With an estimated prevalence of 1 in 100 000 births, 11β-hydroxylase deficiency is the second most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in CYP11B1. Clinical features include virilization, early gonadotropin-independent precocious puberty, hypertension, and reduced stature. The current mainstay of management is with glucocorticoids to replace deficient steroids and to minimize adrenal sex hormone overproduction, thus preventing virilization and optimizing growth. We report a patient with CAH who had been suboptimally treated and presented to us at 6 years of age with precocious puberty, hypertension, tall stature, advanced bone age, and a predicted final height of 150 cm. Hormonal profiles and genetic analysis confirmed a diagnosis of 11β-hydroxylase deficiency. In addition to glucocorticoid replacement, the patient was commenced on growth hormone and a third-generation aromatase inhibitor, anastrozole, in an attempt to optimize his growth. After the initiation of this treatment, the patient’s growth rate improved significantly and bone age advancement slowed. The patient reached a final height of 177.5 cm (0.81 SD score), 11.5 cm above his mid-parental height. This patient is only the second reported case of the use of an aromatase inhibitor in combination with growth hormone to optimize height in 11β-hydroxylase-deficient CAH. This novel treatment proved to be highly efficacious, with no adverse effects. It may therefore provide a promising option to promote growth in exceptional circumstances in individuals with 11β-hydroxylase deficiency presenting late with advanced skeletal maturation and consequent short stature.
- AI —
- aromatase inhibitor
- CAH —
- congenital adrenal hyperplasia
- GH —
- growth hormone
- GnRH —
- gonadotropin-releasing hormone
- SDS —
- standard deviation score
Growth is a major issue in the management of congenital adrenal hyperplasia (CAH), influenced both by the disease itself and its treatment. Final height in patients with CAH is reduced and in 21-hydroxylase deficiency is often between –1 and –2 SDs of the normal height of a control population.1 Reduced adult height is a consequence of both androgen excess due to the condition itself, potentially leading to early puberty and fusion of the epiphyseal plates, and an undesired side effect of the supraphysiologic glucocorticoid treatment required for cortisol replacement and androgen suppression. This reduction in height is more significant the later the condition is diagnosed or as a result of suboptimal treatment.
We report a novel approach to improve linear growth by using recombinant human growth hormone (GH) and anastrozole, an aromatase inhibitor (AI), in combination with glucocorticoids in a patient with late-presenting CYP11B1 deficiency with a markedly advanced bone age. Informed consent was obtained from the patient and his parents to write this case report.
The patient was born in Turkey to consanguineous parents. He was noted to have a large phallus at birth, but no investigations were performed at that stage. He presented at the age of 3 years with pubic hair development and was referred to a pediatric endocrinologist. His blood pressure was 100/70 mm Hg (53rd percentile for age). Tanner staging revealed genitalia stage (G) 3, pubic hair stage (P) 2, axillary hair stage (A) 1, and testes (T) of 1 mL bilaterally; he had a height of 114 cm (5.34 standard deviation score [SDS]) and a significantly advanced bone age of 8 years. Hormonal profiles revealed elevated 11-deoxycortisol, dehydroepiandrosterone sulfate, testosterone, and corticotropin concentrations with suppressed renin and aldosterone, confirming a diagnosis of 11β-hydroxylase-deficient CAH. A computed tomography scan of his abdomen revealed bilateral adrenal hyperplasia. He was commenced on hydrocortisone 20 mg/m2 per day, which was then reduced by 5 mg per week until a dose of 10 mg/m2 per day was reached within 4 weeks of commencement of treatment, with rapid normalization of biochemical markers (11-deoxycortisol 4.6 ng/mL and corticotropin 25 pg/mL). He subsequently developed hypertension, initially treated with enalapril; after an inadequate response, furosemide was added 3 times weekly to optimize control.
The patient was first seen in the United Kingdom at the age of 6.5 years, when he presented with tall stature (height 129 cm, 2.0 SDS), virilization (pubertal ratings G3P3A1 T 2 mL bilaterally), hypertension (146/98 mm Hg; 99.9th percentile for age), and a significantly advanced bone age (13.2 years). Predicted final height was only 150 cm (Bayley-Pinneau method), considerably less than his mid-parental height (166 cm). Genetic analysis revealed a 46,XY karyotype with a homozygous mutation in CYP11B1, c.954G>A, a silent change in the last nucleotide of exon 5 predicted to affect splicing.2
Glucocorticoid replacement was optimized by increasing the hydrocortisone dose from 9 mg/m2 per day to 20 mg/m2 per day. During the patient’s subsequent treatment, his hydrocortisone dose ranged from 20 to 13.7 mg/m2 per day. To better control his hypertension, the patient’s dose of enalapril was increased to 5 mg twice daily, and furosemide was replaced by nifedipine 10 mg twice daily.
In an attempt to optimize the patient’s growth and prevent further bone age acceleration, the patient at the age of 7.38 years was commenced on a third-generation AI, anastrozole (1 mg/d), in combination with GH (0.87 mg/m2 per day). At that point, his height was 131.3 cm (1.43 SDS), and his growth velocity had slowed to 0.8 cm/year (–5.52 SDS).
After this strategy, the patient’s growth rate initially decreased but then normalized, and by 10.75 years, his height was 147.8 cm (0.94 SDS) with a growth velocity of 7.5 cm/year (3.33 SDS). At this stage, his pubertal staging was G4P4A1 T 3 mL bilaterally, and bone age had only slightly progressed to 14 years.
The patient continued on GH, anastrozole, and hydrocortisone with the onset of gonadotropin-dependent puberty at the age of 11.7 years. He had a normal pubertal growth spurt with a maximum growth velocity of 12 cm/year (2.81 SDS) at 12.93 years of age (Fig 1). Blood pressure remained well controlled. The response to GH was monitored by using insulin-like growth factor-1/insulin-like growth factor binding protein-3 measurements and growth velocity. The dose of GH was increased as the patient continued to grow, providing a consistent dose between 0.87 mg/m2 per day and 0.90 mg mg/m2 per day. Androgen concentrations were monitored during treatment. Prepubertally, the testosterone concentration was <0.7 nmol/L; at the age of 11 years, it was 5.9 nmol/L; at 13 years, it was 13.9 nmol/L; and by 14 years, it had increased to 17.9 nmol/L. Androstenedione levels were <1.1 nmol/L prepubertally, increasing to 18.1 nmol/L by 11 years, 24.6 nmol/L at 13 years, and decreasing to 11.6 nmol/L by 14 years of age.
Anastrozole was stopped at 13 years of age, and GH treatment was stopped at 14 years of age when the patient’s height was 172 cm (1.13 SDS). No adverse side effects ensued from the anastrozole. Notably, after the cessation of treatment, the patient had a normal dual-energy radiograph absorptiometry scan with L1–L4 bone mineral density of 1.00 g/cm2 (z score, 1.0) and left hip bone mineral density of 1.10 g/cm2 (z score, 0.8). Results of spinal radiography and spine MRI were also normal. Lipid profile, serum biochemistry including testosterone, and hemoglobin (ranging from 13–14.3 g/dL) were within normal physiologic concentrations. Currently, at 15.35 years of age, his height is 177.5 cm (0.81 SDS), with a pubertal staging of G5P5A3 T 15 mL bilaterally. From the age of 13 years, the patient’s compliance with treatment was problematic as evidenced by elevated corticotropin concentrations (1250 ng/L), and he was therefore switched to prednisolone (7.5 mg in the morning and 5 mg in the evening) to improve his compliance with glucocorticoid treatment. He continues to grow, but his height velocity is now negligible and he has reached his near-final adult height, which has exceeded his mid-parental height by 11.5 cm.
We report a relatively novel approach for the treatment of predicted adult short stature in 11β-hydroxylase-deficient CAH. Despite presenting late with a bone age that was advanced by 7 years, the patient’s linear growth surpassed expectations after treatment with GH and anastrozole. Predicted final height upon his initial presentation in the United Kingdom was exceeded by 27.5 cm and mid-parental height by 11.5 cm. To our knowledge, this report is only the second documented case3 of combination therapy with GH and an AI to optimize growth in a patient with 11β-hydroxylase deficiency.
Efforts to improve final height in children with CAH have led clinicians to investigate alternative and adjunctive therapies, such as GH, gonadotropin-releasing hormone (GnRH) agonists, AIs, androgen blockers, or a combination of these medications. Much of the evidence relating to treatment to improve height potential in CAH has focused on the more common 21-hydroxylase deficiency. One study of 34 patients with 21-hydroxylase deficiency showed that GH, either alone or in combination with a GnRH analogue, improves final adult height, with an average 9-cm height gain in male subjects.4 Evidence for adjunctive treatments to improve growth in 11β-hydroxylase deficiency is more limited.5 There are some case reports which suggest that GH in combination with GnRH agonists may be useful in improving height outcomes in children with 11β-hydroxylase deficiency.5,6
AIs block the action of P450 aromatase, which converts androgens into estrogens, and can be used to decelerate growth plate fusion by minimizing estrogen action. Evidence is accumulating regarding their use to increase final height in a range of conditions affecting stature. In 1 study of 52 patients with GH deficiency, anastrozole in combination with GH therapy was shown to increase predicted adult height (by 6.7 cm vs 1.0 cm with GH alone) while maintaining normal pubertal progression.7 A randomized controlled trial of boys with constitutional pubertal delay treated with the AI letrozole plus testosterone (N = 9) for 1 year during adolescence significantly improved near-final adult heights compared with testosterone with placebo.8 In 1 study of 28 children with 21-hydroxylase deficiency, the combination of a reduced dose of hydrocortisone with an antiandrogen (flutamide) and an AI (testolactone) slowed bone maturation while maintaining growth velocity compared with a conventional high-dose glucocorticoid regimen.9 This study is ongoing, and the patients have now been switched to letrozole.10
The only other reported case using this approach in 11β-hydroxylase deficiency was a patient with a 46,XX karyotype, who was raised as male. This patient had an oophorectomy after presentation at the age of 3 years in Pakistan with virilization and cryptorchidism3 and similarly had received suboptimal initial corticosteroid treatment. After presenting in Canada at the age of 7 years with an advanced bone age and hypertension, the patient was given corticosteroids, which were optimized before commencing GH and letrozole at 8 and 9 years of age, respectively. As in our case, adult height prediction was exceeded, and no adverse effects were found in terms of vertebral malformation, bone fragility, or dyslipidemia.
Although combination treatment with GH and AIs seemed to be efficacious in these 2 individuals with no adverse effects, these data need to be reproduced by conducting randomized controlled trials in a larger number of patients. Given the rarity of this condition, such studies are likely to be difficult, although they may be possible if other forms of CAH (eg, 21-hydroxylase deficiency due to CYP21A2 mutations) presenting with virilization and advanced skeletal maturation are included. Further research is needed to elucidate the optimal timing for the introduction and duration of treatment with AI and GH to optimize linear growth and to identify those patients who may benefit most from this treatment. Current data involving the use of AIs in growth disorders have been generally promising with respect to safety profiles.7,9,11,12 However, additional studies are required to establish the long-term side effects of treatment with AIs in this patient group, including the evaluation of their impact on later fertility, lipid profiles, and bone mineral density.
- Accepted October 10, 2016.
- Address correspondence to Katherine Hawton, MA, MBBS, MRCPCH, Bristol Royal Hospital for Children, Paul O’Gorman Building, Upper Maudlin St, Bristol, BS2 8BJ, UK. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2017 by the American Academy of Pediatrics