Endocrine Disorders in Fanconi Anemia: Recommendations for Screening and Treatment

Abstract

Context:

Endocrine problems are common in patients with Fanconi anemia (FA). About 80% of children and adults with FA have at least one endocrine abnormality, including short stature, GH deficiency, abnormal glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. The goal of this report is to provide an overview of endocrine abnormalities and guidelines for routine screening and treatment to allow early diagnosis and timely intervention.

Evidence Acquisition:

This work is based on a comprehensive literature review, including relevant articles published between 1971 and 2014, and proceedings of a Consensus Conference held by the Fanconi Anemia Research Fund in 2013.

Evidence Synthesis:

The panel of experts collected published evidence and discussed its relevance to reflect current information about the endocrine care of children and adults with FA before the Consensus Conference and through subsequent deliberations that led to the consensus.

Conclusions:

Individuals with FA should be routinely screened for endocrine abnormalities, including evaluation of growth; glucose, insulin, and lipid metabolism; thyroid function; puberty; gonadal function; and bone mineral metabolism. Inclusion of an endocrinologist as part of the multidisciplinary patient care team is key to providing comprehensive care for patients with FA.

Fanconi anemia (FA) is a congenital syndrome associated with anomalies of hands/thumbs/radii, heart, kidneys, trachea, and ears and caused by mutations in the genetic complex required for repair of DNA breakage (1). Most FA patients develop bone marrow failure during childhood, requiring hematopoietic cell transplantation (HCT). In addition, patients with FA have a lifelong risk for cancer.

Both FA and its treatment can affect the endocrine system. Patients with FA are usually shorter than the general population and do not achieve their target heights. Short stature may be due to reduced GH secretion, hypothyroidism, or abnormal glucose homeostasis with deficient pancreatic β-cell insulin secretion and/or insulin resistance. Puberty, gonadal function, and fertility may be abnormal. Children with FA usually have bone mineral density (BMD) Z-scores within the expected range for age when adjusted for short stature, but lower than average. Adults with FA have been reported to have osteopenia or osteoporosis. The goal of this report is to provide an overview of endocrine abnormalities and guidelines for routine screening and treatment to allow early diagnosis and timely intervention.

Short Stature

About 60% of FA patients are shorter than the reference population, with average height SD of −2.2 for children and −2.0 for adults (corresponding to about 150 cm in women and 161 cm in men) (2–4). However, some individuals with FA have normal height, and 10% have height even above average compared to the general population (2). Etiology of short stature in FA is multifactorial, including endocrine and nonendocrine causes.

FA patients with hormone deficiencies (GH deficiency [GHD], hypothyroidism, or hypogonadism) are shorter (average height SD, −2.2) than those with normal hormone production (average height SD, −1.0) (2, 4). However, short stature in FA cannot be explained by endocrine deficiencies alone. Even FA individuals without endocrinopathies tend to be short, with about half being below normal. Thus, hormonal replacement therapy may not always normalize growth.

Certain FA mutations associate with short stature. For example, patients with the IVS4 mutation of FANCC have average height SD of −4.3 (4). Average birth weight in FA is −1.8 SD, with half of FA children born small for gestational age (SGA) (2). In general, 90% of SGA children catch up to normal height. In contrast, in FA only 25% of SGA children catch up to normal height (2). Median height SD in FA SGA is −2.6, compared to −2.0 after appropriate for gestational age birth (2). Medications used in FA such as androgens (to promote red cell generation) may affect growth and bone maturation and impair adult height (5, 6). Although low-dose androgens used in constitutional delay improve growth, androgens have the potential to accelerate epiphyseal maturation, mediated by aromatization of T to estrogen (7, 8). Some medications (eg, corticosteroids to suppress graft-vs-host disease) or radiation therapy used during HCT may affect thyroid or gonadal function and impact longitudinal growth. In addition, total body irradiation used in preparation for HCT directly impacts spinal growth potential (9).

Screening for growth failure

Growth should be closely monitored in FA children, and nutritional/medical causes for poor growth should be identified early. Children with height SD ≤−2.0 or a decline in growth velocity should have assessment of GH and thyroid hormone secretion, pubertal status, and a bone age (BA) radiograph (Table 1). Adult height prediction using BA may overestimate height in FA because the algorithm assumes continued healthy growth, optimal nutrition, normal hormone secretion, and normal timing of puberty, assumptions not necessarily correct in FA. Androgen therapy accelerates BA, whereas hypothyroidism, GHD, hypogonadism, and corticosteroid therapy delay BA. Although midparental height can predict adult height of healthy children, this prediction is usually not helpful in FA. Despite parents' heights being similar to the general population (2), FA children are shorter than average, suggesting that growth impairment is an inherent feature of FA.

Table 1.

Endocrine Screening in FA

	Annual Screening for All	Detailed Testing in Some Patients
Growth	Height, weight, review of growth chart, BMI monitoring, assess Tanner stage, and nutritional intake	For growth failure: · IGF-1, IGFBP3 · BA radiograph · FT4, TSH For suspected GHD: · GH stimulation tests · Pituitary MRI if there is evidence of any pituitary hormone deficiency
Glucose, insulin, and lipid metabolism	Home glucometer testing with pre-meal and 2-h post-meal glucose levels, HbA1c (after HCT), fasting lipid profile (after age 10 y), blood pressure	If patient is overweight/obese or hyperlipidemic: 2-h OGTT If patient had previous abnormal OGTT but is not diabetic: repeat OGTT yearly
Thyroid	Height, weight, early morning TSH, FT4	For suspected central hypothyroidism: determine ratio of 8 am TSH to afternoon TSH
Cortisol		If there is evidence of other pituitary hormone deficiency or pituitary abnormality on MRI: administer low-dose ACTH stimulation test
Puberty and gonadal function	Pubertal staging; assess menstrual history and clinical evidence for hypogonadism (after usual age of start of puberty)	If there is early/delayed puberty or suspected hypogonadism: · BA radiograph · LH, FSH, E2, and AMH (females), T and inhibin-B (males)
Bone mineral metabolism	25OHD level; assess dietary calcium and vitamin D intake	Consider DXA scan for BMD: · Every 5 y starting at age 14 y if no prior HCT · Before HCT and 1 y after HCT · Repeat in 1 y if low BMD · Every 2 y if hypogonadism or premature ovarian failure

Abbreviations: AMH, anti-Müllerian hormone; FT4, free T₄; 25OHD, 25-hydroxyvitamin D; HbA1c, glycosylated hemoglobin.

Recommendations for treatment

Treatment of growth failure or short stature requires identification of underlying causes. Specific hormone therapy is discussed below.

GH Deficiency

Case reports have described GHD in FA (10–14). FA children show reduced overnight spontaneous (4) and stimulated GH secretion, with 54% failing the GH stimulation test after clonidine and 72% after arginine (4). Peak GH response to stimulation is also delayed. Using more stringent criteria for GHD (GH peak ≤ 5 μg/L) and without sex steroid priming, 12% tested as GH deficient (2). GHD was more common after HCT compared to those without HCT (25 vs 8%) (2). Thus, results suggest that some FA children have classical GHD, whereas others may have hypothalamic dysfunction leading to “partial” GHD.

Screening for GHD

Screening for GHD in a short child with slow growth includes measurement of IGF-1 and IGF-binding protein 3 (IGFBP3) (Table 1). If IGF-1 and IGFBP3 are <−1 SD for age, evaluation should include standard GH stimulation testing (15). IGF-1 is known to be a poor marker of GHD in undernutrition or after total body irradiation or cranial radiation. Sex steroid priming should be considered before GH stimulation testing in prepubertal girls ≥10 years of age or in prepubertal boys ≥11 years of age (16, 17). GH stimulation tests include clonidine and arginine, or glucagon (17–19). GH peak is considered normal if it is >10 ng/mL (20). FA patients with GHD should undergo pituitary magnetic resonance imaging (MRI) scan and evaluation for central hypothyroidism and ACTH deficiency.

Safety and efficacy of GH

One study has described the efficacy of GH treatment in four FA children with GHD after HCT (21). Mean age at FA diagnosis was 7.0 ± 1.9 years, at HCT was 8.7 ± 2.2 years, and at the start of GH treatment was 10.7 ± 1.8 years. GH dose was 0.28 ± 0.03 mg/kg/wk, and duration of treatment was 2.4–6.6 years. GH treatment was well tolerated and resulted in an increase in height SD of at least 0.5 in 75% of patients. Mean increase in height SD was 0.9 ± 0.6, with no adverse events.

The long-term risk of GH treatment in FA patients is unknown; therefore, continued surveillance is needed. FA patients are inherently at increased risk of malignancy, including acute leukemia (particularly before HCT), head/neck cancers, and genitourinary cancer (22–24). Although HCT reduces the risk for leukemia, FA patients have increased risk for solid tumors. No data suggest that cancer risk is further increased in FA patients treated with GH. GH registries have provided useful safety and efficacy data on the use of GH in the general population and in cancer survivors, but they include few subjects with FA (25–31). In a large longitudinal study of over 12 000 cancer survivors, including 330 treated with GH, there was no increased risk of cancer recurrence with GH (31–33). The risk for a second neoplasm (mostly solid tumors) was slightly increased in survivors treated with GH, although the relative risk was declining with follow-up (33). Other studies have shown no increased risk of cancer recurrence (34–36). Some found no increase in second neoplasias (36, 37), whereas others found continuing concern (34, 35, 38). A few studies raised concerns about vascular health, including heart disease and stroke (39–41), particularly with higher GH dosing. Other studies have suggested no association of GH therapy with stroke risk (36, 42–45).

Recommendations for treatment

GHD is treated with recombinant human GH according to published guidelines (46). Physicians should counsel FA families as to the risks and benefits of therapy. A short child with FA can be treated with GH if GHD has been convincingly documented (short stature, slow growth rate, and low stimulated GH peak). GH treatment in the absence of GHD is controversial in FA, with no consensus on safety of GH therapy in FA patients. However, severe short stature may have a negative impact on quality of life and daily functioning. In the absence of long-term safety data in the FA population, GH therapy in FA patients should be titrated to achieve IGF-1 concentrations in the mid-normal range for age (between 0 and 1 SD). Therapy should be discontinued immediately if routine hematological examination reveals clonal hematopoietic stem cell proliferation. GH therapy should also be temporarily discontinued before HCT and for at least 6 months afterward, as well as during critical illness (47).

Undernutrition and Low Body Mass Index (BMI)

BMI is normal in about half of FA patients but may range from low to high (2–4). Median BMI SD is −0.2 in children (−3.3 to +5.0 in males; −2.6 to +6.0 in females), and −1.0 in adults (−2.8 to +2.0 in males; −2.7 to +3.2 in females) (2). About 22–38% of FA patients have low BMI (2, 3). Although low BMI correlates with short stature (2), height SD is affected to a much greater degree, indicating that undernutrition is not sufficient to account for the short stature in FA (2, 4). Factors contributing to poor weight gain include increased caloric requirements, decreased intake due to chronic illness or gastrointestinal causes, and insulin deficiency/hyperglycemia (48). SGA is associated with a nonsignificant trend of lower median BMI SD compared to those born appropriate for gestational age (−1.3 vs −0.5; P = .09) (2). There is no apparent relationship of HCT status or complementation group with low BMI (2).

Screening for undernutrition and low BMI

Growth, including height, weight, and BMI, should be measured and plotted on a growth chart at least annually (Table 1). Nutritional intake and gastrointestinal causes should be assessed.

Recommendations for treatment

Regular nutritional assessment and counseling are recommended to maintain normal weight and BMI, optimize growth and bone health, and reduce the risk for impaired glucose tolerance, diabetes, and metabolic syndrome. Any underlying medical cause should be treated.

Abnormal Glucose or Insulin Metabolism

FA patients are at greater risk for diabetes mellitus than the general population (49). The prevalence of diabetes is approximately 8–10% in FA patients, whereas an additional 27–68% may have impaired glucose tolerance (2–4, 48, 50). Diabetes can occur either before or after HCT and has not been associated with an individual FA genotype. The tendency toward hyperglycemia stems from both an impairment in β-cell function and insulin resistance. The insulinogenic index, a surrogate for β-cell secretion during the oral glucose tolerance test (OGTT), is significantly lower among FA patients compared to the control population (48). About 25% of post-HCT FA patients have reduced first-phase insulin release on the iv glucose tolerance test (50). Surrogates of increased insulin resistance (eg, homeostasis model of assessment for insulin resistance; elevated insulin levels) have been demonstrated in some FA cohorts (3, 4). There is also a tendency toward both higher insulin secretion (50) and hyperglycemia (3) in FA patients who are overweight or obese. These data support the contribution of both β-cell dysfunction with impairment of first-phase insulin secretion and insulin resistance (particularly in overweight patients) to the development of diabetes. The cause of impaired insulin secretion/action in FA patients is unknown but may be related to β-cell damage due to increased reactive oxygen species generation (51), or iron overload in heavily transfused patients, or medications used in FA treatment (androgens, corticosteroids) (4, 52–54). Guidelines regarding glucocorticoid use in FA should be the same as in any other subject; ie, use the minimum necessary.

Screening for abnormal glucose and insulin metabolism

All FA patients should be tested for abnormalities of glucose and insulin homeostasis upon diagnosis. Thereafter, annual screening may be considered (Table 1). Because impaired fasting glucose is not typical in FA, screening solely with a fasting sample may fail to identify patients with impaired glucose tolerance. Likewise, fasting or random insulin measurements should not be performed to make a diagnosis of hyperinsulinemia or insulin resistance. Screening of glucose tolerance can be initially performed by home glucometer testing with pre-meal and 2-hour post-meal glucose levels. In those with suspected abnormalities and risk factors (overweight/obesity, hyperlipidemia), a more detailed evaluation should consist of a 2-hour OGTT, with samples for both glucose and insulin obtained every 30 minutes (48). Insulin levels provide a useful adjunctive data source during an OGTT but have not been demonstrated to effectively predict progression to disease. An abnormal OGTT should be reassessed to monitor for progression to frank diabetes. Glycosylated hemoglobin and fructosamine levels may be deceptively normal due to impaired glycosylation or elevated levels of fetal hemoglobin in those with bone marrow failure (2) and are therefore not helpful in FA patients before HCT.

Recommendations for treatment

All patients diagnosed with FA, regardless of OGTT results, should be placed on a healthy diet that avoids excessive intake of concentrated sweets but also provides adequate caloric, protein, calcium, and vitamin D intake. FA patients with diabetes should be treated with insulin or oral medications tailored to the cause of diabetes as in the general population. Administration of short-acting insulin with meals may be more beneficial than metformin, due to the abnormal pattern of insulin release in FA. Treatment with short-acting insulin at mealtime should be considered if postprandial glucose is consistently >180 mg/dL or in patients with impaired glucose tolerance and poor weight gain where chronic hyperglycemia may be contributing. Whether FA patients with normal fasting glucose but impaired glucose tolerance should be treated with insulin is less clear. During HCT, many children with FA require both short-acting and long-acting insulin therapy for steroid-induced hyperglycemia. Metformin may be considered in overweight individuals, accompanied by increased surveillance because there are no long-term data on the risks or benefits of metformin in FA.

Dyslipidemia and Obesity

Of 29 patients with FA that had lipid studies reported, 55% had dyslipidemia (elevated low-density lipoprotein in 21%, low high-density lipoprotein in 31%, and elevated triglycerides in 10%) (3). Dyslipidemia was associated with glucose intolerance and was observed in 40% of patients with hyperglycemia or insulin resistance. In a later report, 17% of pediatric and adult FA patients had hypercholesterolemia (2). Metabolic syndrome (defined as overweight/obesity, dyslipidemia, and insulin resistance) was diagnosed in 21% of adults with FA, whereas 50% of children tested had at least one metabolic abnormality (3). In these studies, the impact of HCT on dyslipidemia was not clear. Thus, FA patients are at increased risk for components of the metabolic syndrome independent of transplant status. The risk for cardiovascular disease in this population is currently unknown.

Screening for metabolic abnormalities

Fasting lipid profile should be considered on an annual basis in patients >10 years of age (Table 1). Screening should also include blood pressure measurement.

Recommendations for treatment

A healthy diet and exercise regimen must be optimized and emphasized.

Hypothyroidism

Many children with FA have mildly abnormal serum thyroid hormone levels, such as borderline low free T₄ or borderline elevated TSH (2–4, 55, 56). About 60% of individuals with FA have primary hypothyroidism. The mechanism of hypothyroidism in FA is uncertain, but it is usually not autoimmune in nature. It has been speculated that unrepaired DNA damage from oxidative injury may lead to thyroid cell apoptosis. Central hypothyroidism is thought to be due to hypothalamic dysfunction.

Screening for hypothyroidism

Thyroid function should be evaluated annually (or more frequently if clinically indicated) by obtaining early morning free T₄ and TSH levels (Table 1). Subclinical hypothyroidism may manifest as only TSH elevation without reduced free T₄ level. Central hypothyroidism is suggested by a low free T₄ and a normal (or low) TSH, or by a low-normal free T₄ with a TSH value that is not significantly higher at 8 am than it is later in the day (56). Individuals with central hypothyroidism should be evaluated for other pituitary hormone deficiencies and have a pituitary MRI. Although thyroid hormone binding may be reduced in FA patients, particularly during androgen therapy (4), it is not clinically significant.

Recommendations for treatment

Hypothyroidism should be treated promptly. Using a TSH cutoff >3 mU/L as a threshold for treatment of subclinical hypothyroidism may offer growth benefit for FA children (55, 57), although it remains controversial. Therapeutic target TSH in primary hypothyroidism should be <3 mU/L. In central hypothyroidism, therapeutic target should be a free T₄ just above the middle of the normal range.

Pituitary Abnormalities

FA children tend to have smaller pituitary size than the reference population (58). The reported midline brain defects include absent corpus callosum, absent septum pellucidum, septo-optic dysplasia, and pituitary stalk interruption syndrome (PSIS) (3, 14, 21, 59–61). PSIS may be associated with permanent GHD and severe growth failure (mean height SD, −4.6; range, −3.7 to −5.7). In addition, these patients are at risk for multiple pituitary hormone deficiencies, including central hypothyroidism and hypogonadotropic hypogonadism. Hypothalamic dysfunction has been reported even in the absence of a detectible midline central nervous system defect (11, 58). Cryptorchidism and microphallus are common in males with PSIS (59). An ectopic pituitary gland has been reported in a patient with FA and GHD (21).

Screening for pituitary hormone deficiencies/abnormalities

Evaluation should include assessment of GH secretion, gonadal and thyroid function, and cortisol sufficiency (Table 1). Although most FA patients have normal circadian cortisol levels and normal responses to ACTH administration (using 0.15 μg/kg of cosyntropin) (3), a low-dose (1 μg) ACTH stimulation test should be performed to evaluate for ACTH insufficiency if other pituitary hormone deficiencies or a pituitary abnormality on MRI are present. Serial endocrine testing is necessary in those with PSIS because pituitary hormone deficiencies may evolve over time.

Recommended treatment

Appropriate treatment should be instituted in patients diagnosed with any of the pituitary hormone deficiencies as described in the corresponding sections.

Puberty, Hypogonadism, and Fertility

Children with FA may have early onset of puberty. More commonly, however, they enter puberty late. Delayed puberty in FA may be due to hypothalamic-pituitary dysregulation manifesting as blunted and/or prolonged LH responses to stimulation. Chronic illness and conditioning regimen used for HCT including radiation and chemotherapy may also affect gonadal function (59). Developmental anomalies of the genital tract are more frequent in FA patients than in the general population. Boys may have cryptorchidism, hypospadias, and small testes for age and pubertal status, reflecting reduced Sertoli cell mass and spermatogenesis. Girls with FA may have a unicornuate uterus or hemi-uteri (62). Adult FA patients have a high incidence of hypogonadism. Hypogenitalism with small testes and phallus is common in men with FA (up to 64%), whereas premature ovarian failure is common in females (up to 77%) (2, 3). Both hypergonadotropic (61) and hypogonadotropic hypogonadism (60) have been reported in FA.

Fertility in FA patients is often impaired, with males often being infertile and females often having premature menopause and a significantly abbreviated window of fertility, although rare cases of fertility have been documented (62, 63). Contraception should always be considered when pregnancy is not desired. Infertility in men with FA is at least in part due to a reduced sperm count. GnRH has been shown to acutely up-regulate the expression of the FANCA mRNA and protein, suggesting that FANCA may play a regulatory role in gonadal function (64). Disruption of FANCA in mice is associated with a reduction in fertility and hypogonadism (65). Animal studies have also shown that the FANCC protein is required for the proliferation of primordial germ cells (66).

Screening for gonadal and pubertal disorders

Onset, pubertal stage, and tempo of pubertal progression should be monitored by annual physical examination (Table 1). BA assessment can be useful in adolescents with delayed or abnormal progression of puberty, whereas hormone concentrations (LH, FSH, estradiol, or T) can be useful in adolescents and in adults with symptoms of hypogonadism. Anti-Müllerian hormone tends to be low in women with FA (67); persistent low levels can be used clinically as a marker of primary ovarian insufficiency and reduced ovarian reserve. Inhibin B, which negatively correlates with FSH, can be a useful marker of Sertoli cell function in males (68).

Recommendations for treatment

In the child with FA with precocious puberty and short stature, GnRH agonist therapy can delay puberty to achieve an average of a 4- to 5-cm increase in adult height over 4 years of therapy (69). In boys with no signs of puberty by age 14 years, low-dose T therapy can be initiated and gradually titrated up over several years to adult replacement levels. In girls with no signs of puberty by age 13 years, low-dose estrogen therapy may be started and slowly titrated to adult dose. Estrogen therapy increases bone mineralization, optimizes growth rate, and induces breast development. Medroxyprogesterone should be added when breakthrough bleeding occurs or after 2 years of estrogen replacement. BA should be monitored during T and estrogen therapy. In FA, there is no medical contraindication to the use of oral contraceptive pills.

Bone Mineral Density

BMD in FA has been reported in a few studies, with differing conclusions. Osteopenia or osteoporosis has been reported in 12 of 13 adults with FA, although only two had undergone prior HCT, suggesting that some of the BMD deficits may exist before HCT (3). A more recent study also found that almost one-third of FA adults had a low BMD Z-score (<−2 SD), which correlated with hypogonadism but not with short stature (Kanakatti Shankar R, Giri N, Lodish MB, Reynolds JC, Sinaii N, Savage SA, Stratakis CA, Alter BP, unpublished data). In contrast, in 34 children and three adults with FA (including about equal numbers with prior HCT and no HCT), lumbar spine BMD Z-scores adjusted for height age were in the normal range (70). Although BMD remained within normal limits, mean 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) (70). Recent data suggest that total body BMD Z-score, but not lumbar spine BMD Z-score, is reduced in children with FA compared to healthy controls by about 0.8 SD, even after adjustment for short stature (71). We recommend that the BMD in children with FA be adjusted for height and Z-scores be calculated (72). There are limited data regarding whether BMD Z-scores in adults with FA should be adjusted for height. BMD may decrease after HCT, particularly during the first 6 months due to a decrease in bone formation and an increase in bone resorption (73, 74). Medications used during HCT (eg, glucocorticoids), hypogonadism, and GHD may all contribute to low BMD.

Screening for bone health

Yearly evaluation includes assessment of dietary calcium and vitamin D intake and measurement of serum 25-hydroxyvitamin D level (75). Dual-energy x-ray absorptiometry (DXA) evaluation of BMD is recommended before HCT and 1 year after HCT. DXA evaluation may begin at about age 14 years if there has been no HCT previously, with follow-up scans every 5 years or as dictated by risk factors (Table 1).

Recommendations for treatment

It is important to maintain adequate dietary intake of calcium and vitamin D. Supplementation should meet the recommended dietary allowance (76). The therapeutic target for vitamin D levels is 30–70 ng/mL (77). Treatment of hypogonadism and GHD is beneficial for bone mineralization. Bisphosphonates are effective in preventing bone loss after HCT in adults (78, 79), but more data are needed before a routine recommendation to treat low BMD in FA children undergoing HCT (80). Treatment with bisphosphonates may be considered (after addressing vitamin D deficiency) in a child with FA who has a height-adjusted BMD Z-score <−2.0 and has sustained clinically significant fractures defined as those that include a long bone fracture of the lower extremities, vertebral compression fracture, or two or more long bone fractures of the upper extremities (81, 82). Fracture risk in FA and the correlation with BMD measures is currently unknown. The risk/benefit ratio (83) must be evaluated by specialists before treatment because the safety profile in this patient population is currently unknown.