Untreated Boys Research Articles

DMD/BMD - GENETICS: EP.116 Establishing clinical and genetic characteristics in young, glucocorticoid-naïve boys with Duchenne muscular dystrophy: the FOR DMD study

We describe the clinical characteristics and genetic profile of a large sample of young glucocorticoid-naïve boys with Duchenne muscular dystrophy (DMD). Screening and baseline data were collected for participants in the FOR-DMD study, an international, multi-centre, randomized, double-blind clinical trial comparing 3 commonly prescribed glucocorticoid regimens in untreated DMD boys with a confirmed genetic diagnosis of DMD between 4 and < 8 years of age. One hundred ninety-six boys were recruited in the study. The mean age at randomization was 5.9 (standard deviation, SD 1 year). The most frequent mutation type was out of frame deletions (130/193, 67.3%) of which 68.5% (89/130) were amenable to exon skipping. Mutations amenable to exon 51 skipping were the most frequent (n=25). Stop codon mutations were reported in 19/193 boys (10%). The mean age of parental concern was 29.8 months (SD 18.7); the mean age of genetic diagnosis was 50.3 months (SD 23.8). The mean ages at independent walking and talking in sentences were 17.1 (SD 4.2) and 29.0 (SD 10.7) months, respectively. Pre-steroid median height and weight were below the 50th percentiles regardless of age group. Boys with exon 8 skippable deletions performed better in time to walk/run 10 meters compared to boys carrying other out of frame deletions not amenable to skipping (4.8±0.7 vs 6.3±4 seconds, p 0.001). Boys with exon 53 skippable deletions showed a lower baseline performance in the 6-minute walk test compared to boys with other out of frame deletions not amenable to skipping (308.9±61 vs 342±46 metres, p 0.003). In conclusion, this study describes clinical, genetic, and anthropometric characteristics of a sample of young glucocorticoid-naïve boys with DMD. Some genotype-phenotype associations were identified. These findings characterise a baseline pre-steroid cohort and, with the longitudinal data to follow, will help to inform eligibility criteria and outcome measures for future clinical trials in DMD.

Long-term Effect of Aromatase Inhibition in Aromatase Excess Syndrome.

Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens. The objective was to study long-term treatment effects of an aromatase inhibitor. Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy. All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30). Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS.

Speech and language development in children with 49,XXXXY syndrome.

49,XXXXY is the rarest X and Y chromosomal variation and is frequently characterized by expressive and receptive language dysfunction, low muscle tonus, and intellectual deficits. Due to the low incidence of this disorder, comprehensive studies analyzing the specific aspects of the speech and language phenotype in these boys have been uncommon. This is the first in-depth investigation of the speech and language profiles in a large cohort of boys with 49,XXXXY. Based on the clinical judgment of speech and language pathologists, there was an increased incidence (91.8%) of Childhood Apraxia of Speech (CAS), which has not been previously described in this disorder. In preschool boys, some significant differences were demonstrated between boys who received early hormonal treatment (n=16) and untreated boys (n=4) on the language scales (p=.047) on the Bayley Scales of Infants and Toddlers, as well as significant differences between treated (n=13) and untreated boys (n=8) on the Expressive One Word Picture Vocabulary Test (p=.008). No significant differences between treatment groups were found in school age children, however, treated groups demonstrated less discrepancies between expressive and receptive language. More research and larger samples are needed to determine the extent of the impact of testosterone treatment on boys with 49,XXXXY. This study identifies CAS as a potential explanation for the significant expressive language dysfunction and subsequent behavioral dysfunction. These findings may assist in facilitating more targeted treatment and improved outcomes for boys with 49,XXXXY.

Neurocognitive development and capabilities in boys with 49,XXXXY syndrome

49,XXXXY was previously associated with profound to severe intellectual deficits. However, prior research papers on the cognitive profiles of this population were confounded by small samples sizes, wide age spreads, and incomplete histories of testosterone replacement therapy. This study is the first comprehensive, international investigation of the neurocognitive aspects of 49,XXXXY, and the potential effects of biological treatment on this profile. Sixty-seven boys from infancy to 11 years of age were enrolled in this longitudinal study, with the majority of boys postnatally diagnosed though chromosomal analysis. These boys received a comprehensive neurocognitive evaluation tailored to specific language-based deficits and cognitive challenges. Results revealed higher neurocognitive capacities, both verbally and nonverbally, than previously reported in this disorder. Infant boys with 49,XXXXY who received early hormonal therapy (EHT) had significantly higher scores on the cognitive domain of the Bayley Scales of Infant Development than untreated infants (p=.013). In addition, treated school-aged participants had significantly better scaled scores than untreated boys in form completion (p=.042), a task that requires deductive reasoning, on nonverbal testing on the Leiter International Performance Scales. This study indicates greater cognitive capacities with a wide range of abilities in the child with 49,XXXXY, thus warranting further investigation to identify and understand the critical influences on the etiology and the variability of those capacities.

Prevalence of Asymptomatic Bacteriuria in Children: A Meta-Analysis

To determine the point prevalence of bacteriuria and bacteriuria without pyuria in asymptomatic children by a systematic review of the literature. We searched MEDLINE and EMBASE for English-, French-, German-, Italian-, and Spanish-language articles. We included articles reporting data on bacteriuria in asymptomatic children up to 19years of age who had urine collected by suprapubic bladder aspiration, bladder catheterization, or by 3 consecutive clean catch samples. Two independent reviewers assessed studies for inclusion and abstracted data. Fourteen studies (49 806 children) were included. The prevalence of asymptomatic bacteriuria was 0.37% (95% CI, 0.09-0.82) in boys and 0.47% (95% CI, 0.36-0.59) in girls. The corresponding values for asymptomatic bacteriuria without pyuria were 0.18% (95% CI, 0.02-0.51) and 0.38% (95% CI, 0.22-0.58), respectively. The subgroups with the highest prevalence of asymptomatic bacteriuria were uncircumcised males <1year of age andfemales>2years of age. In males, the prevalence of asymptomatic bacteriuria after infancy was 0.08% (95% CI, 0.01-0.37). The median duration of asymptomatic bacteriuria in untreated boys and girls, from the one study reporting this outcome, was 1.5 and 2months, respectively. Some clinicians are concerned that when a preverbal child with asymptomatic bacteriuria develops a nonlocalizing febrile illness and presents for evaluation, they may be mistakenly diagnosed as having a urinary tract infection (UTI). Given that the prevalence of asymptomatic bacteriuria is considerably lower than the prevalence of UTI in most subgroups examined, this will occur extremely rarely. These data suggest that the current definition of UTI should be revisited.

Hormonal replacement therapy and its potential influence on working memory and competency/adaptive functioning in 47,XXY (Klinefelter syndrome).

This cross-sectional, retrospective analysis investigated the possible effect of hormonal replacement therapy (HRT) on working memory (WM) and competency/adaptive functioning (CAF) in boys with 47,XXY; the effect of timing of 47,XXY diagnosis on these variables; and the relationship between WM and CAF, if any. A total of 111 boys with 47,XXY, ranging from 6 to 16 years of age (M = 9 years 4 months; SD = 2 years 1 month), were evaluated using the Wechsler Intelligence Scale for Children, and Child Behavior Checklist. Participants were grouped by HRT status and timing of diagnosis. Analysis of variance testing performed on the prenatally diagnosed boys revealed a statistically significant difference in WM for the HRT groups (F[3,84] = 7.467, p = .000174), where WM of the no-HRT group (M = 92.37, SD = 17.83) was lower than that of the early hormonal therapy group (M = 106.39, SD = 12.01; p = .0092). Additionally, there was a positive correlation between low WM capabilities and poor school performance (r = .5106, p = .0027) in the prenatally diagnosed, untreated boys. Our results highlight the potentially positive effects of HRT on WM and CAF in boys with 47,XXY. Further research is required to better determine the underlying relationship among the biological mechanisms of HRT, WM, and CAF outcomes, and timing of diagnosis in boys with 47,XXY.

Treatment of gonadotropin deficiency during the first year of life: long-term observation and outcome in five boys.

STUDY QUESTIONWhat is the peripubertal outcome of recombinant human FSH (r-hFSH) treatment during minipuberty in boys with congenital hypogonadotropic hypogonadism (CHH)?SUMMARY ANSWERSertoli-cell response to r-hFSH, given during the minipuberty of infancy, appears insufficient to maintain Sertoli cell function throughout childhood, as evaluated by inhibin B measurements.WHAT IS KNOWN ALREADYSevere CHH in boys can be diagnosed during the minipuberty of infancy. Combined gonadotropin treatment at that age is suggested to improve testicular endocrine function and future fertility, yet long-term evidence is lacking.STUDY DESIGN, SIZE, DURATIONIn this retrospective cohort study, we describe five CHH boys treated with r-hFSH in Helsinki University Hospital or Kuopio University Hospital between 2004 and 2018. Immediate follow-up data (0.1–1.4 months after cessation of the gonadotropin therapy) was available for four boys and long-term observations (at the age of 10.0–12.8 years) was available for three boys. As a retrospective control cohort, we provide inhibin B values of eight untreated CHH boys at the age of 12.7–17.8 years.PARTICIPANTS/MATERIALS, SETTING, METHODSFour patients had combined pituitary hormone deficiency, and one had CHARGE syndrome due to a CHD7 mutation. The patients were treated at the age of 0.7–4.2 months with r-hFSH (3.4 IU/kg–7.5 IU/kg per week in 2 or 3 s.c. doses for 3–4.5 months) combined with T (25 mg i.m. monthly for three months for the treatment of micropenis). Inhibin B was chosen as the primary outcome measure.MAIN RESULTS AND THE ROLE OF CHANCEDuring the r-hFSH + T treatment, inhibin B increased from 76 ± 18 ng/l to 176 ± 80 ng/l (P = 0.04) and penile length increased by 81 ± 50% (P = 0.04). Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated low inhibin B values in peripuberty: declining from 290 ng/l (4 months) to 16 ng/l (12.4 years), and from 207 ng/l (6 months) to 21 ng/l (12.8 years). All boys underwent orchiopexy at 2.0 ± 0.7 years of age. Inhibin B values in long-term follow-up, available for the three boys, did not significantly differ from the untreated CHH controls.LIMITATIONS, REASONS FOR CAUTIONLimitations of this retrospective study are the small number and heterogeneity of the patients and their treatment schemes.WIDER IMPLICATIONS OF THE FINDINGSWe describe the first long-term follow-up data on CHH boys treated with r-hFSH and T as infants. The results from this small patient series suggest that the effects of infant r-hFSH treatment may be transient, and further longitudinal studies are required to determine the efficacy of this treatment approach to optimise the fertility potential in this patient population.STUDY FUNDING/COMPETING INTEREST(S)This work was supported by the Finnish foundation for Pediatric Research, the Academy of Finland and the Emil Aaltonen Foundation. The authors have no competing interests.TRIAL REGISTRATION NUMBERNon-applicable.

Twice-weekly glucocorticosteroids in infants and young boys with Duchenne muscular dystrophy.

Glucocorticosteroids (GC) are effective in slowing weakness in boys with Duchenne muscular dystrophy (DMD). This is a multisite, 1-year, open-label trial of twice-weekly prednisolone (5 mg/kg/dose) in infants/young boys (0.4-2.4 years) with DMD. We compared changes in Bayley III Scales of Infant Development (Bayley-III) with untreated boys followed for 1 year (historical control cohort [HCC]). Twenty-three of 25 participants completed the study. Treated boys gained an average of 0.5 points on the Bayley-III gross motor scaled score (GMSS) compared with the HCC who, on average, declined 1.3 points (P = 0.03). All boys maintained linear growth, and none developed Cushingoid features. Excessive weight gain occurred in 13 of 23 (56%) boys. This study provides evidence that twice-weekly GC is well tolerated in infants and young boys with DMD and improves GMSS. Excessive weight gain is a potential risk. Longer follow-up is required to determine whether early GC initiation is feasible in most infants/boys with DMD. Muscle Nerve 59:650-657, 2019.

The Effect of Gonadotropin-Releasing Hormone Analogue on Final Adult Height in Children with Idiopathic Short Stature

Objective: To assess final adult height (FAH) in children with short stature treated with gonadotropin-releasing hormone analogue (GnRHa). Methods: All patients with idiopathic short stature (ISS) with normally timed puberty and a Tanner stage between 2 and 3, who achieved their FAH between 2005 and 2015, were included in this clinical historical cohort study. Height gain, FAH, and mid-parental height of 28 children with ISS who received GnRHa treatment for 1.8 ± 1.0 years to delay their puberty were compared to 31 untreated children. Results: The FAHs of the treated and the untreated girls were 151.3 ± 5.1 and 146.8 ± 3.8 cm (p = 0.01), respectively. The FAHs of the treated and the untreated boys were 156.4 ± 4.7 and 152.3 ± 5.7 cm (p = 0.111), respectively. The height gain in the treated and the untreated girls was 1.6 ± 7.8 and –3.6 ± 5.7 cm (p = 0.036), respectively. Height gain in the treated and the untreated boys was –5.1 ± 13.6 and –11.5 ± 8.4 cm (p = 0.171), respectively. Conclusion: GnRHa therapy has a modest effect in improving FAH in adolescent females with ISS but not in boys.

Association between Bronchial Asthma and Pubertal Delay in Pediatric Patients

Background: asthma is a chronic inflammatory disease with a considerable prevalence and unfavorable impacts on various body systems. The natural history of asthma has been extensively investigated in terms of the varied effects on age and gender. Aim of the study: this study aims to achieve a better understanding of the unclear relationship between bronchial asthma and pubertal delay in the pediatric age group. Methods: we reviewed the scientific literature concerned with studying the effect of asthma and its treatment on the growth of children and the onset of puberty using some international medical databases (Medline, Google scholar, EMBASE). Conclusion: Although there have been some community-based surveys and studies based on young children which failed to find an association between asthma and growth, others revealed that asthma can cause growth retardation through different mechanisms, including hypoxia, impaired lung functions, or endocrine malfunctions. Pubertal delay is also observed in untreated asthmatic boys and girls. In addition, inhaled corticosteroids, the best available treatment of asthma, were found also to have an effect on pubertal delay and this effect is dependent on the dose, duration and the outcome of therapy. When concentrating on pubertal delay, it seems that more longitudinal studies are required to comprehensively investigate the effects of asthma and its treatment on this vital stage of life.

Promoting the use of Motor Function Measure (MFM) as outcome measure in patients with Duchenne Muscular Dystrophy (DMD) treated by corticosteroids

Assessing muscle function is a key step in measuring changes and evaluating the outcomes of therapeutic interventions in Duchenne Muscular Dystrophy (DMD). Regarding the large use of corticosteroids (CS) in this population to delay the loss of function, our goal was to monitor the evolution of motor function in patients with DMD treated by corticosteroids (CS) and to study the responsiveness of Motor Function Measure (MFM) in this population in order to provide an estimation of the number of subject needed for a clinical trial. A total of 76 patients with DMD, aged 5.9 to 11.8 years, with at least 6 months of follow-up and 2 MFM were enrolled, 30 in the CS treated group (8 ± 1.62 y) and 46 in the untreated group (7.91 ± 1.50 y). The relationship between MFM scores and age was studied in CS treated patients and untreated patients. The evolution of these scores was compared between groups, on a 6-, 12- and 24-month period by calculating slopes of change and standardized response mean. At 6, 12 and 24 months, significant differences in the mean score change were found, for all MFM scores, between CS treated patients and untreated patients. For D1 subscore specifically, at 6 months, the increase is significant in the treated group (11.3 ± 14%/y; SRM 0.8) while a decrease is observed in the untreated group (–17.8 ± 17.7%/y; SRM 1). At 12 and 24 months, D1 subscore stabilized for treated patients but declined significantly for untreated boys (–15.5 ± 15.1%/y; SRM 1 at 12 mo and–18.8 ± 7.1%/y; SRM 2.6 at 24 mo). 21 patients lost the ability to walk during the study: 6 in the CS treated group (25% at 24 months, mean age: 10.74 ± 1.28 y) and 15 in the untreated group (64.71% at 24 months, mean age: 9.20 ± 1.78 y). Patients with DMD treated by CS present a different course of the disease described in this paper using the MFM. Based on these results, an estimation of the number of patients needed for clinical trial could be done.

Design of clinical trials for new products in hemophilia: communication from the SSC of the ISTH

Design of clinical trials for new products in hemophilia: communication from the SSC of the ISTH

Duchenne muscular dystrophy.

Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies.

Recombinant factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A

AbstractSix recombinant factor VIII (rFVIII) products have been marketed worldwide. In 2013, the Research of Determinants of Inhibitor Development (RODIN) study group reported an unexpectedly high risk of inhibitor development with a second-generation full-length rFVIII (Product D) in previously untreated patients (PUPs) with severe hemophilia A (HA). In 1994, French public health authorities established a prospective cohort to monitor hemophilia treatment safety. A PUP subgroup was designed to investigate inhibitor risk factors. We analyzed this subcohort in view of the RODIN findings. After excluding 50 patients who participated in the RODIN study, the primary analysis focused on 303 boys with severe HA first treated with a rFVIII product. A clinically significant inhibitor was detected in 114 boys (37.6%). The inhibitor incidence was higher with Product D vs the most widely used rFVIII product (adjusted hazard ratio [aHR], 1.55; 95% confidence interval [CI], 0.97-2.49). Similar results were found for high-titer inhibitors and in 10 sensitivity analyses. No heterogeneity was observed between RODIN and our results. Combined aHRs were 1.58 (95% CI, 1.17-2.14) for all inhibitors and 1.70 (95% CI, 1.15-2.52) for high-titer inhibitors. Our results confirm the higher immunogenicity of Product D vs other rFVIII products in PUPs with severe HA.

Inhibitor Development with Recombinant Factor VIII: A Product Comparison

Recombinant factor VIII has supplanted plasma-derived factor VIII for treatment of patients with hemophilia because it is not associated with the transmission of infectious agents. However, it does induce inhibitors (alloantibodies) in up to 35% of patients. To determine whether the risk for inhibitor development varies among recombinant factor VIII products, investigators in France analyzed data from 303 previously untreated boys with hemophilia …

Variation in Timing, Duration, Intensity, and Direction of Adolescent Growth in the Mandible, Maxilla, and Cranial Base: The Fels Longitudinal Study

There is considerable individual variation in the timing, duration, and intensity of growth that occurs in the craniofacial complex during childhood and adolescence. The purpose of this article is to describe the extent of this variation between traits and between individuals within the Fels Longitudinal Study (FLS). Polynomial multilevel models were used to estimate the ages of onset, peak velocity, and cessation of adolescent growth, the time between these ages, the amount of growth between these ages, and peak velocity. This was done at both the group and individual levels for standard cephalometric measurements of the lengths of the mandible, maxilla, and cranial base, the gonial angle, and the saddle angle. Data are from 293 untreated boys and girls age 4-24 years in the FLS. The timing of the adolescent growth spurt was, in general, not significantly different between the mandible and the maxilla, with each having an earlier age of onset, later age of peak velocity, and later age of cessation of growth as compared to the cranial base length. Compared to lengths, angles had in general later ages of onset, peak velocity, and cessation of growth. Accurate characterization of the ontogenetic trajectories of the traits in the craniofacial complex is critical for both clinicians seeking to optimize treatment timing and anatomists interested in examining heterochrony.

CONTRAIS: CONservative TReatment for Adolescent Idiopathic Scoliosis: a randomised controlled trial protocol

BackgroundIdiopathic scoliosis is a three-dimensional structural deformity of the spine that occurs in children and adolescents. Recent reviews on bracing and exercise treatment have provided some evidence for effect of these interventions. The purpose of this study is to improve the evidence base regarding the effectiveness of conservative treatments for preventing curve progression in idiopathic scoliosis.Methods/designPatients: Previously untreated girls and boys with idiopathic scoliosis, 9 to 17 years of age with at least one year of remaining growth and a curve Cobb angle of 25–40 degrees will be included. A total of 135 participants will be randomly allocated in groups of 45 patients each to receive one of the three interventions.Interventions: All three groups will receive a physical activity prescription according to the World Health Organisation recommendations. One group will additionally wear a hyper-corrective night-time brace. One group will additionally perform postural scoliosis-specific exercises.Outcome: Participation in the study will last until the curve has progressed, or until cessation of skeletal growth. Outcome variables will be measured every 6 months. The primary outcome variable, failure of treatment, is defined as progression of the Cobb angle more than 6 degrees, compared to the primary x-ray, seen on two consecutive spinal standing x-rays taken with 6 months interval. Secondary outcome measures include the SRS-22r and EQ5D-Y quality of life questionnaires, the International Physical Activity Questionnaire (IPAQ) short form, and Cobb angle at end of the study.DiscussionThis trial will evaluate which of the tested conservative treatment approaches that is the most effective for patients with adolescent idiopathic scoliosis.Trial registrationNCT01761305

Oral Corticosteroids and Onset of Cardiomyopathy in Duchenne Muscular Dystrophy

To estimate the age when cardiomyopathy develops in boys with Duchenne muscular dystrophy (DMD) and to analyze the effect of corticosteroid treatment on the age of cardiomyopathy onset. We identified a population-based sample of 462 boys with DMD, born between 1982 and 2005, in 5 surveillance sites in the US. Echocardiographic and corticosteroid treatment data were collected. Cardiomyopathy was defined by a reduced fractional shortening (<28%) or ejection fraction (<55%). The age of cardiomyopathy onset was determined. Survival analysis was performed to determine the effects of corticosteroid treatment on cardiomyopathy onset. The mean (SD) age of cardiomyopathy onset was 14.3 (4.2) years for the entire population and 15.2 (3.4) years in corticosteroid-treated vs 13.1 (4.8) in non-treated boys. Survival analysis described a significant delay of cardiomyopathy onset for boys treated with corticosteroids (P < .02). By 14.3 years of age, 63% of non-treated boys had developed cardiomyopathy vs only 36% of those treated. Among boys treated with corticosteroids, there is a significant positive effect of duration of corticosteroid treatment on cardiomyopathy onset (P < .0001). For every year of corticosteroid treatment, the probability of developing cardiomyopathy decreased by 4%. Oral corticosteroid treatment was associated with delayed cardiomyopathy onset. The duration of corticosteroid treatment also correlated positively with delayed cardiomyopathy onset. Our analysis suggests that a boy with DMD treated for 5 years with corticosteroids might experience a 20% decrease in the likelihood of developing cardiomyopathy compared with untreated boys.

Growth Pattern of Untreated Boys with Simple Virilizing Congenital Adrenal Hyperplasia Indicates Relative Androgen Insensitivity during the First Six Months of Life

Context: Mild forms of simple virilizing congenital adrenal hyperplasia (CAH) may be missed in newborn screening. In the pre-newborn-screening era, missed diagnosis of simple virilizing CAH was not infrequent in boys. Elevated adrenal androgens lead to accelerated growth and bone maturation. Traditional treatment of CAH consists of the suppression of ACTH through glucocorticoid replacement, in an attempt to reduce excessive androgen production. Objective: To retrospectively analyze early growth pattern and bone maturation in untreated boys with simple virilizing CAH. Patients: In the pre-newborn screening era, 13 boys had a late diagnosis of simple virilizing classical CAH. Diagnosis of 21-hydroxylase deficiency was confirmed by mutation analysis of the CYP21A2 gene in all patients. Growth data were retrospectively collected from standarized preventive medical checkups at the regular pediatrician until the time of diagnosis of CAH. Results: Length was 0.1 ± 0.8 SDS (mean ± SD) at birth, 0.2 ± 1 SDS at 3 months, 0.2 ± 0.9 SDS at 6 months, 0.7 ± 1 SDS at 1 year, +1.1 ± 0.9 SDS at 2 years and +1.8 ± 1.2 SDS at 4 years. At diagnosis, mean chronological age was 4.4 ± 1.6 years and height SDS was 2 ± 1.7. Bone age was accelerated (9.4 ± 4 years) at diagnosis. Signs that had led to diagnosis were pubic hair (n = 11), accelerated growth rate (n = 6) and birth of an affected sister (n = 3). Despite late start of hydrocortisone treatment, mean final height was –1 ± 0.9 SDS. Seven of 18 patients had a final height within 1 SD of target height. Conclusion: Height velocity is not markedly increased in untreated boys with simple virilizing CAH in the first 6 months of life, indicating that infants are relatively androgen insensitive during that period. After the first 6 months of life, growth velocity increases significantly and elevated androgens lead to advanced skeletal maturation. This observation has implications for lower hydrocortisone doses to be used in CAH children during the first 6 months of life. In addition, staying alert for clinical symptoms and signs of simple virilizing CAH is still warranted, since mild forms may be missed in newborn screening.

Boys with a Simple Delayed Puberty Reach Their Target Height

Introduction: Final height in boys with delayed puberty is thought to be below target height. This conclusion, however, is based on studies that included patients with genetic short stature. We therefore studied final height in a group of 33 untreated boys with delayed puberty with a target height >–1.5 SDS. Methods: Standing height, sitting height, weight and arm span width were measured in each patient. Final height was predicted by the method of Greulich and Pyle using the tables of Bailey and Pinneau for retarded boys at their bone age (PAH1) and the tables of Bailey and Pinneau for average boys plus six months (PAH2). Results: Mean final height (175.8 ± 6.5 cm) was appropriate for the mean target height (174.7 ± 4.5 cm). The prediction method of Bailey and Pinneau overestimated the final height by 1.4 cm and the modified prediction method slightly underestimated the final height (–0.15 cm). Conclusion: Boys with untreated delayed puberty reach a final height appropriate for their target height. Final height was best predicted by the method of Bailey and Pinneau using the tables for average boys at their bone age plus six months.