Growth hormone therapy in a patient with short stature due to fetal alcohol syndrome: seven-year follow-up

Abstract.

Fetal alcohol syndrome (FAS) is associated with persistent growth retardation, but the long-term efficacy of GH therapy for FAS-related short stature remains unclear. A Japanese girl born at 37 wk with birth weight 2,064 g (–2.1 SD) and birth height 41.5 cm (–2.7 SD) was diagnosed with FAS based on characteristic facial features, growth failure, developmental delay, and documented maternal alcohol consumption (120 g/d during pregnancy). She scored 4434 on the FASD 4-Digit Diagnostic Code. At 3 yr of age, her height was 78 cm (–4.18 SD) with poor growth velocity. GH therapy was initiated at 0.19 mg/kg/wk, increased to 0.23 mg/kg/wk, and gradually increased to 0.43 mg/kg/wk. After 7 yr of treatment, serum IGF-1 levels increased significantly from 59 ng/mL (–2.5 SD) at baseline to 306 ng/mL (+2.0 SD) at 8 yr, but height SD scores remained around –4 SD with growth velocity fluctuating between –3 and 0 SD. No adverse effects were observed. While GH therapy appears safe in FAS patients, its efficacy for improving linear growth is limited, suggesting that growth impairment in FAS involves mechanisms beyond GH deficiency, including growth plate dysfunction and peripheral GH resistance.

Highlights

● Limited growth response to GH therapy despite adequate IGF-1 elevation in FAS.

● Seven-year safety data supports GH therapy in selected FAS patients.

● Peripheral GH resistance may be primary mechanism limiting treatment response.

Introduction

Fetal alcohol spectrum disorders (FASD) represent a continuum of conditions caused by maternal alcohol consumption during pregnancy. Fetal alcohol syndrome (FAS) is the most severe form of FASD and is characterized by distinctive facial features, growth retardation, central nervous system dysfunction, and behavioral abnormalities (1, 2). Growth failure associated with FAS is known to persist after birth and continue into adulthood. Adults with FASD have significantly lower mean height compared to controls (164.9 ± 0.9 cm vs. 170.4 ± 0.7 cm, p < 0.001). This difference is observed in both males (171.6 ± 1.0 cm vs. 177.9 ± 0.7 cm, p < 0.0001) and females (158.4 ± 1.0 cm vs. 163.2 ± 0.7 cm, p = 0.0001) (3).

Small for gestational age (SGA) is defined as birth weight and/or height below the 10th percentile for gestational age, with at least one measurement below –2 SD. Children who fail to achieve catch-up growth by 2 yr of age are diagnosed with SGA short stature (4). In Japan, GH therapy for SGA short stature has been covered by national health insurance since 2008, with treatment criteria including chronological age ≥ 3 yr, growth velocity SD score below 0 SD, and height SD score below –2.5 SD.

GH therapy is generally effective in SGA children, resulting in improvements in height SDS and increases in IGF-1 levels. However, growth deficiency plays an essential role in FASD diagnosis and is as prevalent as other core diagnostic features (facial and CNS abnormalities), with postnatal short stature being the most prevalent form (5). Recent multicenter data from Poland indicate that FAS patients may show a limited response to GH therapy. In this study, FAS children treated with recombinant human GH had lower growth velocity and ΔHt SDS compared with other SGA patients, with a substantial proportion classified as poor responders during the first two years of treatment (6).

Nevertheless, the long-term efficacy of GH therapy for growth failure associated with FAS has not been sufficiently evaluated. To our knowledge, this is the first Japanese report of long-term GH therapy in FAS. We report a case of FAS with SGA short stature treated with GH therapy for seven years, providing crucial safety and efficacy data for Asian populations.

Case Presentation

A girl was born at 37 wk and 5 d of gestation via vaginal delivery with birth weight 2,064 g (–2.1 SD), birth height 41.5 cm (–2.7 SD), and head circumference 31.5 cm (–1.0 SD). Apgar scores were 3 at 1 min and 4 at 5 min. Both parents and the patient were Japanese. Parental heights were within the normal range for Japanese adults (father 173 cm, mother 162 cm) with a calculated target height of 161.5 cm. She is the fifth child; her sister has myotonic dystrophy type 1, and her brother drowned at 1 yr of age. The mother had generalized anxiety disorder, alcohol dependence, and consumed approximately 120 g/d of pure alcohol during pregnancy.

Chromosomal analysis revealed a normal female karyotype (46,XX). Basic laboratory investigations showed normal renal function (creatinine 0.3 mg/dL, normal range 0.2–0.4) and normal thyroid function (TSH 3.2 mIU/L, free T4 1.1 ng/dL).

At 2 yr 1 mo of age, physical examination revealed height 71 cm (–4.7 SD), weight 6.2 kg (–4.2 SD), and head circumference 41.5 cm (–2.5 SD). She exhibited characteristic FAS facial features including smooth philtrum, thin upper lip, and short palpebral fissures, along with microcephaly and developmental delay (facial photograph shown in Fig. 1 with parental consent). Brain MRI showed asymmetry of occipital gyri but no cortical dysplasia. Based on these findings and maternal alcohol history, she was diagnosed with FAS using the FASD 4-Digit Diagnostic Code (7), attaining scores of 4434 (Table 1).

Fig. 1.

The patient’s face pictures at 1.2 yr (A) and 10 yr (B).

Table 1. FASD 4-Digit Diagnostic Code.

Despite nutritional interventions, growth remained poor. At 2 yr 1 mo of age, GH stimulation tests showed normal responses (arginine: 11.6 ng/mL, clonidine: 6.92 ng/mL), ruling out GH deficiency. At 3 yr 1 mo of age, with height 78 cm (–4.18 SD), weight 7.3 kg (–3.62 SD), and growth velocity 7.15 cm/yr (–3.11 SD), the patient met criteria for SGA short stature treatment.

Despite concerns about CNS involvement, written informed consent was obtained from her legal guardian after comprehensive counseling regarding realistic expectations and potential limitations of GH therapy in FAS patients. GH therapy was initiated based on: (1) severe growth failure significantly impacting quality of life, (2) normal GH secretion suggesting potential for growth response, (3) family’s strong preference for treatment, and (4) absence of contraindications. Somatropin was initiated at 0.19 mg/kg/wk, increased to 0.23 mg/kg/wk, and gradually escalated to 0.43 mg/kg/wk due to poor response (Fig. 2), with IGF-1 levels and dose adjustments carefully monitored (Fig. 3).

Fig. 2.

Somatropin dosage progression during the 7-yr treatment period. Treatment was initiated at 3 yr of age at 0.19 mg/kg/wk, increased to 0.23 mg/kg/wk, and systematically increased to 0.43 mg/kg/wk due to poor growth response, following standard dose escalation protocols for SGA patients.

Fig. 3.

Growth chart showing height and weight progression during 7-yr GH therapy period. Both height and weight consistently below –2.0 SD throughout the treatment period. GH therapy was initiated at 3 yr of age. Note the minimal improvement in height SD score despite continuous treatment.

Ethical considerations

This case report was approved by the Institutional Review Board of Iizuka Hospital (approval number: IH-2024-015, September 10, 2024) and conducted in accordance with the ethical standards of the Declaration of Helsinki (2013 revision). Written informed consent was obtained from the patient’s legal guardian for publication of this case report and accompanying clinical data.

Results

Treatment adherence was initially poor due to complex family circumstances, with injections administered only 2–4 times per week at home. Adherence improved after 6 yr of age when she was admitted to a child welfare facility where staff supervised daily medication administration. The somatropin dosage was systematically adjusted based on growth response and IGF-I levels, with dose escalations occurring at regular intervals as shown in Fig. 2. The patient’s growth progression is shown in Fig. 3. During the treatment, serum IGF-1 levels increased significantly from 59 ng/mL (–2.5 SD) at baseline (3 yr) to 306 ng/mL (+2.0 SD) at 8 yr (Fig. 4), while height increased from 78 cm (–4.18 SD) at treatment initiation to 110 cm (–4.05 SD) at 10 yr of age. This IGF-I elevation corresponded with the gradual dose escalations of somatropin as illustrated in Fig. 2. However, despite this biochemical response, SD scores remained persistently around –4 SD, with growth velocity SD scores fluctuating between –3 and 0 SD as shown in Fig. 3. The patient showed no significant catch-up growth, with height increasing from 78 cm (–4.18 SD) at treatment initiation to 110 cm (–4.05 SD) at 10 yr of age. Pubertal development began in late age 9 with breast development (Tanner stage 2). Although hormonal evaluation was not performed, clinical assessment confirmed onset of puberty. Thyroid function was monitored regularly during GH treatment. As shown in Fig. 5 (TSH and FT4 progression), thyroid function remained stable throughout the 7-yr treatment period with no evidence of GH-induced thyroid dysfunction. No adverse effects including headache, glucose intolerance, thyroid dysfunction, tonsillar hypertrophy, eosinophilia, or liver dysfunction were observed.

Fig. 4.

Longitudinal changes in serum IGF-1 levels during GH therapy. IGF-I levels increased progressively from 59 ng/mL (–2.5 SD) at baseline to 306 ng/mL (+2.0 SD) at 8 yr, demonstrating adequate GH bioactivity and treatment compliance despite limited linear growth response. Gray bar indicates treatment period.

Fig. 5.

Longitudinal changes in thyroid function (TSH and FT4) during 7-yr GH therapy. Both TSH and FT4 levels remained within normal ranges throughout the treatment period, indicating no GH-induced thyroid dysfunction.

Discussion

This case demonstrates that while GH therapy appears safe in FAS patients, its efficacy for improving linear growth is limited. Despite substantial increases in IGF-1 levels from 59 ng/mL (–2.5 SD) at 3 yr to 306 ng/mL (+2.0 SD) at 8 yr as shown in Fig. 4 indicating adequate GH bioactivity, height and growth velocity showed minimal improvement over 7 yr of treatment as demonstrated in Fig. 3.

The growth impairment in FAS likely involves multiple mechanisms beyond simple GH deficiency. Prenatal alcohol exposure directly affects bone growth through impaired chondrocyte proliferation in growth plates, decreased TGF-β1 expression, and structural abnormalities in proliferative and hypertrophic zones (8). Additionally, peripheral GH resistance has been reported in FAS patients despite normal GH secretion (1).

Furthermore, Glińska et al. (2022) conducted a multicenter study in Poland and reported that children with FAS treated with recombinant human GH exhibited lower growth velocity and ΔHt SDS compared with other SGA patients, and a substantial proportion were classified as poor responders during the first two years of treatment. These findings suggest that the response to GH therapy may be limited in FAS-associated growth failure and emphasize the need for careful individual assessment when initiating treatment in this population (6).

While GH therapy for syndromic SGA generally has limited indications (9), treatment was initiated in this case due to severe short stature, absence of other treatable causes, normal GH secretion, and strong family preference after comprehensive counseling regarding realistic expectations. The systematic dose escalation approach shown in Fig. 2 was implemented to optimize treatment response while monitoring for potential adverse effects. The lack of significant improvement in growth parameters suggests that FAS-associated growth failure involves fundamental alterations in growth plate function that are not readily correctable with GH supplementation.

Nevertheless, GH therapy may have prevented further growth deterioration, as the patient’s growth velocity remained within measurable ranges rather than completely ceasing. The demonstrated safety profile supports consideration of GH therapy in carefully selected FAS patients, although expectations regarding efficacy should be appropriately managed based on these findings.

Several limitations should be acknowledged. First, treatment adherence was suboptimal during the initial years, which may have influenced treatment outcomes. Second, this is a single case report limiting generalizability of findings. Finally, longer-term follow-up data would be valuable to assess final adult height and potential late effects of GH therapy in this population.

Conclusion

This seven-year follow-up case demonstrates that GH therapy for FAS-associated short stature is safe but has limited efficacy in improving linear growth. The persistent growth impairment despite adequate IGF-1 elevation from 59 ng/mL (–2.5 SD) at 3 yr to 306 ng/mL (+2.0 SD) at 8 yr suggests peripheral GH resistance and intrinsic growth plate dysfunction as primary mechanisms. While treatment may prevent further growth deterioration, clinicians should counsel families about realistic expectations when considering GH therapy in FAS patients. These findings provide important guidance for pediatric endocrinologists when counseling families about realistic expectations for GH therapy in syndromic short stature, particularly in the context of FAS. This represents the first Japanese report of long-term GH therapy in FAS, providing valuable data for Asian populations where genetic and environmental backgrounds differ from Western populations.

Conflict of interests

The authors have no conflicts of interest to declare.

Data availability statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request, subject to patient privacy considerations.