Characteristics of Growth in Children With Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency During Adrenarche and Beyond

Abstract

Context Patients with classic congenital adrenal hyperplasia (CAH) often fail to achieve their full growth potential. Adrenarche may accelerate bone maturation and thereby result in decreased growth in CAH. Objective To analyze the impact of growth during adrenarche on final height of adequately treated classic CAH patients. Design Retrospective, multi-center study. Setting Four academic pediatric endocrinology centers. Participants Fourty-one patients with classical CAH, born between 1990 and 2012. Main outcome measures We assessed skeletal maturation (bone age), growth velocity and (projected) adult height outcomes, and analyzed potential influencing factors, such as sex, genotype, and glucocorticoid therapy. Results Patients with classic CAH were shorter than peers (-0.4SDS±0.8SD) and their parents (corrected final height -0.6SDS±1.0SD). Analysis of growth during adrenarche revealed two different growth patterns: patients with accelerating bone age (49%), and patients with non-accelerating bone age compared to chronological age (BA-CA). Patients with accelerating BA-CA were taller than the normal population during adrenarche years (p=0.001) and were predicted to achieve a lower adult height SDS (-0.9SDS, 95%CI -1.3;-0.5) than non-accelerating patients when assessed during adrenarche (0.2SDS, 95%CI -0.3;0.8). Final adult height was similarly reduced in both accelerating and non-accelerating BA-CA groups (-0.4SDS, 95%CI -0.9;0.1 vs -0.3SDS, 95%CI -0.8;0.1). Conclusions Patients with and without significant bone age advancement, and thus differing height prediction during adrenarche, showed similar (predicted) final height when reassessed during pubertal years. Bone age alone should not be used during adrenarche as clinical marker for metabolic control in CAH treatment.

Monitoring treatment in pediatric patients with 21-hydroxylase deficiency

“…A second meta-analysis of 35 studies conducted between 1966 and 2007 showed an average FH SDS of -1.38 and a corrected FH SDS of -1.03 ( 16 ). A recent study reported mean FH SDS values of -0.4 to -1.4 ( 17 – 23 ). Good compliance, early diagnosis (age <1 year), and short duration of HDC treatment in the peripubertal period reportedly improved FH ( 15 , 19 , 20 , 22 ).…”

“…Nonetheless, whatever the definition, several studies reported less pubertal height gain in patients with 21-OHD than in a population of healthy subjects ( 17 , 24 – 29 ). The latest study, in which all the subjects received a diagnosis of 21-OHD in the neonatal period, demonstrated that the pubertal growth spurt was similar to that of healthy children of both sexes ( 23 ). This apparently normal pubertal development suggests that early diagnosis via newborn screening enabled normalization of pubertal height gain and FH.…”

“…At least two points pertinent to HDC use need to be kept in mind: first, bone age should be assessed after age 2 years because even in untreated patients with classic 21-OHD, bone age does not advance until age 1-1.5 years ( 40 ). Second, during puberty bone age alone cannot be used as a clinical marker because it cannot accurately predict the FH ( 23 ). Generally, a once yearly bone age evaluation is considered sufficient, but evaluations should be performed twice yearly if the growth rate shows a rapid change, or the patient enters puberty ( 4 ).…”

“…Although the latest guidelines do not mention the management of 21-OHD during puberty ( 3 , 4 ), two, retrospective studies discussing the optimal treatment method for pubertal patients ( 17 , 62 ) suggested that the pubertal, growth-suppressing effects of HDC outweigh the negative effects of elevated androgens, and that the HDC dosage during puberty should not exceed 17 mg/m 2 /day to optimize FH. However, other studies have not focused on biochemical monitoring during puberty ( 23 – 29 ). It may be difficult to conduct a prospective study of this matter because of the heterogeneity in pubertal progression.…”

“…A high-quality registry system can provide clues to better monitoring methods. Several countries have already established their own, whole case registry system and produced meaningful research outcomes ( 23 , 63 – 65 ). If the challenges of monitoring described above can be solved, treatments can be refined to enable patients with 21-OHD to receive appropriate management over the course of their whole life.…”