Growth Hormone & Down Syndrome Abstracts

Minerva Endocrinol 27 (2): 59-64 (2002 Jun)

Growth disorders in Down's syndrome: growth hormone treatment

Pallotti S, Giuliano S, Giambi C.
Dipartimento di Fisiopatologia Medica, Universita degli Studi di Roma La Sapienza, Rome, Italy

The aim of the study was evaluate the short and long-term effects of growth hormone therapy in subjects affected by Trisomy 21. METHODS: The growth curves of 10 Down's syndrome patients (3 males and 7 females) aged between 21 and 35 years old were analysed. During pre- or peripuberty these subjects had received growth hormone (GH) therapy lasting an average of 3.02 years. At distance of between 10 to 15 years after the end of GH therapy, routine laboratory tests (thyroid hormones, glycemia, glycosylated hemoglobin, transaminase) were carried out together with a full hematological assay (hemochrome using leukocyte formula, morphological study of blood components). RESULTS: GH therapy resulted in an increased rate of growth among these subjects and a improvement in final stature of 5.16 cm in males and 7.35 cm in females. The long-term controls did not reveal any hematological changes or changes in HbA1c concentrations, thyroid function and hepatic function, thus confirming the absence of collateral effects of GH therapy in subjects with Down's Syndrome. CONCLUSIONS: In view of these results, we are convinced that GH therapy is extremely positive in trisomy 21, given the marked improvements in terms of growth, the absence of collateral effects and the possible psychological benefits of increased stature, in particular a better insertion in society.
Growth Horm IGF Res 10 (B): S87-91 (2000 Apr)

Growth hormone therapy in young children with Down syndrome and a clinical comparison of Down and Prader-Willi syndromes

Annerén G, Tuvemo T, Gustafsson J, Wald NJ, Hackshaw AK, Cuckle H, Bozich JG, Albert TW, Villanueva MJ, Navarro F, Sanchez A, Provencio M, Bonilla F, España P

The genetic disorders Prader-Willi syndrome and Down syndrome have a number of features in common, for example, both growth and mental retardation. Growth hormone (GH) treatment is becoming part of the clinical management of children with Prader-Willi syndrome, but in children with Down syndrome, such therapy is still on a research level. In this review, we compare the clinical phenotypes of the two syndromes, and report the effects of long-term GH treatment on the linear growth and psychomotor development of 15 young children with Down syndrome (mean age at start of treatment, 7.4 months). The mean height of the treated children with Down syndrome increased significantly from -1.8 to -0.8 SDS (Swedish standard) during the 3 years of GH therapy (P < 0.001). The mean height of a corresponding control group fell from -1.7 to -2.2 SDS. After the cessation of treatment, growth velocity declined in the treated group. Growth of the head did not increase during GH treatment. There was no effect on mental or gross-motor development, although some improvement in fine- motor development was noted in the GH-treated group (P < 0.01). At present, treatment with GH is not recommended in children with Down syndrome who have not been diagnosed with GH deficiency. Long-term studies with an emphasis also on the metabolic effects of GH therapy are necessary before routine treatment can be considered in such children.
J Craniofac Genet Dev Biol 19 (1): 20-3 (1999 Jan-Mar)

The Effect of Growth Hormone Therapy on Craniofacial Growth and Dental Maturity in Children with Down Syndrome

Carlstedt K, Annerén G, Huggare J, Modeer T, Dahllof G
Department of Pediatric Dentistry, Karolinska Institutet, Huddinge, Sweden

Craniofacial growth was evaluated 3 years after termination of growth hormone (GH) therapy in ten Down syndrome (DS) children. The control group consisted of 16 age-matched children with DS. The treatment started at 6-9 months of age, and the duration was 36 months. There were no statistically significant differences in craniofacial development between DS children treated with GH or DS children not treated. In conclusion, the results of this study indicate that GH therapy for 36 months in children with DS did not change the craniofacial morphology compared to a group of DS children not given GH.
J Endocrinol Invest 80: 334-338 (1999)

Growth Hormone Treatment in Young Children with Down's Syndrome: Effects on Growth and Psychomotor Development

Annerén G, Tuvemo T, Sara VR, et al.
Department of Genetics and Pathology, Unit of Clinical Genetics, Uppsala University. Children's Hospital, Sweden

Background. Learning disability and short stature are cardinal signs of Down's syndrome. Insulin-like growth factor I (IGF-I), regulated by growth hormone (GH) from about 6 months of age, may be involved in brain development. Aims. To study long term effects of GH on linear growth and psychomotor development in young children with Down's syndrome. Study design. Fifteen children with Down's syndrome were treated with GH for three years from the age of 6 to 9 months (mean, 7.4). Linear growth, psychomotor development, skeletal maturation, serum concentrations of IGF-I and its binding proteins (BPs), and cerebrospinal fluid (CSF) concentrations of IGF-II were studied. Results. The mean height of the study group increased from -1.8 SDS (Swedish standard) during treatment, whereas that of a Down's syndrome control group fell from -1.7 to -2.2 SDS. Growth velocity declined after treatment stopped. Head growth did not accelerate during treatment. No significant difference in mental or gross motor development was found. The low concentrations of serum IGF-I and IGFBP-3 became normal during GH treatment. Conclusions. GH treatment results in normal growth velocity in Down's syndrome but does not affect head circumference or mental or gross motor development. Growth velocity declines after treatment stops.
Dement Geriatr Cogn Disord 9 (2): 78-81 (1998 Mar)

Further Evidence of Cholinergic Impairment of the Neuroendocrine Control of the GH Secretion in Down's Syndrome

Beccaria L, Marziani E, Manzoni P, Arvat E, Valetto MR, Gianotti L, Ghigo E, Chiumello G
Paediatric Department, University of Milan, Italy

There are data indicating that cholinergic activity is precociously impaired in Down's syndrome (DS). On the other hand, acetylcholine as well as arginine (ARG) play a major stimulatory role in the neural control of growth hormone (GH) secretion in humans, likely acting via the inhibition of hypothalamic somatostatin release. The aim of the present study was to verify the effects of pyridostigmine (PD, 120 mg p.o.), a cholinesterase inhibitor, and ARG (0.5 g/kg i.v.) on the growth hormone-releasing hormone (GHRH) (1 microgram/kg i.v.)-induced GH rise in 15 adult patients with DS (M/F: 8/7; age 26.5 ± 2.2 years; body mass index, BMI: 25.7 ± 1.0 kg/m2) in which the potentiating effect of PD on GH secretion has been reported to be reduced. The results in DS were compared to those in 15 normal subjects (NS) (M/F: 8/7; age: 30.0 ± 1.3 years; BMI: 21.4 ± 0.4 kg/m2). Basal GH and insulin growth factor I (IGF-1) levels in DS (1.8 ± 0.7 and 206.5 ± 21.0 micrograms/l) were similar to those in NS (1.4 ± 0.3 and 179.4 ± 11.0 micrograms/l). The GH response to GHRH alone in DS (526.5 ± 120.1 micrograms/l/h) was lower (p < 0.05) than that recorded in NS (895.4 ± 153.7 micrograms/l/h). The GHRH-induced GH rise was potentiated by PD both in DS (1,138 ± 184.2 micrograms/l/h; p < 0.02 vs. GHRH alone) and in NS (2,213.8 ± 212.8 micrograms/l/h; p < 0.005 vs. GHRH alone); however, as the percent potentiating effect of PD was similar in both groups (215 and 247%, respectively) the GH response to GHRH + PD in DS was lower (p < 0.005) than that in NS. The GHRH-induced GH rise was also potentiated by ARG in both DS (2,243 ± 362.4 micrograms/h; p < 0.001 vs. GHRH alone) and NS (2,764.3 ± 325.7 micrograms/l/h; p < 0.005 vs. GHRH alone). As the percent potentiating effect of ARG in DS was more marked than in NS (425 vs. 308%, respectively), the GH response to GHRH + ARG became similar in both groups. No sex-related difference was found in the GH response to various stimuli both in DS and NS. In conclusion, these data demonstrate that the potentiating effect of PD but not that of ARG is impaired in adults with DS in whom a reduced somatotrope responsiveness to GHRH is present. These findings indicate that in DS the pituitary GH releasable pool is fully preserved while an impairment of the tuberoinfundibular cholinergic pathways could lead to somatostatinergic hyperactivity and low somatotrope responsiveness to GHRH.
J Intellect Disabil Res 40 (6): 509-17 (1996 Dec)

Hypothalamic versus pituitary dysfunction in Down's syndrome as cause of growth retardation

Castells S; Beaulieu I; Torrado C; Wisniewski KE; Zarny S; Gelato MC
Department of Pediatrics-Children's Medical Center, SUNY-Health Science Center at Brooklyn 11203, USA.

We have found that some children with Down's syndrome (DS) have growth retardation secondary to growth hormone (GH) deficiency. To test the hypothesis that hypothalamic dysfunction is the primary cause for GH deficiency and growth retardation, hypothalamic-pituitary responses of serum GH concentrations to levodopa and clonidine as well as pituitary responses in serum GH concentrations to growth-hormone-releasing hormone (GHRH) were analysed in 14 prepubertal children with DS. Levodopa and clonidine were given, and blood was drawn for determining serum GH levels. Seven prepubertal control children had both levodopa and clonidine tests done. The delta serum GH during levodopa was 5.7 ± 6.3 ng ml in DS and 13.1 ± 9.8 ng ml in controls. The delta serum GH during clonidine administration was 3.0 ± 3.2 ng ml in DS and 17.3 ± 5.6 ng ml in controls. Children with DS had a significantly lower response to levodopa and clonidine, compared with controls by the Mann-Whitney U-test (P < 0.03 and P < 0.009, respectively). Growth-hormone-releasing hormone was given at 1 microgram kg i.v. bolus and bloods for GH were drawn at-15, 0, 15, 30, 60, 90 and 120 min in 14 subjects with DS and 24 normal controls, both groups prepubertal. The mean delta serum GH concentration in DS was 53.6 ± 38.3 ng ml, and it was 35.6 ± 25.1 ng ml in controls with P < 0.23 non-significant by the Mann-Whitney U-test. These results indicate that levodopa and clonidine (drugs stimulating hypothalamic GHRH release and secondary pituitary GH release in normal individuals) do not stimulate GH release in DS. Furthermore, normal GH response to GHRH in DS indicates normal pituitary function (normal somatotroph response to GHRH) and supports hypothalamic dysfunction in DS.
Dementia 7 (5): 288-292 (1996 Sep)

The enhancing effect of pyridostigmine on the GH response to GHRH undergoes an accelerated age-related reduction in Down syndrome

Arvat E, Gianotti L, Ragusa L, Valetto MR, Cappa M, Aimaretti G, Ramunni J, Grottoli S, Camanni F, Ghigo E
Department of Internal Medicine, University of Turin, Italy

Cholinergic agonists are known to potentiate GHRH-induced GH secretion, probably acting via inhibition of hypothalamic somatostatin release. Their effect is reduced in aging and in patients with Alzheimer's disease. This may be the consequence of age-related cholinergic impairment, which, in turn, could cause somatostatinergic hyperactivity leading to GH hyposecretion. As in Down syndrome (DS) neural alterations have been reported similar to those in aging, including cholinergic impairment, we verified the GH response to GHRH (1 microgram/kg i.v. at 0 min) alone or combined with pyridostigmine (PD), a cholinesterase inhibitor (60 and 120 mg, respectively, in children and adults, orally at -60 min) in 15 DS children (13.5 ± 0.6 years) and in 11 DS young adults (24.0 ± 1.2 years). Fifteen normal children (11.9 ± 0.5 years), 15 normal adults (27.3 ± 0.9 years) and 16 normal elderly (76.3 ± 1.5 years) were studied as controls. IGF-I levels showed an age-related reduction both in DS (children vs. adults, mean ± SEM:354.8 ± 44.9 vs. 204.4 ± 29.4 micrograms/l, p < 0.02) and in controls (normal children vs. normal adults vs. normal elderly:281.4 ± 36.3 vs. 175.4 ± 11.2 vs. 72.5 ± 6.6 micrograms/l, p < 0.001). The GH response to GHRH in DS children was higher than in DS adults (areas under curve: 1,197.6 ± 241.5 vs. 434.4 ± 83.3 micrograms/l/h, p < 0.01). On the other hand, in normal subjects the GHRH-induced GH rise was similar in children and adults (1,056.2 ± 128.4 vs. 800.8 ± 124.5 micrograms/l/h) and both were higher than that in elderly subjects (296.0 ± 61.0 micrograms/l/h, p < 0.001). PD enhanced the GH response to GHRH both in DS and in normal subjects (p < 0.005). The GH response to PD+GHRH was lower in DS adults than in DS children (1,068.1 ± 145.7 vs. 1,897.4 ± 198.8 micrograms/l/h, p < 0.001) as well as in normal elderly subjects with respect to that in normal children and normal adults (832.3 ± 144.7 vs. 2,172.1 ± 156.1 and 2,347.6 ± 322.4 micrograms/l/h, respectively, p < 0.001). The GH response to GHRH alone or combined with PD in DS adults was lower (p < 0.01) than that in normal adults and similar to that in normal elderly subjects. In conclusion, the present data demonstrate that the stimulated GH secretion in DS undergoes an accelerated age-related reduction. They also suggest the existence of a precocious impairment of central cholinergic activity in DS, which, in turn, could cause somatostatinergic hyperactivity and reduced GH secretion.
Curr Opin Pediatr 8 (4): 401-5 (1996 Aug)

Ethical issues in emerging new treatments such as growth hormone therapy for children with Down syndrome and Prader-Willi syndrome

Kodish E, Cuttler L
Rainbow Babies and Childrens Hospital, Cleveland, OH, USA

As new therapies and new applications of existing drugs expand, pediatricians are often in the position of trying to decide when and whether use of a new treatment is appropriate. In this paper, we address this dilemma by focusing on ethical issues in the use of growth hormone therapy for children with Down syndrome and Prader-Willi syndrome as an example. We discuss six major questions that link scientific and ethical considerations in analyzing these difficult issues.
Developmental Brain Dysfunction 9 (2-3): 100-113 (1996 Mar-Jun)

Growth hormone neuropathology in Down syndrome (trisomy 21)

Wisniewski, K. E.; Castells, S.; Mandys, V.
New York State Office of Mental Retardation & Developmental Disabilities, Inst for Basic Research in Developmental Disabilities, Dept of Pathological Neurobiology, Staten Island, NY

Reviews the neuropathological changes in the CNS of individuals with Down's syndrome (DS [trisomy 21]) during prenatal and perinatal development, the effect of growth hormone (GH) on the CNS in humans and experimental models, and the effect of nerve growth factor on organotypic cultures of chick dorsal root ganglia. Studies show that the brain of DS children is formed differently from normal children's, most likely as a result of abnormal genetic programming (gene dose effect) causing functional (biochemical and electrophysiological) and structural abnormalities. In DS children, abnormal morphogenesis of the CNS starts prenatally and most likely reflects genetic determined altered brain programming. Some DS children are microcephalic (50% younger than 3 yrs of age and 75% younger than 5 yrs of age), and some have GH deficiency. The authors' preliminary studies, in which 40 DS children were treated with recombinant human GH (rhGH) before 5-yrs of age, suggested that the microcephaly reversed to normocephaly in 32 cases. However, due to the genetic heterogeneity and non-genetic factors that influence CNS function in DS children, more research is needed to establish the beneficial effect of rhGH and other neurotrophic drug therapy.
Developmental Brain Dysfunction 9 (2-3): 114-120 (1996 Mar-Jun)

Growth hormone and sleep in Down syndrome

Ferri, Raffaele; Ragusa, Letizia; Alberti, Antonino; Elia, Maurizio; et al
Oasi Inst for Research on Mental Retardation & Brain Aging (IRCCS), Dept of Neurology, Troina, Italy

Evaluates correlations between neurophysiological sleep parameters, already known to be abnormal, and growth hormone (GH) release in Down syndrome (DS). Nine DS patients (mean age 12.8 yrs) underwent 1 polygraphic night recording after 1 adaptation night; blood samples were contemporarily collected, every 20 min, by means of a continuous withdrawal pump and the level of GH assessed by an immunoradiometric assay. Sleep recordings were visually scored, hypnograms were obtained and plotted together with the profiles of the release of GH, in each patient. GH peaks were analyzed by means of the PULSAR program. The same study was carried out in 1 control subject. DS patients showed a clearly decreased peak amplitude of GH during sleep, even if a certain pulsatility was evident in all of them. However, synchrony with the slow-wave sleep was poor in DS patients because only 22.7% of peaks occurred in such a stage. This study demonstrates that, if evaluated during sleep, GH release in DS subjects often shows a decrease in amplitude of peaks and altered time connection with the sleep structure. An application of the study of sleep is suggested in order to monitor changes in cognitive capabilities induced by the eventual introduction of GH therapy in DS patients.
Developmental Brain Dysfunction 9 (2-3): 133-137 (1996 Mar-Jun)

Growth hormone releasing activity of hexarelin in Down syndrome

Ragusa, Letizia; Alberti, Antonino; Romano, Corrado; Proto, Caterina; et al
Oasi Inst (IRCCS), Dept of Pediatrics, Troina, Italy

Hexarelin (Hex) is a new synthetic growth hormone (GH)-releasing peptide (GHRP) which has a potent dose-dependent stimulatory effect on GH secretion in man. The authors studied the GH secretion response in 12 Ss (aged 1.5-16.2 yrs) affected by Down syndrome (DS) following 2 mgamma/kg IV administration of Hex. The GH releasing effect was compared with that obtained after clonidine test (CT), insulin tolerance test (ITT), GH releasing hormone test (GHRH), and GHRH plus pyridostigmine (P) test. The results show that Hex is a potent GH stimulator in DS. Its response is similar to GHRH plus P and higher than CT, ITT, and even GHRH. Thus it may be useful for evaluating the secretory capacity of somatotroph cells. The possible use of Hex in chronic treatment to increase GH secretion and growth velocity could be also considered.
Developmental Brain Dysfunction 9 (2-3): 138-143 (1996 Mar-Jun)

The effect of growth hormone therapy on growth and mental development in children with Down syndrome

Annerén G.; Carlsson-Skwirut, C.; Sara, V. R.; Tuvemo, T.; et al
Uppsala University, Children's Hosp, Depts of Clinical Genetics & Pediatrics, Uppsala, Sweden

Investigated the long term effects of GH therapy in 15 children with DS. The children were treated from the age of 6-9 mo with Genotropin® for a period of 3 yrs. Children with DS gained height and had a growth rate close to that of healthy Swedish children. As compared to growth charts for children with DS, the mean height started in the 50th centile and reached the 95th centile after 24 mo of treatment. In addition, 7 of the 15 children had a somewhat accelerated skeletal maturation after 3 yrs of GH therapy. However, preliminary results of motor and mental development tests did not reveal any obvious benefit from GH therapy. Thus GH therapy in DS only seems to influence linear growth, but not motor or mental development, and nothing is known about the long-term effect of GH therapy on final height.
Developmental Brain Dysfunction 9 (2-3): 144-157 (1996 Mar-Jun)

Long-term effects of recombinant human growth hormone on children with Down syndrome and growth retardation

Castells, Salvador; Abdel-Khalek, Ihab A.; Wisniewski, Krystyna E.
State University New York, Health Science Center, Depts of Pediatrics & Neurology, Brooklyn, NY

Analyzed hypothalamic dysfunction by the L -dopa and clonidine stimulation tests and the effects of recombinant human growth hormone (rhGH) in 40 prepubertal children with DS treated from several months to 6-yrs and in 12 nontreated children with DS. The starting height standard deviation score (HSDS) of the comparison group did not differ from the pretreatment scores of the treated group. The pre- and posttreatment HSDS of the treated group were examined as function of age at testing and treatment. Changes in HSDS over time were related to age at entry into the study, and treatment produced a change of 0.640 SDS units. Serum insulin-like growth factor I during treatment revealed a marked elevation from pretreatment values. There was no increase in blood concentrations of glucose or in hemoglobin A-sub(1c)%. The authors conclude that treatment with rhGH increases HSDS in prepubertal growth-retarded children with DS, and that predicted adult height normalizes in 91% of the children receiving treatment.
Developmental Brain Dysfunction 9 (2-3): 158-164 (1996 Mar-Jun)

Recombinant human growth hormone treatment in Down syndrome: The Troina experience

Ragusa, L.; Alberti, A.; Proto, C.; Romano, C.; et al
Oasi Inst (IRCCS), Dept of Pediatrics, Troina, Italy

The authors studied 40 Ss with Down syndrome (sDS) (aged 1.6-19.6 yrs) in order to evaluate their growth hormone (GH) secretion. The clonidine test and the insulin tolerance test were performed in all sDS. In case of discordant results (low/normal), the 24-hour integrated concentration of growth hormone or the Growth-hormone-releasing hormone plus pyridostigmine test were carried out. 21 sDS showed abnormal GH secretion. Nine of them were given human recombinant GH (rhGH) ranging in time from 6 mo to 3 yrs. Seven rhGH-treated sDS increased their starting centile, calculated immediately before therapy. L-Thyroxine was administered to Ss showing abnormally high thyroid stimulating hormone values, with prompt normalization. Thus, rhGH treatment seems to be effective in increasing the final height of GH-insufficient sDS.
J Endocrinol Invest 17 (6): 431-6 (1994 June)

Assessment of growth hormone insulin like growth factor-I axis in Down's syndrome

Barreca A; Rasore Quartino A; Acutis MS; Ponzani P; et al
Dipartimento di Scienze Endocrinologiche e Metaboliche, Universita di Genova, Italy

As GH therapy has been reported to increase growth velocity in children with Down's syndrome (DS), we studied the GH-IGF-I axis in some DS patients affected by growth retardation without serious congenital malformation, malnutrition or pathological thyroid or adrenal function. IGF-I and IGF-II were evaluated in 39 patients in basal conditions. The patients were subsequently divided into two groups with respect to the IGF-I basal value: Group 1 (GR 1) consisting of patients with abnormally low basal IGF-I concentration as compared to age matched control subjects, group 2 (GR 2) consisting of patients with IGF-I in the normal range. In 6 GR 1 patients and 12 GR 2 patients we evaluated GH and IGF-I concentrations after stimulation with arginine (0.5 g/kg bw), and recombinant GH (4 IU im). In the same patients, GH radioreceptor assay and serum GH-binding protein were evaluated. In all patients IGF-II proved normal (534 ± 23 ng/ml; mean ± SE), while IGF-I was pathological in 36% of subjects. The cause of the defective IGF-I secretion in these patients does not seem to depend on an impaired GH axis, as no significant difference in arginine-stimulated GH peak values was seen between GR 1 (29.6 ± 5.3 ng/ml) and GR 2 (15.1 ± 2.24 ng/ml). IGF-I concentration evaluated 12, 24, and 48 h after arginine stimulation was significantly increased only in GR 2 patients (peak value: 0.95 ± 0.1, p = 0.0003 vs baseline; GR 1: 0.34 ± 0.05 U/ml).
Res Dev Disabil 14 (4): 291-8 (1993 Jul-Aug)

Growth hormone response after administration of L-dopa, clonidine, and growth hormone releasing hormone in children with Down syndrome

Pueschel SM
Child Development Center, Rhode Island Hospital, Providence 02903

We studied the response of growth hormone secretion after the administration of L-dopa, clonidine, and growth hormone releasing hormone in eight growth-retarded children with Down syndrome aged 1 to 6.5 years. After L-dopa administration, five children had low growth hormone secretion (M = 3.7 ng/ml, SD = 2.12 at 30 min) and three children had elevated growth hormone levels (> 30 ng/ml). After clonidine administration, six children had relatively low growth hormone levels (M = 3.15 ng/ml, SD = 2.53 at 60 min) and two children had high levels (38.3 ng/ml and 16.8 ng/ml, respectively). There was a better response after growth hormone releasing hormone administration; only one child had a growth hormone level of < 10 ng/ml. Most of the children had a modified response of growth hormone secretion subsequent to the various stimulation tests. All children, however, were able to secrete some growth hormone (>e; 10 ng/ml) at least during one of the stimulation tests. In comparison with peak growth hormone levels reported in normal children, our cohort had significantly lower growth hormone levels only after clonidine administration. It is postulated that children with Down syndrome have both anatomical and biochemical hypothalamic derangements that may result in decreased growth hormone secretion and reduced linear growth. In addition, other mechanisms that may be in part responsible for the observed growth retardation are discussed.
J Intellect Disabil Res 37 (4): 381-7 (1993 Aug)

Normalized growth velocity in children with Down's syndrome during growth hormone therapy

Annerén G; Gustafsson J; Sara VR; Tuvemo T
Department of Clinical Genetics, University Hospital, Uppsala, Sweden

Between 6 months and 3 years of age, growth velocity in children with Down's syndrome (DS) is markedly reduced in comparison to that of healthy children. However, after 3 years of age, it is almost normal. Thus, growth retardation becomes pronounced during the period when growth hormone (GH) starts to regulate growth. The present authors report the long-term effects of GH-therapy in 16 children with DS, who are being treated for 3 years from the age of 6-9 months. The treatment, Genotropin, 0.1 U kg-1 BW day-1, was started at a mean age of 7.4 (6-9) months. The results after 12 (n = 16), 24 (n = 12) and 30 (n = 8) months are presented. The mean height standard deviation score, SDS (range; Swedish standard), before therapy was -1.8 (-0.5 to -3.1) and the mean head circumference was -1.2 (-0.4 to -3.5). After 12, 24 and 30 months, the mean height SDS were -1.1 (-0.8 to -1.9), -0.9 (0 to -1.5) and -0.9 (0.1 to -1.5) and the mean head circumference SDS were -1.1 (0 to -2.5), -1.1 (0 to -2.2) and -1.2 (-0.5 to -2.0), respectively. During hGH-treatment, the children with DS thus gained height during the first year, and then followed the growth rate of healthy Swedish children. When compared to growth charts for children with DS the mean height of these children started at the fiftieth centile and reached the ninety-fifth centile after 24 months of treatment. Head circumference only slightly increased during the therapy, and not to the same extent as height. This indicates that small head circumference in DS is not only an effect of growth retardation, but also due to microcephaly.
J Intellect Disabil Res 36 (1): 29-43 (1992 Feb)

Growth hormone deficiency in Down's syndrome children

Castells S; Torrado C; Bastian W; Wisniewski KE
SUNY-Health Center-Brooklyn, Department of Pediatrics, Brooklyn 11203

Down's syndrome (DS) children have been reported to have severe postnatal growth arrest and microcephaly. To determine if growth hormone (GH) deficiency plays a role in growth retardation in DS, 20 children were studied. The subjects (13 boys, 7 girls) were aged between 15 months and 13.9 years, had a height SDS ranging from -1.19 to -5.48, weight SDS ranging from -0.21 to -4.58, head circumference SDS ranging from -0.40 to -6.6, and a skeletal age ranging from 0.9 to 4.6 SD below the mean for normal children of same age and sex. GH was evaluated by levodopa (125 mg up to 15 kg, and 250 mg between 15-30 kg), clonidine (0.15 mg m-2) stimulation tests and hGH secretory patterns by the integrated 24 h. GH concentration (IC-GH) using a constant withdrawal pump with continuous blood collection every 30 min. The serum concentrations were: TSH, 0.7-8.0 mIU ml-1 (0.2-5.5); T4, 6.6-14.3 micrograms dl-1 (5-12); T3, 95-254 ng dl-1 (85-185); LH, less than 2.0-8.3 mIU ml-1 (less than 3); FSH, less than 1.3-7.2 mIU ml-1 (less than 3); testosterone, less than 30 ng dl-1 (5-35); estradiol, less than 5 ng dl-1 (less than 5-25); prolactin, 35.7-2.9 (F: 5-25; m 5-15); and somatomedin-C (Sm-C), 0.14-1.98 U ml-1 (0.08-5.90) (normal values in brackets). Peak serum GH after levodopa and clonidine was found to be below 10 ng ml-1 for both stimulatory tests in seven out of the 20 children studied. Twelve children showed a disparity between levodopa and clonidine testing. Of the 12 children, peak serum GH after levodopa was found to be below 10 ng ml-1 in five children; and peak serum GH after clonidine was found to be below 10 ng ml-1 in six. One child had a clonidine peak increase in serum GH concentration exactly 10 ng ml-1, but had a 12 h IC-GH of 1.5 ng ml-1 (N greater than 3.2). Two children with peak GH after clonidine above 10 ng ml-1 had a 24 h IC-GH of 0.7 and 1.3 ng ml-1. A fourth child who had peak GH concentrations above 10 ng ml-1 with levodopa and clonidine had a 12 h IC-GH of 0.5 ng ml-1.
J Pediatr 120 (2-1): 332-3 (1992 Feb)

Growth hormone therapy for children with Down syndrome

Allen, DB
J Pediatr 119 (3): 478-83 (1991 Sep)

Treatment of children with Down syndrome and growth retardation with recombinant human growth hormone

Torrado C; Bastian W; Wisniewski KE; Castells S
Department of Pediatrics, State University of New York-Health Science Center of Brooklyn

The effect of recombinant human growth hormone on children with Down syndrome who had growth retardation and microcephaly was examined. Thirteen children with trisomy 21 without congenital heart disease who were short for age (-1.19 to -3.5 standard deviation score) and microcephalic (-1.58 to -6.60 standard deviation score) were given recombinant human growth hormone, 0.1 mg/kg subcutaneously, 3 days a week for 1 year. Before treatment, peak serum growth hormone concentrations were less than 10 micrograms/L after levodopa and clonidine stimulation tests in five patients, after clonidine in three patients, and after levodopa in three patients. Three patients had nocturnal integrated growth hormone concentrations of 0.5, 1.5 and 0.65 micrograms/L, respectively. The mean growth rate before treatment was 5.4 ± 1.6 cm/yr and increased to 12.2 ± 3.2 cm/yr (p less than 0.001) after 12 months of recombinant human growth hormone treatment. The mean head circumference standard deviation score before treatment was -3.1 ± 1.3 and increased to -2.3 ± 1.2 (p less than 0.001) at 12 months. Bone age before and 1 year after treatment increased in correspondence with chronologic age. Plasma hemoglobin A1c concentration was normal during treatment with recombinant human growth hormone. The mean plasma concentrations of insulin-like growth factor I at baseline and at 12 months were 0.54 ± 0.19 U/ml and 1.25 ± 0.97 U/ml, respectively (p less than 0.02). We conclude that recombinant human growth hormone therapy can result in a significant increase in annual growth rate and head circumference in children with Down syndrome, without significant side effects.
Pediatr Res 29-35 (1991)

Growth hormone responses to GH releasing hormone suggest hypothalamic dysfunction as a cause for growth retardation in Down syndrome

Castells S. Torrado C. Geiato MC
Am J Med Genet Suppl 7: 59-62 (1990)

Growth retardation in Down syndrome in relation to insulin-like growth factors and growth hormone

Annerén G; Gustavson KH; Sara VR; Tuvemo T
Department of Clinical Genetics, University Hospital, Uppsala, Sweden

Growth retardation is a cardinal characteristic of Down syndrome (DS). It is most pronounced from the age of 6 months, when growth starts to become growth hormone (GH) regulated. DS children have normal serum levels of GH. GH regulates the production of insulin-like growth factors (IGFs), which act as growth hormones. Therefore, the serum IGF pattern and the levels of their receptors were studied in fetuses with trisomy 21 and in patients with DS throughout life. Serum levels of IGF were determined by radioimmunoassays for insulin-like growth factors 1 and 2 (RIA-IGF-1 and RIA-IGF-2) showing normal serum RIA-IGF-2 levels throughout life. However, serum RIA-IGF-1 did not rise during childhood and remained at a low level throughout life. Determination of serum IGF by a radioreceptor assay (RRA-IGF), which detects both IGF-1 and IGF-2 as well as enhanced activity in the fetal circulation, showed a deficit in serum RRA-IGF in fetuses with trisomy 21, but at birth and throughout life elevated serum RRA-IGF levels. In spite of this, no differences were observed in fetal brain or liver binding sites for IGF-1, IGF-2, or insulin. Since in the RRA-IGF method IGF-1, IGF-2, and a fetal form of IGF-1 cross-react, it is possible that there is a delayed maturation with incomplete switching from production of the fetal form of IGF to production of the GH-regulated IGF-1 in DS. The deficit in IGF-1-like peptides might account for the growth retardation in DS. In order to study the effect of human growth hormone (hGH) therapy in DS, 5 growth-retarded children with DS were treated with hGH for 6 months. During this period the growth velocity doubled and the serum IGF-1 levels were restored to normal. Thus, DS children respond to hGH treatment.
Am J Dis Child 142 (2): 1302-6 (1988)

Growth Studies in Infants and Children with Down's Syndrome and Elevated Levels of Thyrotropin

Sharav T, Collins RM, Baab PJ.
Hadassah-WIZO-Canada Research Institute, Jerusalem, Israel

A retrospective survey of 147 patients with Down's syndrome (age range, 4 months to 27 years) showed that 60% had a thyrotropin (TSH) level higher than 5.7 mU/L in the presence of high or normal thyroxine levels. The remaining 40% of the group had low to normal TSH values. High TSH levels were predominant in patients under 4 years of age (94 children), ie, during the phase of active growth, and showed a declining trend with increasing age. All 94 infants had delayed growth of all parameters including head circumference, height, and weight, as compared with normal infants, and growth was particularly retarded in patients with TSH levels greater than 5.7 mU/L. Thyroid dysfunction, expressed as a high TSH concentration, is associated with growth retardation in children with Down's syndrome who are younger than 4 years.
Int J Psychosom 32 (2): 12-16 (1985)

Height increase in children with Down syndrome following treatment with psycho-pharmacotherapeutic agents

Cocchi R
Italy As a result of a preliminary study showing the effectiveness of psycho-pharmacotherapeutic agents on treating Down syndrome children, the present study was undertaken. The experimental subjects (Ss) were 40 Down syndrome children between the ages of one year, six months and thirteen years, two months, who were treated for at least six months with an individually adjusted psycho-pharmacotherapeutic regimen consisting of the drugs l-glutamine, pyridoxine, diazepam and others, which act primarily on GABAergic mechanisms. The control subjects were 24 Down syndrome children between the ages of one year, eight months and eleven years, two months. The height of the control Ss was taken at the initial consultation and was compared to that of normal Ss [as reported in growth charts for Italian Ss]. The eight of the experimental Ss was taken at the last consultation and compared to that of normal Ss. The results showed that: (1) the untreated control group was shorter on the average from normals by about 24.3 cm (9.7 in.) and (2) the treated experimental group was close to the matched normals but was still shorter by about 8.6 cm (3.5 in.). It appears that the psychopharmacotherapeutic agents used with the experimental Ss induced a GABAergic state that resulted in increased release of growth hormone and subsequent increased height.
Arch Dis Child 61 (1): 48-52 (1986 Jan)

Growth and somatomedin responses to growth hormone in Down's syndrome

Annerén G; Sara VR; Hall K; Tuvemo T

Five growth retarded children with Down's syndrome, three girls and two boys aged between 3½ and 6½ years with trisomy 21, were treated with human growth hormone for six months. Before treatment the growth hormone response to sleep and insulin-arginine load, as well as serum concentrations of insulin, thyroid hormones, and cortisol was found to be in the normal range. During the treatment with human growth hormone the growth velocity increased in all the children with Down's syndrome from 2.3-2.8 cm to 3.3-5.8 cm per six months. The serum concentrations of immunoreactive insulin like growth factor 1 (IGF-1) were low before treatment and increased during the treatment with human growth hormone. The serum concentrations of immunoreactive insulin like growth factor 2 (IGF-2), which were within the normal range, however, increased during treatment with human growth hormone. Children with Down's syndrome respond to treatment with human growth hormone, with an increase in both growth velocity and serum somatomedin concentrations.