Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry

Objectives. 1) To determine the extent of short stature in patients with Fa nconi anemia (FA); 2) to determine the extent and nature of endocrinopathy in FA; 3) to assess the impact on height of any endocrinopathies in these p atients; and 4) to study the correlation, if any, between height, endocrino pathy, and FA complementation group. Study Design. Fifty-four patients with FA, 30 males and 24 females from 47 unrelated families, were prospectively evaluated in a Pediatric Clinical Re search Center. The patients ranged in age from 0.1-31.9 years, with the mea n age at assessment 8.6 years. Results. Endocrine abnormalities were found in 44 of the 54 FA patients tes ted (81%), including short stature, growth hormone (GH) insufficiency, hypo thyroidism, glucose intolerance, hyperinsulinism, and/or overt diabetes mel litus. Twenty-one of 48 (44%) participants had a subnormal response to GH s timulation; 19 of 53 (36%) had overt or compensated hypothyroidism, while 8 of 40 participants had reduced thyroid-hormone binding. Two patients were diabetic at the time of study; impaired glucose tolerance was found in 8 of 40 patients (25%), but most surprisingly, hyperinsulinemia was present in 28 of 39 (72%) participants tested. Significantly, spontaneous overnight GH secretion was abnormal in all patients tested (n = 13). In addition, parti cipants demonstrated a tendency toward primary hypothyroidism with serum te traiodothyronine levels at the lower range of normal, while also having thy rotropin (thyroid-stimulating hormone) levels at the high end of normal. Sixteen patients were assigned to FA complementation group A, (FA-A), 12 to FA-C, and 5 to FA-G; 10 of the 12 participants in FA-C were homozygous for a mutation in the intron-4 donor splice site of the FANCC gene. Patients i n groups FA-A and FA-G were relatively taller than the group as a whole (bu t still below the mean for the general population), whereas those in FA-C h ad a significantly reduced height for age. GH response to stimulation testi ng was most consistently normal in participants from FA-G, but this did not reach statistical significance. The tendency toward hypothyroidism was mor e pronounced in participants belonging to complementation groups FA-C and F A-G, whereas insulin resistance was most evident in patients in FA-G, and l east evident in those in FA-C. Short stature was a very common finding among the patients with a mean heig ht >2 standard deviations below the reference mean (standard deviation scor e: -2.35 +/- 0.28). Patients with subnormal GH response and those with over t or compensated hypothyroidism were shorter than the group with no endocri nopathies. The heights of those participants with glucose or insulin abnorm alities were less severely affected than those of normoglycemic, normoinsul inemic participants, although all were significantly below the normal mean. The mean height standard deviation score of patients with entirely normal endocrine function was also >2 standard deviations below the normal mean, d emonstrating that short stature is an inherent feature of FA. Conclusion. Endocrinopathies are a common feature of FA, primarily manifest ing as glucose/insulin abnormalities, GH insufficiency, and hypothyroidism. Although short stature is a well-recognized feature of FA, 23 patients (43 %) were within 2 standard deviations, and 5 of these (9% of the total) were actually above the mean for height for the general population. Those patie nts with endocrine dysfunction are more likely to have short stature. These data indicate that short stature is an integral feature of FA, but that su perimposed endocrinopathies further impact on growth. The demonstration of abnormal endogenous GH secretion may demonstrate an underlying hypothalamic -pituitary dysfunction that results in poor growth.