Guest Editor: P.S.N. Menon - Editorial
http://www.100md.com
《美国医学杂志》
Department of Pediatrics, Armed Forces Hospital, Kuwait
Childhood and adolescence are characterized by growth and development. Most children and their parents are very keen that children should attain a good height by adolescence. Thus the number of children seeking advice from a pediatric endocrinologist or growth expert regarding stature is on increase. This symposium on growth and growth disorders is an attempt to highlight some key issues related to growth and development and their optimal management in children and adolescents.
M. Kamboj's in his article on 'Short Stature and Growth Hormone' highlights the various aspects of assessment of growth and clinical differentiation between and normal and abnormal growth.[1] The most useful parameter in the assessment of a child with growth retardation is clinical evaluation with serial height measurements. Regular use of growth charts and serial recording of height from infancy is the key for early diagnosis of abnormal growth. It is important to evaluate the hypothalamo-pituitary-GH-IGF axis by appropriate laboratory tests and imaging techniques to diagnose growth hormone (GH) deficiency and insensitivity and its cause.[2] It should be remembered that conventional GH stimulation tests are less accurate, poorly reproducible, uncomfortable, expensive and sometimes risky. The cut off levels to diagnose GH deficiency are arbitrary.
The management options available for most growth disorders especially constitutional delay in growth, GH deficiency and Turner syndrome differ from each other. GH is neither the panacea nor the first line of management for every child with growth retardation irrespective of etiology. Good nutrition, physical activity and management of associated chronic diseases such as malabsorption helps in attaining better growth potential. Many short children need only counseling and reassurance. Short course of androgens are beneficial in children with constitutional delay of growth and delayed puberty. GH therapy accelerates growth in Turner syndrome initially, with appropriate estrogen replacement to induce pubertal development later.
GH therapy is the cornerstone of management of children with GH deficiency. Pituitary GH was used for over 25 years with remarkable success. Recombinant GH is now easily available in India and its use in GH deficiency is on the rise. A. Bajpai and P.S.N. Menon discuss the dynamics of administering GH optimally in the article on 'Growth Hormone Therapy'.[3] Daily GH is superior to intermittent administration with regard to growth. Evening administration provides better GH levels and greater IGF response. A variety of automated pen devices have made daily home administration of GH simple and convenient to children. A dose of 0.16 mg/kg/ week probably represents physiological replacement dose for GH. Studies have shown that this dose is unlikely to produce sustained catch-up growth and higher doses as much as 0.33 mg/kg/week are now being recommended for best height results.[4] Close follow up with regular monitoring is essential for a good outcome. In India, high cost of GH prompts most pediatricians to prescribe GH in the lower ranges of normal recommended dosage. Thus counseling and education is an integral part of GH therapy just as insulin is for diabetes mellitus.
It is important to treat concomitant pituitary deficiencies before starting GH therapy. The best indicator of response is height gain itself and investigations such as bone age, IGF-1 levels are at best supportive in most cases. There is a gain of 10-12 cm/year in the first two years with a gain about 7-8 cm/year subsequently. Inappropriate response calls for prompt evaluation of compliance, dose of GH, injection technique, hypothyroidism and re-evaluation of the cause for short stature. It is also observed that higher doses are indicated in children approaching puberty. Optimal therapy during puberty is still an elusive goal with concurrent administration of GnRH analogs for a period of two years being beneficial in some. Early diagnosis, higher dose, longer period of therapy are associated with a good outcome. Despite concerns about potential adverse effects, GH therapy has been shown to be remarkably safe in expert's hands. Continuing GH therapy into adulthood to improve metabolic function and improve quality of life has become important.[5]
The scope of GH therapy has expanded dramatically. In the last few decades it has been used effectively in a variety of growth disorders caused by genetic syndromes, skeletal dysplasias, and chronic systemic diseases. Turner syndrome leads the list followed by chronic renal failure and Prader-Willi syndrome More Details. GH therapy in children with Prader-Willi syndrome improves body composition, energy expenditure and motor development.[6] A number of studies are now evaluating long term results of GH therapy in improving height outcome in intra-uterine growth retardation.
The improved height outcome has prompted the use of GH in a variety of non-GD deficient short stature commonly clubbed as 'idiopathic short stature'. Based on the results observed in long term trials, many experts believe that probably a 6 month trial of GH in optimal doses is indicated for children with short stature of no known cause.
Response to GH therapy in so called 'idiopathic short stature' indicates that ISS may actually be representing a mixed bag of children with varying degrees of defects in GH-IGF axis with low genetic height potential. Indeed many previously uncharacterized cases of 'idiopathic short stature' (ISS) are now attributable to genetic defects in the GH-IGF axis. Several mutations in pituitary specific transcription factors have been identified leading to GHD. HESX-1 has been associated with septo-optic dysplasia and GH deficiency. Mutations in PROP-1 are common genetic causes for multiple pituitary hormone deficiencies. Patients with POUIF1 (Pit-1 or GHF-1) mutations have GH, prolactin and TSH deficiencies. Genetic basis for GH insensitivity has been shown by mutations in the GH receptor gene and STAT proteins, IGF-1 and IGF-1 receptors. Understanding the molecular mechanisms involved in the GH-IGF pathway may help us to understand 'idiopathic short stature' better. J. Lee and R.K Menon describe these entities in their article on 'Molecular Defects in Growth Hormone-IGF Axis' and their characteristic phenotypes of known mutations.[7]
Growth and final height along with puberty is now a major concern of children receiving therapy for a variety of chronic disorders. The article by Dr Louis Low on 'Growth of Children with β-Thalassemia Major' describes how prognosis for adult height can be optimized in children receiving therapy for -thalassemia.[8] Despite advances in medical therapy such as hypertransfusion and chelation, growth failure and hypogonadism are major problems in adolescents with thalassemia. These patients most probably have a state of secondary GH insensitivity as indicated by normal GH reserve with low IGF-1 and IGFBP-3 concentrations. GH therapy can improve the growth velocity in these children without any significant adverse effects on skeletal maturation and metabolic function. The experience gained with the management of thalassemia can pave way for use of GH in a variety other situations without GH deficiency with better quality of survival and good growth potential as adults.
References
1. Kamboj M. Short stature and growth hormone. State of the art review. Indian J Pediatr 2005; 72: 149-157.
2. Sizonenko PC, Clayton PE, Cohen P, Hintz RL, Tanaka T, Laron Z. Diagnosis and management of growth hormone deficiency in childhood and adolescence. Part 1: diagnosis of growth hormone deficiency. Growth Horm IGF Res 2002; 12:1-33.
3. Bajpai A, Menon PSN. Growth hormone therapy. Indian J Pediatr 2005; 72: 139-144.
4. Tanaka T, Cohen P, Clayton PE, Laron Z, Hintz RL, Sizonenko PC. Diagnosis and management of growth hormone deficiency in childhood and adolescence-part 2: growth hormone treatment in growth hormone deficient children. Growth Horm IGF Res 2002; 12: 323-341.
5. Simpson H, Savine R, Sonksen P, Bengtsson BA, Carlsson L, Christiansen JS et al. Growth hormone replacement therapy for adults: into the new millennium. Growth Horm IGF Res 2002; 12:1-33.
6. Carrel AL, Moerchen V, Myers SE, Bekx MT, Whitman BY, Allen DB. Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome. J Pediatr 2004; 145: 744-749.
7. Lee J, Menon RK. Molecular defects in the growth hormone-IGF axis; Recent advances. Indian J Pediatr 2005; 72: 145-148.
8. Low LCK. Growth of children with b-thalassaemia major. Indian J Pediatr 2005; 72: 159-164.(Menon P SN)
Childhood and adolescence are characterized by growth and development. Most children and their parents are very keen that children should attain a good height by adolescence. Thus the number of children seeking advice from a pediatric endocrinologist or growth expert regarding stature is on increase. This symposium on growth and growth disorders is an attempt to highlight some key issues related to growth and development and their optimal management in children and adolescents.
M. Kamboj's in his article on 'Short Stature and Growth Hormone' highlights the various aspects of assessment of growth and clinical differentiation between and normal and abnormal growth.[1] The most useful parameter in the assessment of a child with growth retardation is clinical evaluation with serial height measurements. Regular use of growth charts and serial recording of height from infancy is the key for early diagnosis of abnormal growth. It is important to evaluate the hypothalamo-pituitary-GH-IGF axis by appropriate laboratory tests and imaging techniques to diagnose growth hormone (GH) deficiency and insensitivity and its cause.[2] It should be remembered that conventional GH stimulation tests are less accurate, poorly reproducible, uncomfortable, expensive and sometimes risky. The cut off levels to diagnose GH deficiency are arbitrary.
The management options available for most growth disorders especially constitutional delay in growth, GH deficiency and Turner syndrome differ from each other. GH is neither the panacea nor the first line of management for every child with growth retardation irrespective of etiology. Good nutrition, physical activity and management of associated chronic diseases such as malabsorption helps in attaining better growth potential. Many short children need only counseling and reassurance. Short course of androgens are beneficial in children with constitutional delay of growth and delayed puberty. GH therapy accelerates growth in Turner syndrome initially, with appropriate estrogen replacement to induce pubertal development later.
GH therapy is the cornerstone of management of children with GH deficiency. Pituitary GH was used for over 25 years with remarkable success. Recombinant GH is now easily available in India and its use in GH deficiency is on the rise. A. Bajpai and P.S.N. Menon discuss the dynamics of administering GH optimally in the article on 'Growth Hormone Therapy'.[3] Daily GH is superior to intermittent administration with regard to growth. Evening administration provides better GH levels and greater IGF response. A variety of automated pen devices have made daily home administration of GH simple and convenient to children. A dose of 0.16 mg/kg/ week probably represents physiological replacement dose for GH. Studies have shown that this dose is unlikely to produce sustained catch-up growth and higher doses as much as 0.33 mg/kg/week are now being recommended for best height results.[4] Close follow up with regular monitoring is essential for a good outcome. In India, high cost of GH prompts most pediatricians to prescribe GH in the lower ranges of normal recommended dosage. Thus counseling and education is an integral part of GH therapy just as insulin is for diabetes mellitus.
It is important to treat concomitant pituitary deficiencies before starting GH therapy. The best indicator of response is height gain itself and investigations such as bone age, IGF-1 levels are at best supportive in most cases. There is a gain of 10-12 cm/year in the first two years with a gain about 7-8 cm/year subsequently. Inappropriate response calls for prompt evaluation of compliance, dose of GH, injection technique, hypothyroidism and re-evaluation of the cause for short stature. It is also observed that higher doses are indicated in children approaching puberty. Optimal therapy during puberty is still an elusive goal with concurrent administration of GnRH analogs for a period of two years being beneficial in some. Early diagnosis, higher dose, longer period of therapy are associated with a good outcome. Despite concerns about potential adverse effects, GH therapy has been shown to be remarkably safe in expert's hands. Continuing GH therapy into adulthood to improve metabolic function and improve quality of life has become important.[5]
The scope of GH therapy has expanded dramatically. In the last few decades it has been used effectively in a variety of growth disorders caused by genetic syndromes, skeletal dysplasias, and chronic systemic diseases. Turner syndrome leads the list followed by chronic renal failure and Prader-Willi syndrome More Details. GH therapy in children with Prader-Willi syndrome improves body composition, energy expenditure and motor development.[6] A number of studies are now evaluating long term results of GH therapy in improving height outcome in intra-uterine growth retardation.
The improved height outcome has prompted the use of GH in a variety of non-GD deficient short stature commonly clubbed as 'idiopathic short stature'. Based on the results observed in long term trials, many experts believe that probably a 6 month trial of GH in optimal doses is indicated for children with short stature of no known cause.
Response to GH therapy in so called 'idiopathic short stature' indicates that ISS may actually be representing a mixed bag of children with varying degrees of defects in GH-IGF axis with low genetic height potential. Indeed many previously uncharacterized cases of 'idiopathic short stature' (ISS) are now attributable to genetic defects in the GH-IGF axis. Several mutations in pituitary specific transcription factors have been identified leading to GHD. HESX-1 has been associated with septo-optic dysplasia and GH deficiency. Mutations in PROP-1 are common genetic causes for multiple pituitary hormone deficiencies. Patients with POUIF1 (Pit-1 or GHF-1) mutations have GH, prolactin and TSH deficiencies. Genetic basis for GH insensitivity has been shown by mutations in the GH receptor gene and STAT proteins, IGF-1 and IGF-1 receptors. Understanding the molecular mechanisms involved in the GH-IGF pathway may help us to understand 'idiopathic short stature' better. J. Lee and R.K Menon describe these entities in their article on 'Molecular Defects in Growth Hormone-IGF Axis' and their characteristic phenotypes of known mutations.[7]
Growth and final height along with puberty is now a major concern of children receiving therapy for a variety of chronic disorders. The article by Dr Louis Low on 'Growth of Children with β-Thalassemia Major' describes how prognosis for adult height can be optimized in children receiving therapy for -thalassemia.[8] Despite advances in medical therapy such as hypertransfusion and chelation, growth failure and hypogonadism are major problems in adolescents with thalassemia. These patients most probably have a state of secondary GH insensitivity as indicated by normal GH reserve with low IGF-1 and IGFBP-3 concentrations. GH therapy can improve the growth velocity in these children without any significant adverse effects on skeletal maturation and metabolic function. The experience gained with the management of thalassemia can pave way for use of GH in a variety other situations without GH deficiency with better quality of survival and good growth potential as adults.
References
1. Kamboj M. Short stature and growth hormone. State of the art review. Indian J Pediatr 2005; 72: 149-157.
2. Sizonenko PC, Clayton PE, Cohen P, Hintz RL, Tanaka T, Laron Z. Diagnosis and management of growth hormone deficiency in childhood and adolescence. Part 1: diagnosis of growth hormone deficiency. Growth Horm IGF Res 2002; 12:1-33.
3. Bajpai A, Menon PSN. Growth hormone therapy. Indian J Pediatr 2005; 72: 139-144.
4. Tanaka T, Cohen P, Clayton PE, Laron Z, Hintz RL, Sizonenko PC. Diagnosis and management of growth hormone deficiency in childhood and adolescence-part 2: growth hormone treatment in growth hormone deficient children. Growth Horm IGF Res 2002; 12: 323-341.
5. Simpson H, Savine R, Sonksen P, Bengtsson BA, Carlsson L, Christiansen JS et al. Growth hormone replacement therapy for adults: into the new millennium. Growth Horm IGF Res 2002; 12:1-33.
6. Carrel AL, Moerchen V, Myers SE, Bekx MT, Whitman BY, Allen DB. Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome. J Pediatr 2004; 145: 744-749.
7. Lee J, Menon RK. Molecular defects in the growth hormone-IGF axis; Recent advances. Indian J Pediatr 2005; 72: 145-148.
8. Low LCK. Growth of children with b-thalassaemia major. Indian J Pediatr 2005; 72: 159-164.(Menon P SN)