Endocrine profiling in black South African fanconi anaemia patients, homozygous for a fancg founder mutation

Abstract

Fanconi anaemia (FA) is an uncommon, phenotypically diverse, hereditary condition associated most commonly with bone marrow failure, multiple physical congenital abnormalities, and an increased susceptibility to the development of haematological and solid tissue malignancies. Less recognised manifestations of FA include endocrine abnormalities. International discourse has highlighted that these abnormalities are widespread among individuals with FA. To date there has been no systematic study that has evaluated the endocrine abnormalities in Black South African patients with FA, particularly those homozygous for a founder mutation (c.637_643delTACCGCC) in FANCG. The objectives of this research were to evaluate endocrine gland function in Black South African patients with FA and a single FA genotype, and to determine the frequency and nature of endocrine abnormalities in this group. The study comprised of a cross-sectional, descriptive study of 24 Black South African patients with FA (homozygous for a founder FANCG mutation), between the ages of 2 years and 21 years, recruited from South African tertiary academic hospitals. Measured outcomes included: growth, pubertal status, endocrine hormone function (including screening of the growth hormone axis, thyroid gland function, and glucose and insulin metabolism) and bone age. Endocrine dysfunction was present in 70.8% (17 of 24) of the study cohort, including short stature in 45.8% (11 of 24), abnormal IGF-1/IGFBP-3 in 25.0% (6 of 24), insulin resistance in 41.7% (10 of 24), and abnormal thyroid function in 16.7% (4 of 24). No abnormalities of glucose metabolism were identified. Abnormal pubertal status was seen in three males (12.5% of the study cohort). Abnormal bone ages were present in 34.8% (8 of 23) of the cohort, and abnormally fused carpal bones were present in 13.0% (3 of 23). It was concluded that endocrine abnormalities occur at a high frequency in Black South African patients with FA, similar to other FA cohorts. Our data are specific to FA patients with a single genotype, and therefore this provides the first genotype-phenotype information on endocrine abnormalities in Black South African patients, homozygous for a founder FANCG 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.