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The effect of growth hormone treatment in idiopathic short stature with shox mutation
320
GRS '98 Abstracts
0-29 TREATMENT WITH RECOMBINANT HUMAN G R O W T H H O R M O N E OF C H I L D R E N W I T H MENINGOMYELOCELE AND GROWTH HORMONE DEFICIENCY: 2-YEAR RESULTS
F Hochhaus I, O Butenandt1, HP Schwarz ~, E Ring-Mrozik2. ~University Children's Hospital, Munich; 2University Children's Hospital Ped Surgery, Munich. Short stature in supine length is a frequent finding in children with meningomyelocele (MMC). But also growth in arm span (SP), which has proved to correlate very well with standing height in healthy children, can be very poor. Most of MMC children have brain malformations, such as Arnold-Chiari syndrome or hydrocephalus which can be associated with growth hormone deficiency (GHD). 19 children (9 F, 10 M age 3.6-14.9 years) were diagnosed as GH deficient by stimulation with clonidine and arginine. All patients were treated with recombiant human GH (rhGH) for a period of 2 years (dosage 2.0 IU m 2 BSA daily s.c.). SP was measured with a rigid steel rod. SP, Supine length (SL) and growth velocity (GV) were compared to normal healthy children.
Group (n=19)
Baseline
1-year
2-year results
SDS
Supine length
-4,4 SDS
-3.0 SDS
-2,2 SDS
0,8
Arm span
-3.1 SDS
-1.6 SDS
-0.9 SDS
0.7 4.0
GV supine length
GV arm span
-2,1 SDS
+2.2 SDS
+1.9 SDS
(3.3 cm/y)
(8.1 cm/y)
(7.5 cm/y)
-1.3 SDS
+2.9 SDS
+2.6 SDS
(4.8 cm/y)
(8.3 cm/y)
(7,8 cm/y)
3.9
Correlation of SDS GV SP and SDS GV SL was r=0.85, P<0.0005.
The results of this study indicate that growth of arm span and supine length may increase proportionally during rhGH therapy. We suppose that body proportions do not deteriorate in children with MMC when growth is stimulated. Both arm span and supine length measurements are important parameters for documentation of growth in children with meningomyelocele. 0 - 3 0 T H E EFFECT OF G R O W T H H O R M O N E T R E A T M E N T IN IDIOPATHIC SHORT STATURE WITH SHOX MUTATION
P Vaguin, A Shanske, J Ellison, P Dowling, J Heinrich, P Saenger. Division of Endocrinology and Genetics, Dept. of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Dept. of Pediatrics, Univ. of California, San Francisco; Quest Laboratories, NJ; Division of Endocrinology, Hospital de Ninos R. Gutierrez, Buenos Aires, Argentina. Growth represents a muhifactorial trait influenced by environmental and genetic factors. A new locus involved in linear growth has been implicated within the pseudoautosomal region (EAR) of the human sex chromosomes. Deletions encompassing this novel homeobox gene PHOG/SHOX have been shown to cause growth failure in idiopathic short stature and Turner syndrome. Investigators have estimated that 1.10V0of all patients with idiopathic short stature may carry a SHOX mutation (Nature Genetics 1997; 16:54-63). We report a patient with this defect who had a robust growth response to pharmacologic doses of growth hormone. He was the 2.2 kg product of a term uneventful pregnancy. The family history is unremarkable. Maternal height 153 cm, paternal height 165 cm. His physical examination at 8 7/12 years of age revealed an unstigmatized prepubertal male with normal intelligence, height of 106.4 cm (height age 4 5/12 years) (height SDS -5 SD) weight 19.5 kg, bone age 3 6/12 years, and a growth velocity of 2.8 cm/year. His endocrine evaluation revealed a peak growth hormone level of 30.8ng/ml (nl > 10ng/dl), IGF-1 of 193ng/ml
(nl 158-385 ng/ml), IGF binding protein- 3 of 2.2mg/1), (nl 1.5-3.4 mg/1), and a growth hormone binding protein of 854 pmol/1 (nl 267-1638pmol/1). A peripheral leukocyte culture revealed an unbalanced Y/13 translocation and FISH analysis indicated that the derivative chromosome contained the alpha satellite region and part of the short arm of the Y. Molecular analysis revealed no deletions up to the EAR boundary but dosage Southern blot analysis using cDNA probes indicated that most of the EAR was lost, including PHOG/SHOX. The patient was begun on daily recombinant growth hormone treatment. His growth velocity improved to 9.4 cm/year (IGF-I level 260 ng/ml), during his first year and Z4 cm/year during his second year of treatment (height SDS -3.03). We conclude that haploinsufficiency of PHOG/SHOX is responsible for the growth failure in our patient. Identification of patients with SHOX defects may help predict which children with idiopathic short stature will respond to the treatment. 0 - 3 1 G E N D E R - S P E C I F I C D O S E - R E S P O N S E S TO G H I N G H D C H I L D R E N : R E S U L T S OF A 3 - Y E A R R A N D O M I Z E D TRIAL IN 109 PATIENTS
P Cohen ~, RG Rosenfeld 2, on behalf of the American Norditropin Study Group. ~University of Pennsylvania; 2Oregon Health Sciences University, USA. While growth hormone (GH) is highly effective and widely used in children with GH deficiency (GHD), well-defined doseresponse curves for GH have never been generated, and the effect of gender on GH responsiveness in children has never been examined. We evaluated the dose-response effects of GH on the growth of GHD patients and on their serum growth factors. 109 short (-3 _+ 1 height Z-score), slow-growing [-2 + 1 growth velocity (GV) Z-score], prepubertal (6 _+ 2 years old) children who failed two GH stimulation tests were randomized to receive low (L) (0.025), medium (M) (0.05), or high (H) (0.1 mg/kg/day) subcutaneous GH injections. Length-oftreatment-dependent increase in growth velocity and height Z-scores were observed in all groups. At 3 years, the three groups displayed cumulative increases in height SDS of 1.7 for L, 2.8 for M (/M0.001 relative to L), and 2.9 for H (/M0.001 relative to L, P-NS relative to M). The rise in the serum levels of insulinlike growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) during treatment also demonstrated dependency on the GH dose and correlated with auxological parameters. Bone age advancement and occurrence of puberty during therapy were not different among the three groups. Surprisingly, the GH doseresponse curve for both auxological and biochemical parameters differed between females (n=38) and males (n=71). Males demonstrated a linear GH dose response, while females displayed a bell-shaped dose-response curve. In conclusion, in a large, randomized, long-term study, we demonstrated a doseresponse effect of GH on growth and serum growth factors and observed gender differences in GH sensitivity. [This work was supported by a grant from Novo Nordisk.] 0-32 SUSTAINED-RELEASE GROWTH HORMONE IN CHILDREN AND ADULTS
SF Kemp ~, ML Vance 2, HJ Lee3, J Wright3, DC Bloedow 4, KM Attie4. *Arkansas Childrens Hosp; 2U Virginia HSC; 3Alkermes, I n c ; 4 Genentech, Inc. As an alternative to daily subcutaneous (s.c.) growth hormone (GH) administration, Genemech, Inc. and Alkermes, Inc. developed a sustained-release (ProLease| formulation of recombinant GH (rhGH). In GHD adults (n=13), following s.c. administration of 0.75 mg/kg rhGH (5 mg/kg ProLease| hGH), GH levels reached a mean peak of 74 ~tg/1at 13 h, and returned to baseline at 23 days (median). IGF-I levels reached a mean peak change from baseline of 410 ~tg/1, which occurred by 48 h in most patients; IGF-I levels returned to near baseline by 28 days. In prepubertal GHD children, a single s.c. injection of 0.75mg/kg (n=12) or 1.5mg/kg (n=8) resulted in mean GH
GRS '98 Abstracts
0-29 TREATMENT WITH RECOMBINANT HUMAN G R O W T H H O R M O N E OF C H I L D R E N W I T H MENINGOMYELOCELE AND GROWTH HORMONE DEFICIENCY: 2-YEAR RESULTS
F Hochhaus I, O Butenandt1, HP Schwarz ~, E Ring-Mrozik2. ~University Children's Hospital, Munich; 2University Children's Hospital Ped Surgery, Munich. Short stature in supine length is a frequent finding in children with meningomyelocele (MMC). But also growth in arm span (SP), which has proved to correlate very well with standing height in healthy children, can be very poor. Most of MMC children have brain malformations, such as Arnold-Chiari syndrome or hydrocephalus which can be associated with growth hormone deficiency (GHD). 19 children (9 F, 10 M age 3.6-14.9 years) were diagnosed as GH deficient by stimulation with clonidine and arginine. All patients were treated with recombiant human GH (rhGH) for a period of 2 years (dosage 2.0 IU m 2 BSA daily s.c.). SP was measured with a rigid steel rod. SP, Supine length (SL) and growth velocity (GV) were compared to normal healthy children.
Group (n=19)
Baseline
1-year
2-year results
SDS
Supine length
-4,4 SDS
-3.0 SDS
-2,2 SDS
0,8
Arm span
-3.1 SDS
-1.6 SDS
-0.9 SDS
0.7 4.0
GV supine length
GV arm span
-2,1 SDS
+2.2 SDS
+1.9 SDS
(3.3 cm/y)
(8.1 cm/y)
(7.5 cm/y)
-1.3 SDS
+2.9 SDS
+2.6 SDS
(4.8 cm/y)
(8.3 cm/y)
(7,8 cm/y)
3.9
Correlation of SDS GV SP and SDS GV SL was r=0.85, P<0.0005.
The results of this study indicate that growth of arm span and supine length may increase proportionally during rhGH therapy. We suppose that body proportions do not deteriorate in children with MMC when growth is stimulated. Both arm span and supine length measurements are important parameters for documentation of growth in children with meningomyelocele. 0 - 3 0 T H E EFFECT OF G R O W T H H O R M O N E T R E A T M E N T IN IDIOPATHIC SHORT STATURE WITH SHOX MUTATION
P Vaguin, A Shanske, J Ellison, P Dowling, J Heinrich, P Saenger. Division of Endocrinology and Genetics, Dept. of Pediatrics, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Dept. of Pediatrics, Univ. of California, San Francisco; Quest Laboratories, NJ; Division of Endocrinology, Hospital de Ninos R. Gutierrez, Buenos Aires, Argentina. Growth represents a muhifactorial trait influenced by environmental and genetic factors. A new locus involved in linear growth has been implicated within the pseudoautosomal region (EAR) of the human sex chromosomes. Deletions encompassing this novel homeobox gene PHOG/SHOX have been shown to cause growth failure in idiopathic short stature and Turner syndrome. Investigators have estimated that 1.10V0of all patients with idiopathic short stature may carry a SHOX mutation (Nature Genetics 1997; 16:54-63). We report a patient with this defect who had a robust growth response to pharmacologic doses of growth hormone. He was the 2.2 kg product of a term uneventful pregnancy. The family history is unremarkable. Maternal height 153 cm, paternal height 165 cm. His physical examination at 8 7/12 years of age revealed an unstigmatized prepubertal male with normal intelligence, height of 106.4 cm (height age 4 5/12 years) (height SDS -5 SD) weight 19.5 kg, bone age 3 6/12 years, and a growth velocity of 2.8 cm/year. His endocrine evaluation revealed a peak growth hormone level of 30.8ng/ml (nl > 10ng/dl), IGF-1 of 193ng/ml
(nl 158-385 ng/ml), IGF binding protein- 3 of 2.2mg/1), (nl 1.5-3.4 mg/1), and a growth hormone binding protein of 854 pmol/1 (nl 267-1638pmol/1). A peripheral leukocyte culture revealed an unbalanced Y/13 translocation and FISH analysis indicated that the derivative chromosome contained the alpha satellite region and part of the short arm of the Y. Molecular analysis revealed no deletions up to the EAR boundary but dosage Southern blot analysis using cDNA probes indicated that most of the EAR was lost, including PHOG/SHOX. The patient was begun on daily recombinant growth hormone treatment. His growth velocity improved to 9.4 cm/year (IGF-I level 260 ng/ml), during his first year and Z4 cm/year during his second year of treatment (height SDS -3.03). We conclude that haploinsufficiency of PHOG/SHOX is responsible for the growth failure in our patient. Identification of patients with SHOX defects may help predict which children with idiopathic short stature will respond to the treatment. 0 - 3 1 G E N D E R - S P E C I F I C D O S E - R E S P O N S E S TO G H I N G H D C H I L D R E N : R E S U L T S OF A 3 - Y E A R R A N D O M I Z E D TRIAL IN 109 PATIENTS
P Cohen ~, RG Rosenfeld 2, on behalf of the American Norditropin Study Group. ~University of Pennsylvania; 2Oregon Health Sciences University, USA. While growth hormone (GH) is highly effective and widely used in children with GH deficiency (GHD), well-defined doseresponse curves for GH have never been generated, and the effect of gender on GH responsiveness in children has never been examined. We evaluated the dose-response effects of GH on the growth of GHD patients and on their serum growth factors. 109 short (-3 _+ 1 height Z-score), slow-growing [-2 + 1 growth velocity (GV) Z-score], prepubertal (6 _+ 2 years old) children who failed two GH stimulation tests were randomized to receive low (L) (0.025), medium (M) (0.05), or high (H) (0.1 mg/kg/day) subcutaneous GH injections. Length-oftreatment-dependent increase in growth velocity and height Z-scores were observed in all groups. At 3 years, the three groups displayed cumulative increases in height SDS of 1.7 for L, 2.8 for M (/M0.001 relative to L), and 2.9 for H (/M0.001 relative to L, P-NS relative to M). The rise in the serum levels of insulinlike growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) during treatment also demonstrated dependency on the GH dose and correlated with auxological parameters. Bone age advancement and occurrence of puberty during therapy were not different among the three groups. Surprisingly, the GH doseresponse curve for both auxological and biochemical parameters differed between females (n=38) and males (n=71). Males demonstrated a linear GH dose response, while females displayed a bell-shaped dose-response curve. In conclusion, in a large, randomized, long-term study, we demonstrated a doseresponse effect of GH on growth and serum growth factors and observed gender differences in GH sensitivity. [This work was supported by a grant from Novo Nordisk.] 0-32 SUSTAINED-RELEASE GROWTH HORMONE IN CHILDREN AND ADULTS
SF Kemp ~, ML Vance 2, HJ Lee3, J Wright3, DC Bloedow 4, KM Attie4. *Arkansas Childrens Hosp; 2U Virginia HSC; 3Alkermes, I n c ; 4 Genentech, Inc. As an alternative to daily subcutaneous (s.c.) growth hormone (GH) administration, Genemech, Inc. and Alkermes, Inc. developed a sustained-release (ProLease| formulation of recombinant GH (rhGH). In GHD adults (n=13), following s.c. administration of 0.75 mg/kg rhGH (5 mg/kg ProLease| hGH), GH levels reached a mean peak of 74 ~tg/1at 13 h, and returned to baseline at 23 days (median). IGF-I levels reached a mean peak change from baseline of 410 ~tg/1, which occurred by 48 h in most patients; IGF-I levels returned to near baseline by 28 days. In prepubertal GHD children, a single s.c. injection of 0.75mg/kg (n=12) or 1.5mg/kg (n=8) resulted in mean GH