Short stature is common in patients with Fanconi anemia (FA) and may be due to growth hormone deficiency (GHD) [1–4], especially after hematopoietic cell transplantation (HCT) [5]. Yet, there are no published data on the effectiveness of recombinant human GH treatment in these patients. Therefore, we conducted a retrospective case review study that included 4 patients with FA treated with GH for ≥2 years who reached near adult height. All patients received allogeneic HCT at the University of Minnesota between 2002 and 2008. We hypothesized that height would increase by at least 0.5 SDS in response to therapy.
Patients who met two of the three criteria: height ≤−1.5 SDS, growth velocity ≤−2.0 SDS, or height SDS >2 SD below the mid-parental height, underwent GH stimulation testing with clonidine and arginine. GHD was defined as a stimulated GH level <10 μg/L [6]. Evaluation included physical examination, bone age radiograph, magnetic resonance imaging (MRI) or computed tomography scan of the brain, thyroid tests, and growth factor levels. This study was approved by the University of Minnesota Institutional Review Board.
The mean age at FA diagnosis was 7.0±1.9 years and was 8.7±2.2 years at HCT. All patients had GHD. Patient 1 had an ectopic pituitary gland with pituitary stalk anomaly and Patient 3 had a pituitary microadenoma on MRI. Patients 2 and 4 had normal brain scans. Patient 2 was diagnosed with premature ovarian failure at 12 years and was treated with estrogen replacement throughout the course of GH therapy. Patients 1 and 4 had a transient subclinical hypothyroidism, which resolved without treatment within a year. Patient 2 had normal thyroid function. Patient 3 had primary hypothyroidism prior to starting GH therapy and was euthyroid on levothyroxine during GH treatment.
Table I shows GH treatment data. The average age at GH start was 10.7±1.8 years. GH dose was 0.28±0.03 mg/kg/week. The initial bone age was delayed (2 SD below the mean) for Patients 1 and 2. The average growth rate was 4.0±1.1 cm/yr (−2.2±1.8 SD) at baseline, 6.6±3.9 cm/yr (1.7±4.9 SD) in year 1, 9.2±3.1 cm/yr (4.0±1.0 SD) in year 2, 5.6±2.0 cm/yr (1.1±3.7 SD) in year 3, and 5.7±1.1 cm/yr (1.2±2.1 SD) in year 4. The mean increase in height was 0.9±0.6 SDS (p=0.05). The smallest response to GH therapy was seen in Patient 4 who was the oldest and showed no improvement in insulin-like growth factor-1 (IGF-1) SDS, suggesting that optimization of GH dose based on IGF-1 levels may have improved outcome. There were no adverse events from GH.
Table I
Growth hormone treatment data
In conclusion, GH treatment was well tolerated and had a positive effect on growth, resulting in an increase in height of at least 0.5 SDS in three out of four patients. It should be noted, however, that the long-term risk of GH treatment in these patients is unknown. Although HCT reduces the risk of leukemia, all patients with FA are at increased risk of solid tumors, including head and neck cancers, and gynecological cancers [7–9]. Therefore, continued surveillance is needed.