Anemia, the authors found that the median height SDS of hypothyroid patients was lower than that of the euthyroid patients [4]. Similarly, in another study of 63 children with Fanconi Anemia, 63% of patients had borderline thyroid tests and were also noted to be significantly shorter than those with normal thyroid function [3]. In this same study, eight children with FA were treated for seven months with thyroid hormone and for seven months with placebo; the treatment and placebo phases occurred in random order. Children grew significantly better on thyroid hormone than on placebo, and parents reported that their children had better energy levels during the thyroid hormone phase [3]. This study suggests that children with FA who have short stature and borderline results on thyroid function tests may benefit from using thyroid hormone therapy; however, it should be noted that only a small number of patients were studied over a short duration, and it is unknown whether this would translate to improved adult height.

GROWTH HORMONE DEFICIENCY

Growth hormone deficiency (GHD) has been described in case reports of a few patients with Fanconi anemia (FA) [37, 38, 39, 40, 41]. In one study, more than half (54%) of patients younger than 20 years failed to produce growth hormone (GH) in response to clonidine, a medication known to stimulate GH. Similarly, most patients (72%) failed to raise GH levels in response to another GH stimulator, arginine. Using a more stringent criterion for diagnosing GHD (specifically, peak GH levels < 5 mcg/L), but without priming the patients in advance, 12% of 32 children tested had GHD and nearly half of them had a small pituitary gland on MRI [7]. In studies from other centers, nearly half of the patients evaluated for GHD had low GH levels [10]. One in five patients with suspected GHD had a midline defect on the brain MRI [4]. Growth hormone deficiency was more common in patients who had undergone HCT (25%) than in patients who did not have HCT (8%) [7]. The processes that underlie secretion of GH may be abnormal in children with FA during spontaneous overnight GH secretion studies [10], although these results are sometimes difficult to interpret because of the significant overlap with values observed in children without GHD [7]. Taken together, these test results suggest that while few children with FA have GHD, others may have an underactive hypothalamus, leading to “partial” GH deficiency or, alternatively, to neurosecretory GH deficiency. In these individuals, GH and insulin-like growth factor 1 (IGF-1) values may not be as severely affected as the patient’s height. Ectopic posterior pituitary, an anatomic abnormality associated with GHD, is known to be present in up to 17% of iFA [16, 17].

Evaluation for Growth Hormone Deficiency

Screening for GHD in a child with poor growth can be performed by drawing a blood sample and measuring IGF-1 and IGFBP-3 levels (Table 2). If IGF-1 and IGFBP-3 values are below -2 SD for the patient’s age, evaluation should include standard GH stimulation testing. One caveat is that IGF-1 is known to be a poor marker of GHD in thin individuals or in those who have received total body or cranial radiation. Sex steroid priming should be considered prior to GH stimulation testing in pre-pubertal girls age 10 years and older, and in pre-pubertal boys age 11 years and older or who are in stage two of puberty [42, 43]. Evaluation of GH secretion in a slowly growing child should be done through the use of two standard GH stimulation tests, including clonidine (5 mcg/kg or 150 mcg/m2, maximum dose 300 mcg), arginine (0.5 g/kg, maximum dose 30 g), or glucagon (0.3 mg/kg, maximum dose 1 mg) [43, 44, 45]. Peak GH levels are considered normal if they rise to 10 ng/mL or greater [46], though the GH threshold varies by assay and region. Patients diagnosed with GHD should be evaluated for central hypothyroidism, central adrenal insufficiency, and also should undergo an MRI scan of the pituitary gland. If multiple pituitary hormones are deficient, particularly if an anatomic pituitary abnormality is present, a low IGF-1 may be sufficient for the diagnosis of GHD and GH stimulation testing may not be required.

TREATMENT OF GROWTH HORMONE DEFICIENCY

Patients with FA who have GHD can be treated with recombinant human GH therapy. A short child with FA is a candidate for treatment with GH if GHD has been convincingly documented by the child’s short stature, slower than normal growth rate, and low GH peak on a stimulation test. Physicians should counsel FA patients and families about the risks and benefits of therapy. To date, there is no clear consensus on the safety of GH therapy in FA patients. Though having FA is not an absolute contraindication to GH treatment, there is some controversy surrounding the use of GH in patients without GHD. It should be recognized that in some instances, treatment with GH may be instituted in the absence of GHD if deemed appropriate by the patient care team, either before or after HCT. In the absence of safety data, GH therapy in FA patients should be titrated to achieve IGF-1 concentrations in the mid-to-normal range for the patient’s age (i.e., between 0 and 1 SD). Therapy should be discontinued immediately if routine hematological examination reveals clonal hematopoietic stem cell proliferation or precursors of oropharyngeal squamous cell carcinoma such as leukoplakia or erythroplakia [47]. Growth hormone therapy should be temporarily discontinued immediately prior to HCT and for at least six months after HCT, as well as during critical illness [48].

One study found positive effects of GH treatment in 75% of children with FA treated with HCT, with at least a 0.5 SDS increase in height [49]. In studies of patients without FA, the response to GH treatment after HCT has varied [50, 51, 52, 53]. Ongoing use of glucocorticoids after HCT may limit the patient’s growth response. In a study that included HCT recipients, GH treatment was associated with significantly improved adult height (on average, patients treated with GH grew about 4-5 cm taller than untreated children) [54] and did not increase the risks of recurrent leukemia, secondary malignancies, or diabetes in post-HCT patients treated with GH compared with those who were not treated. A beneficial effect of GH treatment on growth rate after HCT also has been reported by others [55, 56].

Patients with FA are inherently at an increased risk of cancer, particularly for acute leukemia prior to HCT, as well as malignancies of the head and neck, and gynecological cancers [57, 58, 59]. At this time, there is no evidence that this risk is enhanced in FA patients treated with GH. Patient registries have provided useful safety and efficacy data on the use of GH in the general population and in cancer survivors, but have included few patients with FA [60, 61, 62, 63, 64, 65, 66]. A large study of 13,539 cancer survivors, including 361 patients treated with GH, did not find an increased risk of cancer recurrence in GH-treated survivors [67]. However, the risk of a second neoplasm, mostly solid tumors, was slightly increased in survivors treated with GH.

Three brands of long-acting GH therapy (LAGH) have been approved in the United States of America (USA) and European Union (EU) for treatment of children with GHD [68]. Each of the approved LAGH products was approved for once weekly administration based upon phase 3 clinical trial results demonstrating non-inferior one year height velocity when compared to daily GH in children with GHD and no new safety signals [69, 70, 71]. A characteristic of each LAGH that is different from daily GH is an exaggerated peak of GH and IGF-1 following each weekly LAGH injection [72]. Although the majority of children receiving the different LAGH therapies have had IGF-1 values measured within the normal range (-2 to +2 SDS), peak IGF-1 values may be above the normal range even when average IGF-1 values are in the normal range. The average IGF-1 is expected to be the best predictor of efficacy with LAGH, though it is unclear whether average IGF-1 or peak IGF-1 will be the best predictor of safety [73]. Due to the transiently higher values of GH and IGF-1 with LAGH, there is theoretical concern about the use of LAGH In cancer survivors [74]. Similar caution, including careful discussion of the risks and benefits, should be used if considering LAGH therapy in cFA.

One brand of long-acting GH therapy (LAGH) has been approved for treatment of adults with GHD [75]. Somapacitan was approved for once weekly administration based upon phase 3 clinical trial results demonstrating superior reduction of truncal fat percentage over 34 weeks when compared to placebo in adults with GHD [76]. There were no new safety signals with once weekly somapacitan compared to previous studies of daily GH. Due to the lifelong nature of GH replacement in adults with GHD, a very careful discussion of the risks and benefits of using LAGH in aFA needs to used when initiating therapy and intermittently over time. If iFA are treated with daily GH or LAGH, it will be important to monitor for safety concerns. Post-marketing patient registries, such as the Global Registry For Novel Therapies In Rare Bone & Endocrine Conditions (GloBE-Reg), will be crucial in collecting long-term safety data for individual receiving daily and/or LAGH therapy [77].

Despite the possible risks, it should be noted that severe short stature as well as severe GHD may have a negative impact on the patient’s quality of life and daily functioning. Patients and families should be coun­seled regarding the predicted adult heights, the effects of available treatment modalities on growth rate, the effects of GH replacement therapy on body composition and risks of long-term cardiovascular disease along with the potential risks and benefits of GH treatment—with the caveat that there is no clini­cal information about the long-term safety of GH therapy in patients with FA.

CORTISOL SUFFICIENCY

Most FA patients have normal circadian cortisol levels and experience normal responses to treatment with adrenocorticotrophic hormone (ACTH). ACTH stimulation testing has been normal even in patients with reported pituitary stalk interruption syndrome (PSIS) and multiple pituitary hormone deficiencies [4]. However, cortisol sufficiency should be evaluated in young children with FA who have poor growth and who require major surgery because of possible central hypothalamic dysfunction, even in the absence of a detectible midline central nervous system defect [9, 37]. ACTH stimulation testing is recommended to rule out central adrenal insufficiency if the patient has other pituitary hormone deficiencies. Following HCT, glucocorticoid medications may be used as an immunosuppressive treatment for graft versus host disease (GVHD).  Chronic exposure to glucocorticoids can result in iatrogenic adrenal insufficiency due to suppression of pituitary ACTH release.  Guidelines for chronic glucocorticoid management in excess of 4 weeks’ duration suggest consideration of a wean off treatment in order to prevent adrenal crisis before recovery of endogenous adrenal function [78]. While taking physiologic doses of glucocorticoids during a steroid wean, “stress dosing” is an important consideration during episodes of febrile illnesses, injuries, sedation events, and intolerance of enteral nutrition.  Patients receiving additional medications that are more common after HCT, such as megestrol (Megace) for the treatment of poor weight gain or ketoconazole, a fungicide, can also result in adrenal Insufficiency and should be monitored for signs of adrenal suppression and treated accordingly [79, 80].

MULTIPLE PITUITARY HORMONE DEFICIENCIES

In previous studies, MRI scans of the brain and pituitary gland have suggested that the pituitary gland is smaller and has a thinner stalk in patients with FA compared with age-matched children without FA [9, 81]. Studies also have shown midline and other central nervous system abnormalities on brain MRI [82]. Three patients with FA at the National Institutes of Health (NIH) had pituitary stalk interruption syndrome (PSIS) with or without septo-optic dysplasia. This syndrome has previously been reported in eight other patients with FA [38, 83, 84, 85], and was associated with permanent GHD and severe growth failure. Specifically, the average height SD of all the children with PSIS at diagnosis was -4.6, with a range of -3.7 to -5.7. These patients also were at risk for multiple pituitary hormone deficiencies: 5 of 10 patients with FA and PSIS had hypothyroidism, 1 of 10 patients had hypogonadotropic hypogonadism, and the remaining 4 patients were too young to evaluate. Furthermore, 5 of 6 male patients had cryptorchidism, in which one or both testicles fail to descend, and 4 of 6 male patients had microphallus. Together, these findings suggest that in addition to GHD, the male patients had hypogonadotropic hypogonadism, a condition in which the testes produce lower than normal amounts of sex hormones due to an underlying problem with the pituitary gland or hypothalamus. In two additional studies, ectopic posterior pituitary, an anatomic abnormality associated with pituitary hormone deficiencies, was reported in 7 iFA [16, 17].

Based on the available evidence, a brain MRI with emphasis on the pituitary/hypothalamic area should be obtained in any FA patient who has one or more pituitary hormone deficiencies, including GHD, central hypothyroidism, or ACTH deficiency. Serum IGF-1 testing has been proposed as a screening test, as all patients with PSIS and GHD had low IGF-1 levels [85]. Serial endocrine testing is essential in patients with PSIS and ectopic posterior pituitary because pituitary hormone deficiencies may evolve over time.

GENITAL TRACT ABNORMALITIES

Developmental anomalies of the genital tract are more frequent in patients with FA than in the general population. In a recent analysis of the distribution of genital tract anomalies in patients with FA, at least 50% of male patients may be born with one or more genitourinary anomalies, including undescended testicles (22%-27%), small or absent testes (27%-64%), small penis (30%-41%), and hypospa­dias, a condition where the urethra opens on the underside of the penis (9%-18%) [26]. Boys with FA who have small testes for their age and pubertal status, most likely have reduced Sertoli cell mass and spermatogenesis. Following HCT, testicular Sertoli cell mass can be additionally compromised by toxicity from alkylating chemotherapeutic agents used during HCT preparation.  Therefore, measurement of testicular volume in the assessment of pubertal status can be misleading and may not correlate with pubertal activity of Leydig cells as measured by serum testosterone. Female patients with FA appear to be less likely than males to have genital tract abnormalities at birth (11%-14%). More commonly seen female genital tract anomalies include underdeveloped uterus (1%-6%), small/absent ovaries (5%-6%), and additional malformations such as small birth canal, tubal abnormalities, or differences in external genitalia (1%-3%) [26, 96].

PUBERTY

Children and adolescents with FA may enter puberty earlier than their healthy peers. If puberty starts too early or progresses too quickly, it may limit the number of years a child can grow and, thus, compromise adult height. A child with FA who experiences an early onset of puberty and has short stature may benefit from gonadotropin-releasing hormone agonist therapy. One study suggests this therapy can delay puberty to increase the patient’s adult height by an average of 4-5 cm after four years of therapy [86]. More commonly, children with FA enter puberty later than their healthy peers. Studies have shown that 12-14% of girls with FA had delays in starting their menstrual cycles [4, 7]. While delayed puberty is fairly common, its underlying cause is not well understood. There may be blunted and/or prolonged gonadotropin (primarily luteinizing hormone (LH)) responses to stimulation, suggesting abnormal regulation of the hypothalamic and pituitary glands (see Chapter 7). Chronic illness also is associated with delayed pubertal maturation.

In patients with FA who receive HCT, gonadal dysfunction is quite common.  In a longitudinal study following males and females after HCT, compromised ovarian function, known as primary ovarian Insufficiency (POI), was noted in slightly more than 50% of females [87]. The same study found that slightly less than 50% of males with FA develop testicular failure following HCT [87].

EVALUATION FOR PUBERTAL DISORDERS

In patients with FA, the onset, pubertal stage, and tempo of progression of puberty should be monitored during annual physical examinations. Physical exams should include Tanner staging of pubic hair, and assessments of breast development in girls and testicular size in boys (Table 1). Assessment of bone maturation can be useful in adolescent children who experience delayed or abnormal progression of puberty, while measuring the concentrations of certain hormones (particularly LH, FSH, estradiol, or testosterone) can be useful in adolescents and in adults who develop symptoms of hypogonadism. Genotype-phenotype correlation studies of larger populations of patients with FA to date have shown a relatively high incidence of reproductive abnormalities in patients with mutations in FANCA and FANCG [26, 88]. Additional research is needed in this area to determine whether the genotype associate with FA predicts relatively better or worse gonadal or reproductive function during the lifespan of patients with FA.  Following HCT, it is critical to monitor LH, FSH, estradiol (females), and testosterone (males) to monitor for gonadal dysfunction.  Detection of gonadal insufficiency due to hypergonadotropic hypogonadism is often evident from an early/normal pubertal age (10-12 years), which can allow for the proper planning of future pubertal treatments.  Furthermore, pubertal hormone testing is considered more reliable than genital examination, especially in males, due to the compromise of testicular volume that accompany the toxic effects of alkylating chemotherapeutic agents used for HCT preparation. In addition, abnormalities of gonadal function may be seen in children with FA who have not received HCT. This Is likely due to a negative impact of impaired DNA repair leading to damage of the germ cells, sertoli cells (males) and granulosa cells (females).

TREATMENT OF DELAYED PUBERTY

A boy with FA who shows no signs of puberty by age 14 years should be evaluated for possible causes of delayed puberty. After evaluation, low-dose testosterone therapy can be initiated according to the child’s height and growth potential. Young boys with confirmed hypogonadism can be treated using topical gel preparations or by injections of testosterone started at an appropriately low dose and gradually increased over several years to adult replacement levels. It is important to avoid rapid increases in testosterone levels in adolescents to ensure continued height gain and avoid premature fusion of the growth plates. Bone age should be monitored during therapy. Testosterone replacement has been shown to benefit bone density, body composition, and psychosocial outcomes in adolescents with gonadal insufficiency [89, 90].

Similarly, a girl with FA who shows no signs of puberty by age 13 years should receive a full hormonal work up. After evaluation, low-dose estrogen therapy may be started and slowly titrated under the care of the pediatric endocrinologist or adolescent gynecologist, taking into account the child’s height and potential for growth. It is important to avoid rapid increase in estradiol levels in adolescents to ensure continuing height gain and to avoid premature fusion of the growth plates (see Chapter 7). Transdermal estrogens are preferred to avoid hepatic first pass effects with more beneficial profile on the outcomes of lipid profiles, blood pressure, and inflammation. For induction of puberty, low dose estradiol treatment can be initiated with slow titration of doses over time over a period of 18-24 months. Upon evidence of breakthrough vaginal bleeding, progestins can be prescribed to allow for endometrial protection and to achieve regular menstrual periods. In post-pubertal patients with POI, pubertal induction is not necessary, and a variety of different hormone-based regimens can be utilized depending upon the goals of treatment, which can include regular menstrual cycles, avoidance of withdrawal bleeding, and regimens that provide contraception as an additional benefit [91]. Bone age should be monitored during therapy. Estrogen therapy will increase bone mineralization, optimize the child’s growth rate, and achieve breast development. Estrogen therapy is not needed if a female patient with FA has normal pubertal development or is having normal menstrual cycles, even if there is evidence of partial ovarian hormone deficiency.

HYPOGONADISM

Hypogonadism is very common in adults with FA. In addition, hypogenitalism with small testes and penis size affects 64% of men with FA, while premature ovarian failure affects 77% of women with FA [4]. In another study, 40% of adults with FA had evidence of hypogonadism [7]. Both hypergonadotropic (either testicular or ovarian) hypogonadism [84] and hypogonadotropic (specific to the hypothalamic-pituitary glands) hypogonadism have been reported in FA patients. Gonadal function may be affected by several factors, including FA itself, SGA status at birth, gonadotropin deficiency, cryptorchidism, and/or the conditioning regimen used for HCT, including radiation and chemotherapy [85].

FERTILITY

Reproductive function and infertility are also common in FA patients with approximately fifty percent of female patients with FA with infertility and extremely few reported cases of affected males having offspring [92]. Studies have found that the deletion of FA gene is closely related to reproductive diseases, especially interference with primordial germ cells (PGCs), leading to lower ovarian reserve in females and azoospermia in males [93, 94].

Females or persons with ovaries

Female individuals affected by FA may face challenges in conceiving and maintaining pregnancies due to both the condition’s impact on their reproductive health and their reduced life expectancy [95]. Research indicates that only 15% of female FA patients conceive, a significantly reduced rate compared to the general population [96]. Pregnancy complications are also increased in patients with FA which may impact FA patients’ decision to attempt conception [96, 97].

Females with FA typically experience normal menarche but often undergo early menopause, indicating a reproductive timeline that progresses more rapidly than in non-FA individuals [98]. In these patients, reduced fertility is commonly seen as primary ovarian insufficiency (POI). The etiology of POI is often unknown even in FA patients but is due to 1) diminished ovarian follicular pool from conception, 2) accelerated loss of primordial ovarian follicles, or 3) follicular dysfunction [99, 100].

Antimullerian hormone (AMH) has emerged as a marker for POI. In females, AMH is produced exclusively by the granulosa cells of small growing follicles within the ovaries and is correlated with antral follicle count. Although AMH has not been able to predict future fecundity [101], levels can be tracked over time to monitor the follicular pool decline [102]. Sklavos et al. have demonstrated that individuals with Fanconi Anemia (FA) exhibit a unique pattern of Anti-Müllerian Hormone (AMH) levels, which are notably low or undetectable in prepubertal and post-menarchal adolescent girls and women with FA [24]. This finding underscores the potential of AMH as a valuable indicator for evaluating ovarian function in FA patients and for identifying reproductive health issues related to the condition.

In addition to the genetic etiologies increasing ovarian follicle loss, treatment for FA with HCT can increase this risk. HCT utilizes gonadotoxic chemotherapy to deplete the patient’s current HSC prior to transplant. The chemotherapy protocols, including reduced intensive conditioning or RIC regimens, have been associated with a higher risk for infertility and low ovarian reserve, which has been confirmed in FA patients [25, 87, 103]. Another significant reproductive challenge for female FA patients is the markedly increased risk of gynecological cancers [24].

Fertility Management

FA guidelines and the American Society of Reproductive Medicine recommend that providers counsel patients about fertility preservation options prior to undergoing gonadotoxic therapies [98, 104]. Given the early decline in ovarian follicle pool, fertility preservation techniques should be offered more broadly to all female FA patients upon diagnosis and not delayed until gonadotoxic therapy is planned.

Fertility preservation options include oocyte, ovarian tissue, and embryo cryopreservation. For oocyte or embryo cryopreservation, mature oocytes are retrieved following hormonal stimulation, a process that can take up to three weeks. However, this may delay gonadotoxic treatments, making it unsuitable for many patients, especially prepubertal girls. In such cases, ovarian tissue cryopreservation (OTC) is the preferred method, involving the removal and preservation of ovarian tissue for later transplantation. Although over 150 live births have resulted from OTC, most studies focus on young adults, with limited data on outcomes in younger patients [105]. ASRM removed the experimental label from OTC in 2019 but noted that data on prepubertal patients remain limited.

Ovarian tissue freezing is likely the most feasible option for most female patients, given their clinical hematological conditions. However, lower ovarian reserve may impact the success of this treatment. In less severe FA cases presenting after puberty, oocyte freezing could be an option. However, it is important to note that the efficacy of ovarian tissue or oocyte freezing in FA patients hasn’t been fully described. Studies have shown a decrease in ovarian reserve even at a young age in FA patients, potentially due to reduced number of primordial germ cells formed in fetal life. Thus, their reproductive prognosis may be compromised despite fertility preservation efforts. Patients should be referred to fertility specialists to review ovarian reserve markers, including AMH and history to discuss fertility preservation.

Other considerations with an FA patient attempting pregnancy are to have the sperm source or patient’s partner screened for the same FA genes the patient carries to provide the best counseling risk to offspring. Preimplantation genetic testing for monogenic disorders can be utilized if both parents carry FA genes. FA patients should be referred centers for managing high-risk pregnancies, as close monitoring and multidisciplinary care are warranted based upon patient age and the disease stage or progression.

Males or persons with testes

The male population affected by FA exhibits a pronounced decline in fertility. While there is limited documented evidence of males with FA fathering children, references to at least three cases have been made [92, 96]. In FA males, the clinical manifestations associated with diminished reproductive capacity manifest as abnormal and severely reduced spermatogenesis. These conditions often coincide with diagnoses of non-obstructive azoospermia and Sertoli cell-only syndrome [98, 106]. Similar to female patients, the gonadotoxic therapy for HCT is also a high risk for infertility and azoospermia in males with FA [103, 107].

Fertility Management

Semen analysis remains the gold standard for assessing male fertility but results of semen analyses typically reveal very low or absent sperm counts as well as evidence of abnormal spermatogenesis [98]. Spermatogenesis is a complex, multi-stage process influenced by various factors, including hormones like follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estradiol, prolactin, thyroid-stimulating hormone (TSH), and inhibin B. Recently, the roles of FSH and inhibin B have gained attention and maybe markers for spermatogenesis. Inhibin B, produced exclusively by Sertoli cells in the testis, is now recognized as a key marker of male fertility. It regulates FSH secretion through negative feedback and reflects the functioning of seminiferous tubules. Inhibin B could be utilized to determine if spermatogenesis is present in this patient population; however, a semen analysis is needed to determine fertility.

Fertility preservation prior to HCT would include sperm cryopreservation. Another experimental option for prepubertal boys is testicular tissue cryopreservation. However, given the genetic disruptions in primordial germ cells in FA, it is difficult to know if this procedure would preserve fertility in this population.  

ENDOCRINE ABNORMALITIES SPECIFIC TO ADULTS WITH FANCONI ANEMIA

Endocrinopathies clearly persist into adulthood, though the treatment of FA with hematopoietic cell transplant (HCT) can alter the course of disease. Early endocrine diagnosis and therapy may improve the patient’s quality of life. Treatment of endocrine issues in adults with FA should be monitored by endocrinologists who care for adults, with attention to the patient’s thyroid status, glucose tolerance, lipid abnormalities, maintenance of normal BMI, gonadal function, and bone mineral density. Thus far, results from endocrine studies have been reported only for a small number of adults with FA [4, 7, 8, 10]. With the availability of daily GH and LAGH for adults with GHD (discussed above), the risk to benefit ratio of GH replacement therapy needs to be carefully discussed with patients.

Lipid abnormalities were frequently seen in nearly 40 patients with FA who were followed at the NIH (unpublished data). More than half of the adults had one or more of the following lipid abnormalities: total cholesterol >200 mg/dL, HDL cholesterol <40 mg/dL, LDL cholesterol >129 mg/dL, or triglycerides >150 mg/dL. Insulin resistance, as determined by the homeostatic model assessment (HOMA), and metabolic syndrome also were common in adults.

Thyroid abnormalities remain prevalent in FA patients older than 18 years, with 37% to 57% of patients having hypothyroidism. These patients typically present with either elevated TSH levels or low Free T4 levels [4, 7]. In one study, a low stimulated GH peak was observed in a small number (6 of 16) of adults with FA [4, 7]. Hypogonadism with small testes was present in at least half (50%) of men with FA, and hypogonadism was present in one-third (30%) of women with FA. In addition, many women with FA experience premature menopause (see Chapter 7).

One study reported decreased BMD (osteopenia or osteoporosis) in 12 of 13 adults with FA [4]. Of the eight females with decreased BMD, seven experienced premature ovarian failure and early menopause [4]. In 15 adult female patients with FA from the same center, five (33%) had osteoporosis and all had hypogonadism, which appears to be the predominant cause of low BMD in adult female patients with FA [108]. However, the BMD was not adjusted for height in this study, and the measured BMD may have underestimated the volumetric BMD in several individuals with short stature whose bones were likely smaller than those of other participants [109]. It is not clear whether BMD in adults with FA should be routinely adjusted for height. The correlation of fracture risk with height-adjusted BMD in adults with FA also is unknown. Additionally, many FA adults have hypogonadism, other endocrine deficiencies, and have undergone HCT—all of which may adversely affect bone health and trigger the early development of osteoporosis.

MEDICATIONS AND TREATMENTS THAT AFFECT ENDOCRINE FUNCTION

Androgen Therapy

Synthetic androgen therapy, such as oxymetholone and danazol, have been used to improve the blood counts of patients with FA for more than 50 years [110]. However, androgens can cause endocrine-related side effects that need to be monitored (see Chapter 3). Androgens can improve growth rates in children, but often hasten the maturation of growth plates, which reduces the time available for childhood growth. Children treated with androgens may appear to be growing well, but their potential adult height may decline due to rapid skeletal maturation and premature fusion of cartilage plates at the end of long bones, known as epiphyseal fusion. The impact of androgen therapy on height and bone maturation should be discussed with the patient’s family. Prior to beginning androgen therapy, a bone age X-ray should be performed. During androgen therapy, the patient’s bone age should be reassessed periodically, and may be checked every 6-12 months [111]. Dyslipidemia associated with androgen therapy is an additional concern in patients with FA because androgens can cause elevated levels of low-density lipoprotein, low levels of high-density lipoprotein, and elevated triglycerides [112] (see Dyslipidemia section).

Danazol, an attenuated synthetic androgen, is currently the most commonly used androgen and produces fewer virializing effects than oxymetholone that was used in the past [113, 114]. Long-term androgen usage may lead to shrinkage and/or impaired development of the testis in males due to suppression of the hypothalamic-pituitary-gonadal axis.

Endocrine dysfunction is an important clinical concern for patients treated with androgens. Careful evaluation for endocrine-related side effects is important for the management of patients on androgen therapy.

Hematopoietic Cell Transplantation 

Transplantation is inherently associated with a state of illness. Illness is not an optimal time to assess any hormone concentrations, as illness often alters thyroid levels, growth, gonadal func­tion, nutrition, and glucose regulation. The treatments and radiation used during HCT may exacerbate the patient’s underlying intrinsic risk for endocrine disorders and lead to growth failure as a consequence of GHD, primary hypothyroidism, gonadal failure, and decreased BMD. Therefore, FA patients who undergo HCT should be closely monitored for hormonal abnormalities [30]. The late effects screening guidelines [30] recommend that a full endocrine evaluation including height/weight measurements, Tanner staging, bone age and growth factors should be assessed after HCT in children. In addition, screening is recommended for diabetes, dyslipidemia, vitamin D deficiency and osteoporosis (DXA scan before HCT and every two years after HCT). Some of these guidelines have been outlined by the Children’s Oncology Group [115]. Many agents used in HCT have side effects on the endocrine system. Busulfan can adversely affect thyroid function [116] and sometimes growth [117, 118]. It is highly toxic to gonads and can lead to gonadal failure, particularly in females [119, 120, 121]. Cyclophosphamide has a known dose-related effect on gonadal function in both males and females, particularly when used in combination with busulfan [29, 122, 123, 124]. Glucocorticoids can lead to increased appe­tite, weight gain, insulin resistance, and hyper­glycemia, sometimes creating the need for insulin therapy. Prolonged use of glucocorticoids may cause linear growth failure and delayed puberty as well as suppression of adrenal function that may necessitate a careful wean off treatment to avoid adrenal crisis. Glucocorticoids adversely affect bone mineralization [5]. Methotrexate increases the risk for bone loss [125, 126]. Total body irradiation (TBI) increases the risk of primary hypothyroidism [127, 128], growth impairment [118, 129], hypogonadism [122, 130], and poor bone mineralization [131, 132].