Endocrine profiling in patients with Fanconi anemia, homozygous for a FANCG founder mutation

Abstract

Background Fanconi anemia (FA) is phenotypically diverse, hereditary condition associated with bone marrow failure, multiple physical abnormalities, and an increased susceptibility to the development of malignancies. Less recognized manifestations of FA include endocrine abnormalities. International discourse has highlighted that these abnormalities are widespread among children and adults with FA. To date there has been no systematic study that has evaluated the endocrine abnormalities in a cohort of patients with FA, homozygous for a founder mutation (c.637_643del (p.Tyr213Lysfs*6)) in FANCG . The objectives of the study were to evaluate endocrine gland function in patients with FA of a single FA genotype, and to determine the frequency and nature of endocrine abnormalities in this group. Methods Cross‐sectional, descriptive study of 24 South African patients of African ancestry with FA (homozygous for a FANCG founder mutation). Outcomes measured included growth, pubertal status, growth hormone axis screening, thyroid gland function, glucose and insulin metabolism and bone age (BA). Results Endocrine dysfunction was present in 70.8% (17 of 24), including abnormal insulin‐like growth factor 1 (IGF‐1)/insulin‐like growth factor‐binding protein 3 (IGFBP‐3) in 25.0% (6 of 24), insulin resistance in 41.7% (10 of 24), abnormal thyroid function in 16.7% (4 of 24) and short stature in 45.8% (11 of 24). No abnormalities of glucose metabolism were identified. Abnormal pubertal status was seen in three males (12.5%). Abnormal BAs were present in 34.8% (8 of 23). Conclusion Endocrine abnormalities occur at a high frequency in patients with FA, homozygous for a FANCG founder mutation, similar to other FA cohorts. Our data are specific to FA patients with a single genotype, and therefore provide the first genotype‐phenotype information on endocrine abnormalities in South African patients, homozygous for a FANCG founder mutation. Recommendations regarding endocrine screening in this patient subgroup are made, including, but not limited to, baseline testing of thyroid function, fasted insulin and glucose, and IGF‐1 and IGFBP‐3.

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG

“…Also, the frequency of renal abnormalities (37%) was higher than reported elsewhere [42]. A second study that included 24 patients and focused in endocrinologic data, showed that 33%, 46%, and 42% had microcephaly, short stature, and low weight for age, respectively [43]. When comparing the phenotype of the three Mixe patients to the Black South African patients, in whom the genotype also leads to a truncated protein (p.Tyr213Lysfs*6), the anthropometric alterations appear to be less severe in the South African patients [43].…”

“…A second study that included 24 patients and focused in endocrinologic data, showed that 33%, 46%, and 42% had microcephaly, short stature, and low weight for age, respectively [43]. When comparing the phenotype of the three Mixe patients to the Black South African patients, in whom the genotype also leads to a truncated protein (p.Tyr213Lysfs*6), the anthropometric alterations appear to be less severe in the South African patients [43]. We take these observations with caution, both because of the small size of the Mixe cohort and the influences of environmental factors and additional loci in these multifactorial traits cannot be overlooked.…”

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG

“…Also, the frequency of renal abnormalities (37%) was higher than reported elsewhere [44]. A second study that included 24 patients and focused in endocrinologic data, showed that 33% had microcephaly, 45.8% had short stature for age and 41.7% had low weight for age [45]. When comparing the phenotype of the three Mixe patients to the Black South African patients, in whom the genotype leads to a truncated protein (p.Tyr213Lysfs*6), the anthropometric alterations appear to be more more severe [45].…”

“…A second study that included 24 patients and focused in endocrinologic data, showed that 33% had microcephaly, 45.8% had short stature for age and 41.7% had low weight for age [45]. When comparing the phenotype of the three Mixe patients to the Black South African patients, in whom the genotype leads to a truncated protein (p.Tyr213Lysfs*6), the anthropometric alterations appear to be more more severe [45]. We take these observations with caution, both because of the small size of the Mixe cohort and the influences of environmental factors and additional loci in these multifactorial traits cannot be overlooked.…”

Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

“…About 80% of FA children and adults show at least one endocrine defect, including GH deficiency, atypical glucose or insulin metabolism, dyslipidemia, hypothyroidism, pubertal delay, hypogonadism, or impaired fertility. Very recently, the first genotype‒phenotype correlation of FA endocrine defects has been studied in a cohort of 24 patients homozygous for a founder mutation (c.637_643del (p.Tyr213Lysfs*6)) in FANCG [ 72 ]. Defects usually observed in FA patients are related to glucose and insulin metabolism as well as to lipid dysregulation [ 73 ].…”