Short stature is a well-recognized feature of FA and is often secondary to hormonal deficiencies, which include pituitary hypofunction with hypogonadism, growth hormone deficiency, thyroid dysfunction and insulin deficiency or resistance with glucose intolerance. The syndrome is usually associated with abnormal growth parameters both prenatally and postnatally. The mean height, weight and head circumference of FA patients in the IFAR is near the 5th centile. A prospective study by Wajnrajch et al.
of 54 IFAR patients with FA, 30 males and 24 females from 47 unrelated families, showed that endocrinopathies are a common feature of FA, primarily manifesting as glucose/insulin abnormalities, growth hormone insufficiency and hypothyroidism [11
]. Although short stature is a feature of FA, it is notable that in this study 23 patients (43%) were within two standard deviations of the 50th
centile, and five (9%) were above the mean height for the general population. As expected, patients with endocrine dysfunction are more likely to have short stature. These data indicate that short stature is an integral feature of FA, but that the addition of endocrinopathies magnifies the growth failure in a significant proportion of patients. The finding of abnormal endogenous growth hormone secretion may demonstrate an underlying hypothalamic-pituitary dysfunction that results in poor growth. Since correction of growth hormone or thyroid hormone deficiency may improve final height outcome and quality of life, endocrine evaluations are recommended for all FA children at an early age well before use of androgens and HCT if possible.
Results of this IFAR study were recently confirmed among 23 patients intensively evaluated at the National Institutes of Health, in whom anthropometric measurements, GH, IGF-I, IGF binding protein-3, thyroid, gonadal hormone, lipid levels, glucose homeostasis, brain imaging, and bone mineral density were obtained [12
]. Endocrine abnormalities were present in 73%, including short stature and/or GH deficiency, hypothyroidism, midline brain abnormalities (these patients had very short stature and 60% were GH-deficient); abnormal glucose/insulin metabolism; obesity; dyslipidemia; and metabolic syndrome. Patients with any endocrine abnormality were shorter than those without; only GH deficiency correlated significantly with short stature (P
= 0.01). In addition, 65% of peripubertal or postpubertal patients had gonadal dysfunction. Ninety-two percent of the patients 18 yr or older had osteopenia or osteoporosis. These authors conclude that endocrine dysfunction is widespread in children and adults with FA and expand the FA phenotype to include early onset osteopenia/osteoporosis and lipid abnormalities.
Further evidence of the importance of endocrine abnormalities in FA was obtained in a study of 44 patients with FA referred to Cincinnati Children's Hospital Medical Center (CCHMC) between 1975 and 2005 [13
]. Of these, 33 had neuroimaging studies, including 11 who had cranial magnetic resonance imaging (MRIs). When compared to the age-gender matched on-site control sample, the mean pituitary height of FA patients was significantly smaller (P < 0.0001). 50% of patients with small pituitary gland were short. In another recent study from CCHMC it was found that among 63 children with FA, 63% had borderline thyroid function tests [14
]. Those with borderline thyroid hormone results, compared to those with completely normal thyroid function, were shorter. A separate report describes thirty-nine children with FA referred to Cincinnati Children's Hospital Medical Center (CCHMC) who underwent 2-hr oral glucose tolerance test (OGTT). This study confirmed that abnormalities in glucose metabolism are frequent in young FA patients without prior diagnosis of diabetes, and are associated with marked defects in insulin secretion [15