title: Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry.
abstract: OBJECTIVE
  1) To determine the extent of short stature in patients with Fanconi 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 patients; and 4) to study the correlation, if any, between height, endocrinopathy, and FA complementation group.
  
  
  METHODS
  Fifty-four patients with FA, 30 males and 24 females from 47 unrelated families, were prospectively evaluated in a Pediatric Clinical Research Center. The patients ranged in age from 0.1-31.9 years, with the mean age at assessment 8.6 years.
  
  
  RESULTS
  Endocrine abnormalities were found in 44 of the 54 FA patients tested (81%), including short stature, growth hormone (GH) insufficiency, hypothyroidism, glucose intolerance, hyperinsulinism, and/or overt diabetes mellitus. Twenty-one of 48 (44%) participants had a subnormal response to GH stimulation; 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, participants demonstrated a tendency toward primary hypothyroidism with serum tetraiodothyronine levels at the lower range of normal, while also having thyrotropin (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 in groups FA-A and FA-G were relatively taller than the group as a whole (but still below the mean for the general population), whereas those in FA-C had a significantly reduced height for age. GH response to stimulation testing was most consistently normal in participants from FA-G, but this did not reach statistical significance. The tendency toward hypothyroidism was more pronounced in participants belonging to complementation groups FA-C and FA-G, whereas insulin resistance was most evident in patients in FA-G, and least evident in those in FA-C. Short stature was a very common finding among the patients with a mean height >2 standard deviations below the reference mean (standard deviation score: -2.35 +/- 0.28). Patients with subnormal GH response and those with overt or compensated hypothyroidism were shorter than the group with no endocrinopathies. The heights of those participants with glucose or insulin abnormalities were less severely affected than those of normoglycemic, normoinsulinemic 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, demonstrating that short stature is an inherent feature of FA.
  
  
  CONCLUSIONS
  Endocrinopathies are a common feature of FA, primarily manifesting 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 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 superimposed endocrinopathies further impact on growth. The demonstration of abnormal endogenous GH secretion may demonstrate an underlying hypothalamic-pituitary dysfunction that results in poor growth.
authors.affiliation: Department of Pediatrics and Children's Clinical Research Center, New York Presbyterian Hospital-Cornell University Medical Center, New York, New York 10021, USA. mpwajnr@med.cornell.edu
authors.forename: M P
authors.initials: MP
authors.lastname: Wajnrajch
authors.forename: J M
authors.initials: JM
authors.lastname: Gertner
authors.forename: Z
authors.initials: Z
authors.lastname: Huma
authors.forename: J
authors.initials: J
authors.lastname: Popovic
authors.forename: K
authors.initials: K
authors.lastname: Lin
authors.forename: P C
authors.initials: PC
authors.lastname: Verlander
authors.forename: S D
authors.initials: SD
authors.lastname: Batish
authors.forename: P F
authors.initials: PF
authors.lastname: Giampietro
authors.forename: J G
authors.initials: JG
authors.lastname: Davis
authors.forename: M I
authors.initials: MI
authors.lastname: New
authors.forename: A D
authors.initials: AD
authors.lastname: Auerbach
mesh_terms: D000293:Adolescent; D000328:Adult; D000886:Anthropometry / Q000379:methods; D001827:Body Height / Q000235:genetics / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D003000:Clonidine; D003920:Diabetes Mellitus / Q000175:diagnosis / Q000453:epidemiology; D004393:Dwarfism, Pituitary / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D005199:Fanconi Anemia / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D005816:Genetic Complementation Test / Q000706:statistics & numerical data; D005951:Glucose Tolerance Test; D019382:Human Growth Hormone / Q000097:blood*; D006801:Humans; D006946:Hyperinsulinism / Q000175:diagnosis / Q000453:epidemiology; D007037:Hypothyroidism / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology; D007223:Infant; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D009154:Mutation; D011446:Prospective Studies; D013960:Thyroid Function Tests
chemical_list: D019382:Human Growth Hormone; D003000:Clonidine