Height augmentation in 11β-hydroxylase deficiency congenital adrenal hyperplasia

A number of complex treatment issues arise in the management of patients with CAH. Issues such as gender-identity, growth, blood pressure management, surgical correction, and pubertal management are among the clinical difficulties addressed by the multidisciplinary medical team. The presented case illustrates a number of these in a young patient with CAH due to 11β-OH deficiency. Among these issues, in particular, we highlight the unique aspects of optimizing height in this patient with dramatic improvement in final adult height.

The influence of CAH due to 11β-OH deficiency on final adult height has not been thoroughly examined in the literature. While no reviews exist in 11β-OH deficiency, a recent systematic review and meta-analysis of 21-OH deficiency CAH demonstrated the final height S.D. score was – 1.38 (−1.56 to −1.20; I² = 90.2%) in patients, despite optimization of CAH treatment [6]. Optimization of height is often a delicate balance between corticosteroid replacement to suppress androgen excess while attempting to limit effects of glucocorticoid excess. The treatment of 11β-OH deficiency involves achieving a similarly challenging balance. Although, as demonstrated with the presented patient, CAH due to 11β-OH deficiency may require higher glucocorticoid doses than those currently recommended for patients with CAH due to 21-OH deficiency [7]. Patients with suboptimal control or inadequate treatment, such as our patient, may have substantial reduction in their growth potential [3].

Current Endocrine Society guidelines do not endorse the use of growth augmenting therapies outside of the context of research studies [7]. Our case highlights the success of these treatments in the setting of late diagnosis and initial suboptimal control leading to a significant threat to final height attainment. While we do not advocate for such therapies in all CAH patients, in certain dire circumstances their use may be justified. Prior to initiation of GH and Letrozole, our patient had a predicted adult height of 150.4 – 151.1 cm (depending on female or male reference standard used respectively) which increased by 16.4 – 17.1 cm by the time of attainment of final adult height (167.5 cm; −1.3 S.D. male standard). This final height is considerably greater than these early predictions and also higher than his genetic calculated mid-parental height for a female of 164 cm (−1.8 S.D.). He received a total of 5.3 years of GH treatment and 4.6 years of AI treatment. A recent prospective study of GH use in 21-OH deficiency CAH found a final height gain of 9.2 ± 6.7 cm in males and 10.5 ± 3.7 cm in females with a mean GH treatment duration of 5.6 ± 1.8 and 4.5 ± 1.6 years, respectively [8]. We would advocate that in the setting of extreme impairment of predicted final height, consideration of these therapies may be beneficial. Similar to dosages used in idiopathic short stature, we used a relatively high dose of GH in our patient given the degree of predicted growth impairment.

Our patient benefited from a combined therapeutic approach using corticosteroids, GH and aromatase inhibition. Growth hormone treatment was initiated due to ongoing impairments in predicted final adult height despite corticosteroid treatment. While the GH treatment had benefit in growth velocity (4.2 cm/year vs. 7.8 cm/year respectively) further advancement in bone age continued to compromise projected height benefit. The addition of Letrozole, a third generation steroidal AI, to the treatment regime resulted in dramatic benefit in final height by inducing a slowing bone maturation. Over the span of approximately 2 years there was virtually no advancement of bone maturation.

Aromatase inhibition has been used in an off-label manner in a select group of pediatric conditions, including hyperestrogenism, hyperandrogenism, pubertal gynecomastia and short stature [9]. Their use in CAH has been limited. To date only one study has been conducted examining the use of AIs for height augmentation in CAH [10]. In this trial, children were randomized to 2 year treatment with 1) Flutamide, testolactone and reduced hydrocortisone dose and fludrocortisone vs. 2) Standard treatment with hydrocortisone and fludrocortisone. The study demonstrated a slight trend to increased predicted final adult height (+0.6 S.D.) in the testolactone/flutamide group, however, the difference was not statistically different. This trial has been ongoing and in 2004, subjects were switched to Letrozole; however, results have not yet been published [11].

The use of AIs in the pediatric setting must be used with caution due to unknown potential long term complications and thus far only modest height benefits. In males treated with AIs, hypertestosteronemia has been observed [12]. This rise in serum testosterone is due to the reduced estrogen feedback on the hypothalamus leading to increased levels of LH. No adverse effects from hypertestosteronemia have been reported. In our patient, previous oophorectomy and female karyotype obviated this risk. Of interest, however, a slight increase in serum androgens was noted with AI introduction. This increase would be possible either through decreased conversion of androgens or an increase in adrenal androgen production. Other potential concerns with AI use have included impaired bone mineral density, body composition and metabolic effects such as dyslipidemias [9]. In addition, there is hesitancy in using AIs in females due to concerns of undesirable effects of hyperandrogenemia. In our patient, these potential effects were viewed as desirable due to his male gender identification. Vertebral malformations have also been reported to be associated with the use of AIs with particular risk when used during the pre-puberty or early puberty phases [13].

Various other growth augmenting therapies have been explored in the setting of CAH with variable success. In addition to standard therapy with glucocorticoids, these have included growth hormone, GnRH analogs, and anti-androgens to increase final height [14]. In our patient, GnRH analogs would have been of no benefit given the previous oophorectomy.

Of particular concern for our patient were the cultural and societal implications of height attainment. Being raised male, our patient had societal expectations of a higher final height attainment. While evolutionarily this increased final height in males is less drastic than in other species, it remained an important factor for this family when determining treatment goals [15]. The notion that short stature has a negative impact on psychosocial adaptation has been disproved by recent studies done in healthy children [16]. However, in the context of short stature associated with a chronic condition such as CAH, patient and family preferences may need to be considered. In particular, a patient already stigmatized with having a chronic medical condition, gynecomastia, infertility, and abnormal genital anatomy, the normalization of height was an attainable and beneficial goal for patient care.

While assessing bone maturation remains an important tool in monitoring treatment in CAH [17], considerable difficulty exists in determining the most accurate method to predict final adult height, particularly in patients such as the one presented. Although our patient was raised as male, he had a 46, XX karyotype. The endogenous androgen exposure of our patient was significantly higher than that of an otherwise healthy female. These exposures may have significant influence on bone growth and development. Thus, the interpretation of bone age radiography may be difficult as the differential effect of chromosomal and hormonal influences are ultimately unknown. Interestingly, despite significant variations in bone age interpretation based on gender, the effect on final height prediction for our patient was minimal (see Table 2 and Figure 1). Ultimately, consistency with regard to interpretation of these tests is paramount.