Effect of Growth Hormone Therapy in Patients with Noonan Syndrome: A Retrospective Study

Background: Noonan syndrome is an autosomal dominant condition with an incidence of 1:1000 to 1:2500. The disorder is associated with distinct dysmorphic features, cardiac anomalies, developmental delay and delayed puberty. Short stature is a recognised feature of Noonan syndrome. Objectives: The aim of this study is to assess the effect of growth hormone treatment in patients with Noonan syndrome. Methods: Retrospective data was collected from patients with Noonan syndrome treated with growth hormone. The results were analysed with variables expressed as mean values and standard deviation scores. Results: Twelve Noonan syndrome patients (M: F = 10:2) treated with growth hormone were identified. The mean age of starting growth hormone was 8 years, with baseline height standard deviation score of -2.96 (range: -1.64 to -5.54). The height standard deviation score significantly improved to -2.50 (P = 0.0035) and then -2.22 (P = 0.0025), following one and two years of treatment, respectively. The average height velocity for the patients prior to starting treatment was 5.16cm/year (range: 2.4 - 8.2 cm/year), which significantly improved to 7.76cm/year (ranging from 4.1 to 12.8 cm/year) after one year of growth hormone treatment (P = 0.020) and to 6.51cm/year at the end of two years. Conclusions: Our study has shown that growth hormone treatment significantly improves the height standard deviation score of patients with Noonan syndrome over a two-year course of growth hormone therapy without any side effects. Further research is required to analyse the long-term effect of growth hormone therapy in patients with Noonan syndrome, including the impact on final adult height.

Is a Combination of a GnRH Agonist and Recombinant Growth Hormone an Effective Treatment to Increase the Final Adult Height of Girls with Precocious or Early Puberty?

The aim of treatment for idiopathic central precocious puberty (ICPP) is to increase final adult stature, for which gonadotropin-releasing hormone agonist (GnRHa) is the gold standard. Early puberty is frequently similar to ICPP, with pubertal onset only slightly advanced. Short stature may result from early pubertal onset. Some studies have suggested that recombinant human growth hormone (rhGH) should be combined with a GnRHa to improve adult height, while others have not. Here, the aim was to compare the efficacy of combined GnRHa and rhGH treatment with GnRHa or rhGH treatment alone, or no therapy, for the improvement of the final height of girls with ICPP or early puberty. Electronic databases of randomized and quasi-randomized controlled trials, in which the efficacy of GnRHa preparations was compared with that of rhGH for the treatment of children with precocious or early puberty, were searched and a meta-analysis conducted. Five studies of early puberty and four studies of ICPP were identified. There were no statistically significant differences between final adult height standard deviation score and initial height standard deviation score in the treatment of early puberty (GnRHa and rhGH versus rhGH alone or no treatment). The overall analysis of the data failed to indicate any benefit of combined therapy, while individual reports suggested that in specific instances combined therapy may be beneficial in preserving or reclaiming growth potential and improving adult height.

Short Stature Homeobox-Containing Haploinsufficiency in Seven Siblings with Short Stature

Deficiency of the short stature homeobox-containing (SHOX) gene is a frequent cause of short stature in children (2–15%). Here, we report 7 siblings with SHOX deficiency due to a point mutation in the SHOX gene. Index case was a 3-year-old male who presented for evaluation of short stature. His past medical history and birth history were unremarkable. Family history was notable for multiple individuals with short stature. Physical exam revealed short stature, with height standard deviation score (SDS) of −2.98, as well as arm span 3 cm less than his height. His laboratory workup was noncontributory for common etiologies of short stature. Due to significant familial short stature and shortened arm span, SHOX gene analysis was performed and revealed patient is heterozygous for a novel SHOX gene mutation at nucleotide position c.582. This mutation is predicted to cause termination of the SHOX protein at codon 194, effectively causing haploinsufficiency. Six out of nine other siblings were later found to also be heterozygous for the same mutation. Growth hormone was initiated in all seven siblings upon diagnosis and they have demonstrated improved height SDS.

Normal growth in the short normal prepubertal child: the Wessex Growth Study

Objective The study aimed at defining the normal rate of growth for short, prepubertal children, and comparing their pattern of growth with those of average stature. Setting Community based. Design Observation of an unselected population of 109 very short, normal prepubertal children (<3rd height centile) and 107 controls matched for age and sex (10th to 90th centile). Main outcome measuresHeight, velocity, change in height standard deviation score, from 6 to 9 years of age. Results The absolute mean rate of growth was significantly different between groups—short normal 5.3 cm/year, controls 5.9 cm/year—corresponding to velocities on the 25th and 50th centiles, respectively. The relative growth rates, however, as shown by the changes in height standard deviation score (short normal 0.10 (SD 0.22), controls 0.10 (SD 0.24) did not differ, and each group remained close to its original 3rd and 50th centiles. Two short children showed “catch up” growth after adoption, but, otherwise, the divergence from their original height centile was the same for short normal and control children. No social or biological factors were found to predict growth rate in the short normal children, and only target height in controls. “Normal” velocity is conditional on height. Short normal children do grow more slowly than children of average stature, but they do not necessarily grow more poorly. From 6 to 9 years of age they are no more likely to fall off their height centiles than children of average stature. The value of height monitoring at this age is questioned.

GH response to provocation and circulating IGF-I and IGF-binding protein-3 concentrations, the IGF-I generation test and clinical response to GH therapy in children with beta-thalassaemia

The causes of growth retardation of children with thalassaemia major are multifactorial. We studied the GH response to provocation by clonidine and glucagon, measured the circulating concentrations of insulin, IGF-I, IGF-binding protein-3 (IGFBP-3) and ferritin, and evaluated IGF-I generation after a single dose of GH (0.1 mg/kg per dose) in 15 prepubertal patients with thalassaemia, 15 age-matched children with constitutional short stature (CSS) (height standard deviation score less than -2, with normal GH response to provocation) and 11 children with isolated GH deficiency (GHD). Children with thalassaemia had significantly lower peak GH response to provocation by clonidine and glucagon (6.2 +/- 2.3 and 6.8 +/- 2.1 microg/l respectively) than the CSS group (18.6 +/- 2.7 and 16.7 +/- 3.7 microg/l respectively). They had significantly decreased circulating concentrations of IGF-I and IGFBP-3 (47.5 +/- 19 ng/ml and 1.2 +/- 0.27 mg/l respectively) compared with those with CSS (153 +/- 42 ng/ml and 2.06 +/- 0.37 mg/l respectively), but the IGF-I and IGFBP-3 concentrations were not different from those with GHD (56 +/- 25 ng/ml and 1.1 +/- 0.32 mg/l respectively). These data demonstrate that the GH-IGF-I-IGFBP-3 axis in thalassaemic children is defective. Serum ferritin concentration correlated significantly with GH peak response to provocation (r = -0.36, P < 0.05) and circulating IGF-I (r = -0.47, P < 0.01) and IGFBP-3 (r = -0.42, P < 0.01) concentrations. In the IGF-I generation test, after GH injection, the thalassaemic children had significantly lower IGF-I and IGFBP-3 levels 86.7 +/- 11.2 ng/ml and 2.05 +/- 0.51 mg/l respectively) than those in the CSS group (226 +/- 45.4 ng/ml and 2.8 +/- 0.43 mg/l respectively). The IGF-I response was significantly higher in children with GHD (158 +/- 50 ng/ml) than in thalassaemic children. Six short (height standard deviation score less than -2) thalassaemic children who had defective GH response to provocation (< 10 microg/l), all the children with GHD and eight short normal children (CSS) were treated for 1 year with human GH (18 units/m2 per week divided into daily s.c. doses). After 1 year of GH therapy there was a marked acceleration of growth velocity in both thalassaemic children (from 3.8 +/- 0.6 cm/year to 7.2 +/- 0.8 cm/year) and controls. However, the linear acceleration of growth velocity on GH therapy was significantly slower in thalassaemic children (3.3 +/- 0.3 cm/year increment) compared with those with CSS (5.3 +/- 0.4 cm/year increment) and GHD (6.9 +/- 1.2 cm/year increment) (P < 0.05). Their circulating IGF-I concentration (105 +/- 36 ng/ml) was significantly lower than those for CSS (246 +/- 58 ng/ml) and GHD (189 +/- 52 ng/ml) after 1 year of GH therapy. These data prove that some children with beta-thalassaemia major have a defective GH-IGF-I-IGFBP-3 axis and suggest the presence of partial resistance to GH.

Growth Screening and Urban Deprivation

Objectives — To assess the effect of urban deprivation on childhood growth in a modern British society by analysing data from a regional growth survey, the Tayside growth study. Setting — The Tayside Region in Scotland, which has three districts with distinct socioeconomic status: Dundee (D, urban city), Angus (A, rural), and Perth (P, rural and county town). Subjects and methods — Height and weight of 23 046 children (>90% of the regional childhood population) were measured as part of a child health surveillance programme, by community health care workers at 3, 5, 7, 9, 11, and 14 years. Height standard deviation score (calculated against Tanner) and body mass index (BMI-weight (kg)/height (m)2) were calculated for each child by a central computer program; mean height standard deviation score and BMI standard deviation score were calculated for each measuring centre (school, health clinic). A deprivation score for each centre was calculated from the prevalence of single parent families; families with more than three children; unemployment rate; the number of social class V individuals; the percentage of council houses. Results — Mean height standard deviation score for Tayside was 0·11. An intra-regional difference was demonstrated: mean height standard deviation score (SD) D = 0·04 (1·0); A = 0·14 (1·1); P = 0·21 (1·1); P<0·002. There was a positive association between short stature and increasing social deprivation seen throughout Tayside (P<0·05), with a strong association in Dundee primary school children (r = 0·6; P<0·001). Analysis by district showed that the association was significant only above the age of 8 (P<0·004). There was no relation between BMI and social deprivation. Conclusions — In an industrialised developed society, urban deprivation appears to influence height mostly in late childhood, and this association should be taken into consideration in the clinical management of short stature. Height seems to be a better physical indicator of urban deprivation, and hence an index of childhood health, than BMI.

The Effect of Phosphate Supplementation on Linear Growth in Children with X-Linked Hypophosphatemia

Background. X-linked hypophosphatemia is the most common inherited cause of rickets. Current therapy for this disorder includes vitamin D and phosphate supplementation; however, phosphate therapy has been associated with nephrocalcinosis. The purpose of this study is to evaluate the effect of oral phosphate therapy on growth in patients with X-linked hypophosphatemia treated with either calcitriol or dihydrotachysterol (vitamin D). Methods. We retrospectively evaluated the prepubertal growth of 36 children with X-linked hypophosphatemia. The height standard deviation score (Z-score) of patients initially treated with vitamin D alone and the Z-scores of patients treated with vitamin D and phosphate therapy were compared. In addition, the growth of patients treated with vitamin D was compared with that of patients treated with vitamin D and phosphate from the outset of therapy. Results. Patients treated with vitamin D alone for 5.36 ± 2.18 years had an improvement in Z-score from -3.18 ± 1.10 to -2.49 ± 0.66 SDS, ,P &lt; .05. Adding phosphate therapy for patients initially treated with vitamin D alone for 4.83 ± 2.99 years did not further improve Z-score (-2.49 ±0.66 vs -2.35 ± 0.83). Initial therapy with vitamin D and phosphate for 4.33 ± 2.19 years also improved Z-score, (-2.84 ± 1.02 vs -1.98 ± 0.82, P &lt; .05). The change in Z-score was similar to the group treated with vitamin D alone compared with the group treated initially with vitamin D and phosphate (0.65 ± 0.54 vs 0.85 ± 0.65, respectively). Conclusion. These data demonstrate that both vitamin D alone and in combination with phosphate improved linear growth. Adding oral phosphate for children initially treated with vitamin D alone did not improve Z-score. Initial therapy with vitamin D and vitamin D plus phosphate produced similar changes in linear growth.

The Frequency of Bleeding and Height of Adolescent Haemophiliacs

SummaryThe relation between the height of adolescent haemophiliacs and their bleeding frequency has been studied. 45 haemophiliacs aged 10-19 years were divided into 3 groups: small, medium and tall, using a Height Standard Deviation Score. The average bleeding frequency per 100 days in the group of small haemophiliacs was 8.71 ± SD 4.47, in the medium height group 10.18 ± SD 6.71, while the tall individuals bled in average 15.97 ± SD 3.15 every 100 days. There was no relationship between age and bleeding frequency.