Growth Hormone With Aromatase Inhibitor May Improve Height in CYP11B1 Congenital Adrenal Hyperplasia Katherine Hawton, MA, MBBS, MRCPCH,a Sandra Walton-Betancourth, MD,b Gill Rumsby, PhD, FRCPath,c Joseph Raine, MD, FRCPCH, DCH,d Mehul Dattani, MBBS, DCH, FRCPCH, FRCP, MDb

With an estimated prevalence of 1 in 100 000 births, 11β-hydroxylase abstract 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 a Bristol Royal Hospital for Children, Bristol, United sex hormone overproduction, thus preventing virilization and optimizing Kingdom; bGenetics and Epigenetics in Health and Disease Section, Genetics and Genomic Medicine Programme, growth. We report a patient with CAH who had been suboptimally UCL Institute of Child Health and Great Ormond Street treated and presented to us at 6 years of age with precocious puberty, Hospital, London, United Kingdom; cUniversity College d hypertension, tall stature, advanced bone age, and a predicted final height London Hospital, London, United Kingdom; and Whittington Hospital, London, United Kingdom of 150 cm. Hormonal profiles and genetic analysis confirmed a diagnosis of 11β-hydroxylase deficiency. In addition to glucocorticoid replacement, Dr Hawton was responsible for interpretation of growth data and drafting of the initial manuscript; the patient was commenced on growth hormone and a third-generation Dr Walton-Betancourth collated data for the aromatase inhibitor, anastrozole, in an attempt to optimize his growth. patient and drafted parts of the initial manuscript; After the initiation of this treatment, the patient’s growth rate improved Dr Rumsby performed genetic analyses and conducted the initial analyses; Dr Raine suggested significantly and bone age advancement slowed. The patient reached a final writing a case report and provided supervision; height of 177.5 cm (0.81 SD score), 11.5 cm above his mid-parental height. and Dr Dattani suggested the novel treatment of This patient is only the second reported case of the use of an aromatase the patient. All authors reviewed and revised the inhibitor in combination with growth hormone to optimize height in manuscript, approved the fi nal manuscript as submitted, and agree to be accountable for all 11β-hydroxylase-deficient CAH. This novel treatment proved to be highly aspects of the work. efficacious, with no adverse effects. It may therefore provide a promising DOI: 10.1542/peds.2016-0730 option to promote growth in exceptional circumstances in individuals Accepted for publication Oct 10, 2016 with 11β-hydroxylase deficiency presenting late with advanced skeletal Address correspondence to Katherine Hawton, MA, maturation and consequent short stature. MBBS, MRCPCH, Bristol Royal Hospital for Children, Paul O’Gorman Building, Upper Maudlin St, Bristol, BS2 8BJ, UK. E-mail: [email protected] Growth is a major issue in the to early puberty and fusion of the PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, management of congenital adrenal epiphyseal plates, and an undesired 1098-4275). hyperplasia (CAH), influenced both side effect of the supraphysiologic Copyright © 2017 by the American Academy of by the disease itself and its treatment. glucocorticoid treatment required for Pediatrics Final height in patients with CAH cortisol replacement and androgen FINANCIAL DISCLOSURE: The authors have is reduced and in 21-hydroxylase suppression. This reduction in height indicated they have no fi nancial relationships relevant to this article to disclose. deficiency is often between –1 is more significant the later the and –2 SDs of the normal height condition is diagnosed or as a result of of a control population. 1 Reduced suboptimal treatment. To cite: Hawton K, Walton-Betancourth S, Rumsby adult height is a consequence of G, et al. Growth Hormone With Aromatase Inhibitor both androgen excess due to the We report a novel approach to May Improve Height in CYP11B1 Congenital Adrenal Hyperplasia. Pediatrics. 2017;139(2):e20160730 condition itself, potentially leading improve linear growth by using

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 :e 20160730 CASE REPORT recombinant human growth hormone years, when he presented with tall years of age ( Fig 1). Blood pressure (GH) and anastrozole, an aromatase stature (height 129 cm, 2.0 SDS), remained well controlled. The inhibitor (AI), in combination with virilization (pubertal ratings G3P3A1 response to GH was monitored by glucocorticoids in a patient with T 2 mL bilaterally), hypertension using insulin-like growth factor-1/ late-presenting CYP11B1 deficiency (146/98 mm Hg; 99.9th percentile insulin-like growth factor binding with a markedly advanced bone age. for age), and a significantly advanced protein-3 measurements and Informed consent was obtained from bone age (13.2 years). Predicted final growth velocity. The dose of GH was the patient and his parents to write height was only 150 cm (Bayley- increased as the patient continued this case report. Pinneau method), considerably less to grow, providing a consistent dose than his mid-parental height (166 between 0.87 mg/m2 per day and cm). Genetic analysis revealed a 46, 0.90 mg mg/m2 per day. Androgen CASE REPORT XY karyotype with a homozygous concentrations were monitored mutation in CYP11B1, c.954G>A, a during treatment. Prepubertally, The patient was born in Turkey to silent change in the last nucleotide of the testosterone concentration was consanguineous parents. He was exon 5 predicted to affect splicing. 2 <0.7 nmol/L; at the age of 11 years, noted to have a large phallus at birth, it was 5.9 nmol/L; at 13 years, it Glucocorticoid replacement was but no investigations were performed was 13.9 nmol/L; and by 14 years, optimized by increasing the at that stage. He presented at the it had increased to 17.9 nmol/L. hydrocortisone dose from 9 mg/m2 age of 3 years with pubic hair Androstenedione levels were <1.1 per day to 20 mg/m2 per day. During development and was referred to nmol/L prepubertally, increasing the patient’s subsequent treatment, a pediatric endocrinologist. His to 18.1 nmol/L by 11 years, 24.6 his hydrocortisone dose ranged blood pressure was 100/70 mm Hg nmol/L at 13 years, and decreasing to from 20 to 13.7 mg/m2 per day. To (53rd percentile for age). Tanner 11.6 nmol/L by 14 years of age. staging revealed genitalia stage (G) better control his hypertension, the patient’s dose of enalapril was 3, pubic hair stage (P) 2, axillary hair Anastrozole was stopped at 13 increased to 5 mg twice daily, stage (A) 1, and testes (T) of 1 mL years of age, and GH treatment was and furosemide was replaced by bilaterally; he had a height of 114 cm stopped at 14 years of age when the nifedipine 10 mg twice daily. (5.34 standard deviation score [SDS]) patient’s height was 172 cm (1.13 and a significantly advanced bone In an attempt to optimize the SDS). No adverse side effects ensued age of 8 years. Hormonal profiles patient’s growth and prevent further from the anastrozole. Notably, after revealed elevated 11-deoxycortisol, bone age acceleration, the patient at the cessation of treatment, the dehydroepiandrosterone sulfate, the age of 7.38 years was commenced patient had a normal dual-energy testosterone, and corticotropin on a third-generation AI, anastrozole radiograph absorptiometry scan with concentrations with suppressed (1 mg/d), in combination with GH L1–L4 bone mineral density of renin and aldosterone, confirming (0.87 mg/m2 per day). At that point, 1.00 g/cm2 (z score, 1.0) and left hip β a diagnosis of 11 -hydroxylase- his height was 131.3 cm (1.43 SDS), bone mineral density of 1.10 g/cm2 deficient CAH. A computed and his growth velocity had slowed (z score, 0.8). Results of spinal tomography scan of his abdomen to 0.8 cm/year (–5.52 SDS). radiography and spine MRI were revealed bilateral adrenal also normal. Lipid profile, serum After this strategy, the patient’s hyperplasia. He was commenced on biochemistry including testosterone, 2 growth rate initially decreased but hydrocortisone 20 mg/m per day, and hemoglobin (ranging from then normalized, and by 10.75 years, which was then reduced by 5 mg per 13–14.3 g/dL) were within normal 2 his height was 147.8 cm (0.94 SDS) week until a dose of 10 mg/m per physiologic concentrations. with a growth velocity of 7.5 cm/ day was reached within 4 weeks of Currently, at 15.35 years of age, year (3.33 SDS). At this stage, his commencement of treatment, with his height is 177.5 cm (0.81 SDS), pubertal staging was G4P4A1 T 3 mL rapid normalization of biochemical with a pubertal staging of G5P5A3 bilaterally, and bone age had only markers (11-deoxycortisol T 15 mL bilaterally. From the age of slightly progressed to 14 years. 4.6 ng/mL and corticotropin 13 years, the patient’s compliance 25 pg/mL). He subsequently developed The patient continued on GH, with treatment was problematic as hypertension, initially treated anastrozole, and hydrocortisone with evidenced by elevated corticotropin with enalapril; after an inadequate the onset of gonadotropin-dependent concentrations (1250 ng/L), and response, furosemide was added 3 puberty at the age of 11.7 years. He he was therefore switched to times weekly to optimize control. had a normal pubertal growth spurt prednisolone (7.5 mg in the morning The patient was first seen in the with a maximum growth velocity and 5 mg in the evening) to improve United Kingdom at the age of 6.5 of 12 cm/year (2.81 SDS) at 12.93 his compliance with glucocorticoid

Downloaded from www.aappublications.org/news by guest on September 23, 2021 e2 HAWTON et al FIGURE 1 Growth chart, including height, bone age, pubertal staging, and medication.

Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 139 , number 2 , February 2017 e3 treatment. He continues to grow, but children with 11β-hydroxylase and hypertension, the patient was his height velocity is now negligible deficiency.5, 6 given corticosteroids, which were and he has reached his near-final AIs block the action of P450 optimized before commencing GH adult height, which has exceeded his aromatase, which converts and letrozole at 8 and 9 years of age, mid-parental height by 11.5 cm. androgens into estrogens, and can respectively. As in our case, adult be used to decelerate growth plate height prediction was exceeded, DISCUSSION fusion by minimizing estrogen action. and no adverse effects were found Evidence is accumulating regarding in terms of vertebral malformation, We report a relatively novel approach their use to increase final height bone fragility, or dyslipidemia. for the treatment of predicted adult in a range of conditions affecting Although combination treatment short stature in 11β-hydroxylase- stature. In 1 study of 52 patients with GH and AIs seemed to be deficient CAH. Despite presenting late with GH deficiency, anastrozole efficacious in these 2 individuals with a bone age that was advanced in combination with GH therapy with no adverse effects, these data by 7 years, the patient’s linear was shown to increase predicted need to be reproduced by conducting growth surpassed expectations after adult height (by 6.7 cm vs 1.0 cm randomized controlled trials in a treatment with GH and anastrozole. with GH alone) while maintaining larger number of patients. Given the Predicted final height upon his normal pubertal progression. 7 rarity of this condition, such studies initial presentation in the United A randomized controlled trial of are likely to be difficult, although they Kingdom was exceeded by 27.5 cm boys with constitutional pubertal may be possible if other forms of CAH and mid-parental height by 11.5 cm. delay treated with the AI letrozole (eg, 21-hydroxylase deficiency due to To our knowledge, this report is plus testosterone (N = 9) for 1 year CYP21A2 mutations) presenting with 3 only the second documented case during adolescence significantly virilization and advanced skeletal of combination therapy with GH and improved near-final adult heights maturation are included. Further an AI to optimize growth in a patient compared with testosterone with research is needed to elucidate the β with 11 -hydroxylase deficiency. placebo. 8 In 1 study of 28 children optimal timing for the introduction with 21-hydroxylase deficiency, the and duration of treatment with AI Efforts to improve final height in combination of a reduced dose of and GH to optimize linear growth and children with CAH have led clinicians hydrocortisone with an antiandrogen to identify those patients who may to investigate alternative and (flutamide) and an AI (testolactone) benefit most from this treatment. adjunctive therapies, such as GH, slowed bone maturation while Current data involving the use of gonadotropin-releasing hormone maintaining growth velocity AIs in growth disorders have been (GnRH) agonists, AIs, androgen generally promising with respect compared with a conventional blockers, or a combination of these to safety profiles. 7, 9, 11, 12 However, high-dose glucocorticoid regimen. 9 medications. Much of the evidence additional studies are required to This study is ongoing, and the relating to treatment to improve establish the long-term side effects patients have now been switched to height potential in CAH has focused of treatment with AIs in this patient letrozole. 10 on the more common 21-hydroxylase group, including the evaluation of deficiency. One study of 34 patients their impact on later fertility, lipid with 21-hydroxylase deficiency The only other reported case using profiles, and bone mineral density. showed that GH, either alone or in this approach in 11β-hydroxylase combination with a GnRH analogue, deficiency was a patient with a 46, XX improves final adult height, with an karyotype, who was raised as male. ABBREVIATIONS This patient had an oophorectomy average 9-cm height gain in male AI: aromatase inhibitor 4 after presentation at the age of 3 subjects. Evidence for adjunctive CAH: congenital adrenal years in Pakistan with virilization treatments to improve growth in hyperplasia β and cryptorchidism 3 and similarly 11 -hydroxylase deficiency is more GH: growth hormone 5 had received suboptimal initial limited. There are some case reports GnRH: gonadotropin-releasing corticosteroid treatment. After which suggest that GH in combination hormone with GnRH agonists may be useful presenting in Canada at the age of SDS: standard deviation score in improving height outcomes in 7 years with an advanced bone age

FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.

Downloaded from www.aappublications.org/news by guest on September 23, 2021 e4 HAWTON et al REFERENCES 1. J ääskeläinen J, Voutilainen R. Growth defi ciency. J Pediatr Endocrinol Metab. testolactone, and reduced of patients with 21-hydroxylase 2006;19(6):855–857 hydrocortisone dose maintain normal defi ciency: an analysis of the factors 6. Or ío Hernández M, Yebra Yebra J, growth velocity and bone maturation infl uencing adult height. Pediatr Res. Bezanilla López C, Gracia Bouthelier despite elevated androgen levels 1997;41(1):30–33 R. 11β-Hydroxylase defi ciency: in children with congenital adrenal 2. Skinner CA, Rumsby G, Honour improvement of fi nal height with hyperplasia. J Clin Endocrinol Metab. JW. Single strand conformation growth hormone and gonadotropin- 2000;85(3):1114–1120 polymorphism (SSCP) analysis for releasing hormone analog [in 10. Shulman DI, Francis GL, Palmert MR, the detection of mutations in the Spanish]. An Pediatr (Barc). Eugster EA; Lawson Wilkins Pediatric CYP11B1 gene. J Clin Endocrinol Metab. 2007;67(2):153–156 Endocrine Society Drug and Therapeutics 1996;81(6):2389–2393 Committee. Use of aromatase inhibitors 7. Mauras N, Gonzalez de Pijem L, Hsiang in children and adolescents with 3. Nour MA, Pacaud D. Height HY, et al. Anastrozole increases β disorders of growth and adolescent augmentation in 11 -hydroxylase predicted adult height of short development. Pediatrics. 2008;121(4). defi ciency congenital adrenal adolescent males treated with growth Available at: www.pediatrics. org/ cgi/ Int J Pediatr Endocrinol hyperplasia. . hormone: a randomized, placebo- content/full/ 121/ 4/ e975 2015;2015(1):12 controlled, multicenter trial for one to three years. J Clin Endocrinol Metab. 11. Dunkel L. Update on the role of 4. Lin-Su K, Harbison MD, Lekarev O, 2008;93(3):823–831 aromatase inhibitors in growth Vogiatzi MG, New MI. Final adult height disorders. Horm Res. 2009;71(suppl in children with congenital adrenal 8. Hero M, Wickman S, Dunkel L. 1):57–63 hyperplasia treated with growth Treatment with the aromatase 12. Wickman S, Kajantie E, Dunkel L. hormone. J Clin Endocrinol Metab. inhibitor letrozole during adolescence Effects of suppression of estrogen 2011;96(6):1710–1717 increases near-fi nal height in boys with action by the p450 aromatase constitutional delay of puberty. Clin inhibitor letrozole on bone mineral 5. Bajpai A, Kabra M, Menon PS. Endocrinol (Oxf). 2006;64(5):510–513 Combination growth hormone and density and bone turnover in pubertal gonadotropin releasing hormone 9. Merke DP, Keil MF, Jones JV, Fields boys. J Clin Endocrinol Metab. analog therapy in 11β-hydroxylase J, Hill S, Cutler GB Jr. Flutamide, 2003;88(8):3785–3793

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