Growth reference charts for children with hypochondroplasia.

Hypochondroplasia (HCH) is a rare skeletal dysplasia causing mild short stature. There is a paucity of growth reference charts for this population. Anthropometric data were collected to generate height, weight, and head circumference (HC) growth reference charts for children with a diagnosis of HCH. Mixed longitudinal anthropometric data and genetic analysis results were collected from 14 European specialized skeletal dysplasia centers. Growth charts were generated using Generalized Additive Models for Location, Scale, and Shape. Measurements for height (983), weight (896), and HC (389) were collected from 188 (79 female) children with a diagnosis of HCH aged 0-18 years. Of the 84 children who underwent genetic testing, a pathogenic variant in FGFR3 was identified in 92% (77). The data were used to generate growth references for height, weight, and HC, plotted as charts with seven centiles from 2nd to 98th, for ages 0-4 and 0-16 years. HCH-specific growth charts are important in the clinical care of these children. They help to identify if other comorbidities are present that affect growth and development and serve as an important benchmark for any prospective interventional research studies and trials.

Maternal nutrition during mid-pregnancy and children's body composition at 7 years of age in the SELMA study.

Optimal nutrition during pregnancy is vital for both maternal and child health. Our objective was to explore if prenatal diet is associated with children's height and body fat. Nutrient intake was assessed through a FFQ from 808 pregnant women and summarised to a nutrition index, 'My Nutrition Index' (MNI). The association with children's height and body fat (bioimpedance) was assessed with linear regression models. Secondary analysis was performed with BMI, trunk fat and skinfolds. Overall, higher MNI score was associated with greater height (ß = 0·47; (95 % CI 0·00, 0·94), among both sexes. Among boys, higher MNI was associated with 0·15 higher BMI z-scores, 0·12 body fat z-scores, 0·11 trunk fat z-scores, and larger triceps, and triceps + subscapular skinfolds (ß = 0·05 and ß = 0·06; on the log2 scale) (P-value < 0·05). Among girls, the opposite associations were found with 0·12 lower trunk fat z-scores, and smaller subscapular and suprailiac skinfolds (ß = -0·07 and ß = -0·10; on the log2 scale) (P-value < 0·05). For skinfold measures, this would represent a ± 1·0 millimetres difference. Unexpectedly, a prenatal diet in line with recommended nutrient intake was associated with higher measures of body fat for boys and opposite to girls at a pre-pubertal stage of development.

Lifetime impact of achondroplasia study in Europe (LIAISE): findings from a multinational observational study.

BACKGROUND: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults. METHODS: Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes. RESULTS: Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0-84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes. CONCLUSIONS: The findings of this study suggest that, across an individual's lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 - prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368.

Gait in children with achondroplasia - a cross-sectional study on joint kinematics and kinetics.

BACKGROUND: Children with achondroplasia have extreme short stature due to short limbs, as well as several other clinical features that may affect their gait. The purpose of this cross-sectional study was to provide a detailed description of gait in children with achondroplasia compared to age-matched controls. METHODS: Between the years 2007 and 2010, 16 children with achondroplasia [mean age 9.6 years (range 5-16; six female)] with no previous history of orthopaedic lower limb surgery and 19 age-matched controls conducted three-dimensional (3D) gait analysis at one occasion. The gait analysis rendered pelvis and lower limb joint kinematics and kinetics, and time and distance data. Descriptive statistics, independent samples t-tests, and Fisher's exact test were used to describe the cohort including gait data and participant characteristics. RESULTS: Children with achondroplasia had kinematic gait pattern deviations in all three planes, especially in the sagittal plane, when compared to the control group. Peak anterior pelvic tilt and peak ankle dorsiflexion were found to be increased. Increased knee flexion was noted at initial contact and again at terminal stance. During stance, children with achondroplasia had a higher peak hip abduction angle and a higher peak knee varus angle in the frontal plane. In the sagittal plane, kinetic gait pattern deviations were found at the hip, knee, and ankle, consistent with a flexion pattern. Compared to the control group, children with achondroplasia walked with reduced walking speed and step length, and increased cadence. There was no difference in walking speed when leg length was taken into account. Normalised step length and normalised cadence, on the other hand, were found to be increased in children with achondroplasia. CONCLUSIONS: The observed gait characteristics in children with achondroplasia are related to anatomical attributes and strategies to increase step length, and hence walking speed.

International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia.

Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life.

Gene expression signatures predict response to therapy with growth hormone.

Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.

Lifetime impact of achondroplasia: Current evidence and perspectives on the natural history.

Achondroplasia, the most common form of disproportionate short stature, is caused by a variant in the fibroblast growth factor receptor 3 (FGFR3) gene. Advances in drug treatment for achondroplasia have underscored the need to better understand the natural history of this condition. This article provides a critical review and discussion of the natural history of achondroplasia based on current literature evidence and the perspectives of clinicians with extensive knowledge and practical experience in managing individuals with this diagnosis. This review draws evidence from recent and ongoing longitudinal natural history studies, supplemented with relevant cross-sectional studies where longitudinal research is lacking, to summarize the current knowledge on the nature, incidence, chronology, and interrelationships of achondroplasia-related comorbidities across the lifespan. When possible, data related to adults are presented separately from data specific to children and adolescents. Gaps in knowledge regarding clinical care are identified and areas for future research are recommended and discussed.

Clinical charts for surveillance of growth and body proportion development in achondroplasia and examples of their use.

Clinical surveillance of infants and children with achondroplasia necessitates syndrome-specific charts due to extreme short stature with deviating body proportions. Height, arm span and leg length develop far below normal population ranges. We present growth and body proportion charts for ages 0-20 years, constructed from semi-longitudinal standardized measurements of about 450 children, along with some examples of achondroplasia typical and atypical growth pattern. We combine head circumference, height and weight for 0-4 years into one (infancy) page and height and weight for 4-20 years in another (childhood-adolescence) using nonlinear axes to account for the rapidly decreasing growth velocity. Similarly, weight and BMI are based on nonlinear axes to balance wide SD-channels at higher and narrow SD-channels at lower levels of weight/BMI. Charts for following sitting height, sitting height/height ratio, arm span, leg and foot length are also presented. Clinical examples illustrating the applicability of the charts include cases of extreme prematurity, extreme head circumference development before and after shunting, achondroplasia complicated by chromosomal or additional genetic abnormality and by growth hormone deficiency as well as of evaluating growth promoting therapy.

Meeting report from the achondroplasia foramen magnum workshop, Salzburg, Austria 22nd June 2019.

A pre-meeting workshop on foramen magnum stenosis in children with achondroplasia was held in Salzburg, Austria at the 9th International Conference on Children's Bone Health (ICCBH) 22-25 June 2019. The screening, monitoring and surgical approach to foramen magnum stenosis still remains controversial with conflicting guidance in the literature. The structure of the workshop consisted of lectures, a debate, expert and delegate discussion and concluded with a research proposal and further next steps. In total, representation by 40 institutions from 22 different countries that care for approximately 1375 children with achondroplasia, were in attendance.

Development of body proportions in achondroplasia: Sitting height, leg length, arm span, and foot length.

The aims of this study was to construct references for sitting height, leg length, arm span, relative sitting height (sitting height/height), and foot length and to discuss the development for these anthropometric variables in achondroplasia. Sex-specific references covering ±2 SD are presented for ages 2-20 years. Legs and arms in achondroplasia are already at 2 years of age considerably shorter than in the general population and this deviation increases with age. At adult ages, legs are almost 50% shorter than in the general population and arm span roughly 35% shorter. As sitting height is only mildly affected, relative sitting height position develops far beyond normal ranges. Foot length is also not as affected as limbs.

Growth in achondroplasia: Development of height, weight, head circumference, and body mass index in a European cohort.

As growth references for achondroplasia are limited to reports from United States, Japan, Argentina, and Australia, the aim of this study was to construct growth references for height, weight, head circumference, and body mass index (BMI) from a European cohort of children with achondroplasia and to discuss the development of these anthropometric variables. A mix of cross-sectional and longitudinal, retrospective, and prospective data from 466 children with achondroplasia and 4,375 measuring occasions were modeled with generalized additive model for location, scale and shape (GAMLSS) to sex-specific references for ages 0 to 20 years. Loss in height position, that is, reduction in height standard deviation scores, occurred mainly during first 2 years of life while pubertal growth seemed normal if related to adult height. Adult height was 132 cm in boys and 124 cm in girls with a variability comparable to that of the general population and seems to be remarkably similar in most studies of children with achondroplasia. BMI had a syndrome-specific development that was not comparable to BMI development in the general population. Weight and BMI might be misleading when evaluating, for example, metabolic health in achondroplasia. Head circumference reached adult head size earlier than in the general population. Increased tempo of head circumference growth necessitates thus close clinical follow-up during first postnatal years.

Colombian reference growth curves for height, weight, body mass index and head circumference.

AIM: Published Growth studies from Latin America are limited to growth references from Argentina and Venezuela. The aim of this study was to construct reference growth curves for height, weight, body mass index (BMI) and head circumference of Colombian children in a format that is useful for following the growth of the individual child and as a tool for public health. METHODS: Prospective measurements from 27 209 Colombian children from middle and upper socio-economic level families were processed using the generalised additive models for location, scale and shape (GAMLSS). RESULTS: Descriptive statistics for length and height, weight, BMI and head circumference for age are given as raw and smoothed values. Final height was 172.3 cm for boys and 159.4 cm for girls. Weight at 18 years of age was 64.0 kg for boys and 54 kg for girls. Growth curves are presented in a ± 3 SD format using logarithmic axes. CONCLUSION: The constructed reference growth curves are a start for following secular trends in Colombia and are also in the presented layout an optimal clinical tool for health care.

Growth hormone dose-dependent pubertal growth: a randomized trial in short children with low growth hormone secretion.

BACKGROUND/AIMS: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i.e. idiopathic isolated GH deficiency. METHODS: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH 33 µg/kg/day for ≥1 year. They were randomized to receive 67 µg/kg/day (GH(67)) given as one (GH(67×1); n = 35) or two daily injections (GH(33×2); n = 36), or to remain on a single 33 µg/kg/day dose (GH(33×1); n = 40). Growth was assessed as heightSDSgain for prepubertal, pubertal and total periods, as well as AHSDS versus the population and the midparental height. RESULTS: Pubertal heightSDSgain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33×1), 0.41, p < 0.05). AHSDS was greater on GH(67) (GH(67×1), -0.84; GH(33×2), -0.83) than GH(33) (-1.25, p < 0.05), and heightSDSgain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target heightSDS. CONCLUSION: Pubertal heightSDSgain and AHSDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once- and twice-daily GH(67) regimens. © 2014 S. Karger AG, Basel.

Growth charts and long-term sequelae in extreme preterm infants--from full-term age to 10 years.

AIM: To describe growth pattern from full-term age to 10 years in infants born before 26 weeks of gestation. METHOD: This retrospective longitudinal cohort contained 123 children from Karolinska Hospital, Stockholm, during 1990-2002. Length/height (Ht), weight (Wt) and head circumference (HC) were recorded monthly during the first year, every 3 months until 2 years and yearly thereafter, but HC at 15 months and at median age of 8.1/9.7 years (range 2-14) in boys/girls. RESULTS: For boys/girls at birth, the mean Z-score for Ht was -0.2/-0.2, for Wt 0.0/-0.2 and for HC 0.0/-0.3. At term, the mean Z-score for Ht was -3.8/-3.1, for Wt -3.0/-2.5 and for HC -1.7/-1.2. At 1 year, the mean Z-score for Ht was-1.3/-1.3, for Wt -1.9/-1.7 and for HC -1.2/-1.0. At 2 years, the mean Z-score for Ht was -1.3/-1.1, for Wt -1.6/-1.2 and at 10 years for Ht -0.7/-0.4; that was on average -0.3 below mid-parental height; for Wt -0.2/-0.2. Long-term sequelae were found in 48% of the boys and 34% of the girls. CONCLUSION: By 10 years of age, the attained mean Ht was in accordance with their genetic potential and almost half of these children had significant long-term sequelae.

Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype.

Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS-MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan-like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co-occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A > G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c.1226G > C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, café-au-lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p.Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co-occurrence of RAS-MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis-NS phenotypes. Taken together, the results suggest that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway may contribute to the clinical variability observed among NS patients.

Growth dependence on insulin-like growth factor-1 during the ketogenic diet.

PURPOSE: To examine the influence of the ketogenic diet (KD) on linear growth and insulin-like growth factor I (IGF-I) levels in children with pharmacotherapy-resistant epilepsy. METHODS: A prospective study was designed to evaluate growth, serum IGF-I levels, blood beta-hydroxybutyric acid (beta-OHB), and seizure frequency before and during KD in 22 children (median age 5.5 years). Growth was assessed by measurements of weight, height, body mass index (BMI), and height velocity. Standard deviation scores (SDS) were calculated for all measured parameters as well as for serum IGF-I to eliminate the influence of age- and sex-related differences among patients. RESULTS: Fourteen of the 22 patients responded to the KD. Weight, height, BMI, and height velocity decreased significantly during the KD. We found that the KD had profound influence on growth and IGF-I levels. No correlation was found between seizure response and growth alterations. Height velocity correlated negatively with beta-OHB during the KD. The slope of the regression of height velocity against IGF-I decreased significantly during the KD. CONCLUSIONS: Height velocity was most affected in those with pronounced ketosis, which implies that, in clinical practice, the level of ketosis should be related to outcomes in seizure response and growth. Our data indicate that growth disturbances and the decreased sensitivity of growth to similar IGF-I levels during KD are independent of seizure reduction. The metabolic status induced by KD may be the mechanism underlying both alterations of linear growth and seizure reduction.

Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency.

CONTEXT: The effect of GH therapy in short non-GH-deficient children, especially those with idiopathic short stature (ISS), has not been clearly established owing to the lack of controlled trials continuing until final height (FH). OBJECTIVE: The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls. DESIGN AND SETTING: A randomized, controlled, long-term multicenter trial was conducted in Sweden. INTERVENTION: Two doses of GH (Genotropin) were administered, 33 or 67 microg/kg.d; control subjects were untreated. SUBJECTS: A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (AllITT) population, and 108 in the per protocol (AllPP) population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) population and 68 subjects in the PP (ISSPP) population. MAIN OUTCOME MEASURES: We measured FH sd score (SDS), difference in SDS to midparenteral height (diff MPHSDS), and gain in heightSDS. RESULTS: After 5.9+/-1.1 yr on GH therapy, the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 (33 microg/kg.d, -1.7+/-0.70; and 67 microg/kg.d, -1.4+/-0.86; P<0.032), vs. -2.4+/-0.85 (P<0.001); the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 (P<0.001); and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 (P<0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations. CONCLUSION: GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls.

[Normal and deviating puberty in boys]. / Normal och avvikande pubertet hos pojkar.

BACKGROUND: Onset of puberty in boys is more complex than in girls, and delayed onset is the most common puberty complication in boys. This article presents the physiology of normal development of male puberty and the background for commonly associated disturbances. MATERIAL AND METHOD: The article builds on clinical experience and relevant publications within pediatric endocrinology. RESULTS AND INTERPRETATION: Mechanisms involved in pubertal development of gonads remain unclear despite intensive research. Height growth as well as the age for onset of puberty are influenced by environmental factors. Genetic factors are however more important determinants within a defined population and one usually inherits the probability for both early and delayed puberty. Gonadotropin releasing hormone (GnRH) neurons in the hypothalamus secrete GnRH in intermittent pulses to the pituitary glands that respond with pulsatile LH and FSH production. These neurons are thus decisive for testicle activity and therefore puberty development. GnRH-neurons are inactive during childhood because many types of hypothalamic neurons suppress them. Puberty starts when this suppression is reduced and kisspeptin-producing neurons stimulate GnRH neuron activity. At a testicle volume of 4 mL the Leydig cells' testosterone production has reached such a level that pubertal changes become apparent. Delayed or incomplete puberty sometimes occurs in certain syndromes, and complete lack of puberty can also be syndrome-related. Klinefelter's syndrome is associated with gonad dysgenesis expressed as gradual reduction of gonadal function starting after puberty. Cancer treatment during childhood; especially radiation therapy of the gonads, may cause hypogonadism and infertility. It is therefore essential to follow gonad function closely in these patients. In conclusion, each doctor treating children should be able to evaluate the degree of puberty development and when needed request adequate laboratory tests.

Omitting control biopsy in paediatric coeliac disease: a follow-up study.

AIM: To evaluate the practice of diagnosing coeliac disease with only one small-bowel mucosal biopsy in a selected group of children with suspected coeliac disease. METHODS: A retrospective review of medical records and a follow-up interview of 102 children (65 girls, 37 boys) at diagnosis of coeliac disease. The inclusion criteria were age >18 months, increased levels of serum antitissue transglutaminase IgA antibodies and pathologic small-bowel mucosal biopsy. Anthropometric data were calculated for children 1.5-11 years of age. RESULTS: The levels of serum antitissue transglutaminase IgA antibodies were either normal (92%) or slightly elevated (8%) in all children after 1 year on a gluten-free diet. The height-for-age Z score increased in 52 of 61 (85%) children, (median 0.26 SD, range -0.45 to 1.83 SD) and the weight-for-age Z score increased in 50 of 61 (82%) children (median 0.42 SD, range -0.77 to 2.24 SD). Sixty of 61 (98%) children showed normal or catch-up growth. Regression of symptoms after 1 year on a gluten-free diet was reported for 71 of 72 (98%) children. CONCLUSION: We propose that a control biopsy is not necessary for the diagnosis of coeliac disease in these children.

Growth hormone treatment in 35 prepubertal children with achondroplasia: a five-year dose-response trial.

BACKGROUND: Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature. AIM: In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia. METHODS: Patients were randomized to either 0.1 IU/kg (n = 18) or 0.2 IU/kg (n = 17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6.6 y. RESULTS: Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased significantly by 0.6/0.8 during the first year of treatment and in total by 1.3/1.6 during the 5 y of study. Sitting height SDS improved significantly from -2.1/-1.7 to -0.8/0.2 during the study. Body proportion (sitting height/total height) or arm span did not show any significant change. CONCLUSION: GH treatment of children with achondroplasia improves height during 4 y of therapy without adverse effect on trunk-leg disproportion. The short-term effect is comparable to that reported in Turner and Noonan syndrome and in idiopathic short stature.