Short stature and growth hormone
http://www.100md.com
《美国医学杂志》
Division of Pediatric Endocrinology, Michigan State University, Kalamazoo Center for Medical Studies, Kalamazoo, USA
Abstract
Normal growth and development is a prime concern during childhood. Accurate assessment is essential for differentiating between normal and abnormal growth. Increased accessibility to growth hormone has equipped the pediatrician and pediatric endocrinologist to treat and improve growth in many clinical scenarios. At the same time, there is added responsibility to use this tool judiciously. This review summarizes the basics of proper growth assessment, differentiation of normal and abnormal growth causes of and works up of short stature, and delineation of indications for growth hormone treatment.
Keywords: Short stature; Growth hormone (GH); Insulin like growth factor 1 (IGF-1); Idiopathic short stature (ISS); Small for gestational age (SGA)
Growth is a complex process and represents an integration of the genetic potential, appropriately functioning endocrine system, nutritional status, effect of any chronic illness or diseases, and level of physical activity. A disorder at any of these levels may potentially cause significant growth deficit resulting in short stature. Short stature per se is not an illness but may be a manifestation of a multitude of underlying problems. Short stature is arbitrarily defined as height below the 3rd percentile or two standard deviations below the mean for that age and sex in the same ethnic group (a similar reference group); therefore, 3% of all children would be essentially classified as short. The common causes of short stature are listed in table1.[1]
The concept of following children for appropriate growth and development is familiar to all pediatricians. Short stature in children becomes the primary focus of concern for parents as well as their pediatricians. It is of the utmost importance to define the underlying factors responsible for short stature on an individual basis to be able to delineate patients requiring growth hormone (GH) therapy versus others who may not require any medical intervention. The widespread availability of GH albeit at a considerable expense has brought on great debate about the clinical scenarios in which GH should be used.
Assessment of growth
There is great variability in the rate of growth at different periods of childhood table2.[2] accurate height and weight measurements are essential for proper assessment of growth. The height measurements are preferably obtained using a Harpenden stadiometer. A minimum interval of six months is generally recommended between height measurements for a reliable evaluation and extrapolations regarding growth velocity. Accurate growth assessment can be made by comparing data using standard reference growth charts. The mid-parental target height is calculated for obtaining the genetic potential of the individual table3.[3] An estimation of skeletal age/bone age is traditionally done by assessing the skeletal maturation on a left hand and wrist radiograph using the Greulich and Pyle methods or Tanner-Whitehouse technique. The Bayley-Pinneau method is most commonly used for calculating the predicted adult height.[4],[5],[6] Dental development is helpful in assessing the skeletal maturation as well. A number of auxologic abnormalities may be suggestive of GH deficiency table4.[7]
History and Physical Examination
Detailed dietary history is important to rule out malnutrition as a cause of growth retardation. Malnutrition may also give falsely low levels of insulin like growth factor 1 (IGF-1). The nutritional status of the patient should preferably be restored to normal before testing for GH deficiency. History of consanguinity, intrauterine infections, medications, maternal pre-eclampsia, smoking, alcohol, and exposure to toxins in-utero are important determinants of intrauterine growth. An accurate assessment of birth weight, birth length, gestational age at birth, and type of delivery are essential. Presence of midline craniofacial abnormalities, microphallus, septo-optic dysplasia, neonatal hypoglycemia, and prolonged jaundice may be early indicators for presence of GH deficiency.
The patient should be evaluated for the presence of chronic illnesses such as pulmonary, cardiac, renal, gastrointestinal diseases, malabsorption, celiac disease or HIV. Past history of intracranial tumors, leukemia or signs and symptoms suggestive of the same need to be ruled out. Treatment modalities in the form of chemotherapy, cranio-spinal irradiation, bone marrow transplantation, immuno-suppressive therapy, and high dose steroid regimens may lead to growth deficits. A note should be made of complaints of anorexia, nausea, vomiting, and diarrhea along with a detailed dietary history. Effort should be made to detect any psychosocial stress factors at home or school that may impact the child's growth. Family history of short stature and mid-parental target height calculation is helpful for categorization into familial short stature. However, it is important to remember that several conditions associated with growth hormone deficiency may be familial as well.
Detailed physical examination including assessment of body proportions in addition to the auxological data is helpful in the differential diagnosis of the underlying disorder. Specific syndromic stigmata may help identify Turner syndrome, Russel Silver syndrome, Prader Willi syndrome, Albright's hereditary osteodystrophy, and pseudohypoparathyroidism. The simple most useful parameter in the assessment of the child with growth retardation is the clinical evaluation with emphasis placed on serial measurements of height and determination of the height velocity.[8] Children with auxologic parameters and risk factors suggestive of pathology in the hypothalamo- pituitary-GH-IGF-1 axis should be screened with appropriate laboratory evaluation table5.
GH Stimulation Tests
GH stimulation tests are performed generally using at least two sequential stimuli. The commonly used secretagogues are arginine, clonidine, levodopa, insulin, glucagon, and rGHRH (Geref). The insulin induced hypoglycemia test for GH stimulation probably remains the most reliable test and is still considered the gold standard. However, it is unpleasant for the patient, requires very close medical supervision and hence not commonly undertaken in pediatrics. Serum levels of GH are measured at baseline and then serially after each secretagogue. Levels of GH above 10 ng/ml are considered normal, and levels less than 10 ng/ml are consistent with GH deficiency. Random measurements of GH are not helpful because of the diurnal variation and pulsatility of GH secretion. Twenty four hour spontaneous GH measurements may give more accurate and useful information about the GH profile of a child with short stature. However, the test is more tedious, needs hospitalization for close monitoring and thus not feasible for routine use. The practice of sex steroid priming before GH stimulation tests is still debated. However, it is well recognized that unprimed GH stimulation tests done in the peri-pubertal periods may give subnormal results.[9] It is also important to correct hypothyroidism adequately before GH stimulation testing because GH secretion may be subnormal due to hypothyroidism itself. Although widely used, GH stimulation tests are by themselves of limited accuracy as they rely on arbitrary cutoff values for a normal or subnormal response. These tests have poor reproducibility, are uncomfortable, expensive, and also carry some risk of side effects. In addition, the response varies with age as well as sexual development.
A more reliable comprehensive assessment for GH deficiency may be made based on history, physical examination, auxologic assessment in association with IGF-1, IGF-BP3 and GH stimulation test results. MRI or CT scan with and without contrast offers the best visualization for the identification of pituitary tumors or anatomical abnormalities of the pituitary associated with GH deficiency. It is recommended that patients diagnosed with severe GH deficiency, visual disturbances, signs of increased intracranial pressure or acquired growth failure should have an MRI study. An MRI may also be helpful in prediction of permanent GH deficiency.[10]
Testing in the Neonate
A random GH level of less than 20 ng/ml in the presence of neonatal hypoglycemia is suggestive of GH deficiency. IGF-BP3 is more helpful than IGF-1 in this age group. GH stimulation tests are usually not advised in neonates although a glucagon stimulation test is generally considered safe. Any newborn with history of significant birth trauma, hypoglycemia, prolonged hyperbilirubinemia, or micropenis should be investigated for GH deficiency.[7]
Treatment of growth disorders
After an assessment of short stature has been made, appropriate therapy may be instituted. Treatment must be directed initially and primarily towards correction of any underlying condition such as malabsorption, celiac disease, inflammatory bowel disease, malnutrition, chronic renal insufficiency, cystic fibrosis or chronic pulmonary conditions requiring specific medical intervention. GH therapy may help in accelerating growth in some of these patients but adequate catch up growth is unlikely unless the underlying disorder has been corrected. Any concurrent endocrine deficits such as hypothyroidism or adrenal insufficiency also need adequate hormone replacement. table6 summarizes the conditions for which GH has been approved by the United States Food and Drug Administration (US-FDA).[11]
Constitutional Delay in Growth
The growth pattern in constitutional delay involves slow growth in the first few years of life followed by normal growth velocity after three to four years of age. These children thus grow along or even below the normal lower growth percentiles. They have a delayed skeletal age versus genetic/familial short stature where the bone age is consistent with chronological age. Constitutional growth delay is characterized by a positive family history of the same and the predicted adult height falls within range of mid parental target height. In the absence of any medical intervention, patients with constitutional delay of growth and puberty will reach a final height which is consistent with their genetic potential. Growth and development can be followed by assessing serial bone ages while providing ample reassurance to the family. Most endocrinologists advocate no medical intervention. If reassurance does not suffice and there are issues of poor self image, growth can be accelerated in boys with testosterone injections (50 - 100 mg every 4 weeks for 3 to 6 months). New forms of testosterone supplementation such as testosterone gel are now available but their efficacy in boys with constitutional delay has not been well documented. Girls seem to be referred less commonly than boys for constitutional delay; short term estrogen therapy may be helpful in these cases. In cases of severe short stature resulting from genetic short stature and constitutional delay, a six month trial of GH therapy can be initiated and continued if growth velocity is increased to 7 to 10 cm/year.[12]
GH Deficiency
There is no controversy about starting GH therapy with recombinant human GH (rhGH) once the diagnosis of GH deficiency is made irrespective of the underlying cause. The aim is to normalize growth and growth velocity in order to achieve normal final adult height.[9] Formal recommendations are still not available about oral GH secretagogues and rGHRH (Geref) which is now available but not thought to be as effective.[11]
The majority of children with GH deficiency are diagnosed based on auxologic criteria, poor growth velocity, low IGF-1 and IGF- BP3 levels and failure of adequate response on GH stimulation testing. The Lawson Wilkins Pediatric Endocrine Society (LWPES) also recommends GH treatment in the following clinical scenarios:[11]
Children who meet all the above criteria but have a normal response on GH stimulation tests should be given a trial of GH therapy for 6 months. This treatment may be continued further if there is an adequate clinical response.
It should not be compulsory to order GH stimulation test if empty sella, pituitary stalk agenesis, sellar on suprasellar mass lesions, or ectopic pituitary is seen on MRI/CT scan in the clinical scenario suggestive of GH deficiency.
GH Dosing
Dosage recommendations for GH in GH deficiency in children are 0.17-0.30 mg/kg/week table7. It has been demonstrated that the efficacy and safety of GH can be optimized by modulating the dose of GH dose in a gender specific manner by following the growth response and levels of serum IGF-1.[13] Sustained release preparations of GH were marketed but have been recently discontinued. The dosing convenience offered by such formulations, when available, may promote long term compliance. [14]
GH therapy for children born small for gestational age (SGA)
SGA is defined as birth weight and/or length at least 2 SD below the mean for gestational age, based on appropriate reference population criteria.[15] Therefore the accurate identification of gestational age, birth weight, and length measurements becomes essential. The etiology of SGA may be multifactorial including maternal, fetal or placental factors. Mutations in the IGF-1 receptor gene have also being implicated in intrauterine and post natal growth deficits. [16] Most children with SGA exhibit catch-up growth by 2 years of age and failure to do so by 3 years of age warrants comprehensive evaluation and assessment. These children may exhibit classical GH deficiency or mild neurosecretory dysfunction. [16] The diagnosis of SGA does not exclude GH deficiency, and bone age estimation may not be a reliable predictor of adult height. Thus, it is recommended that the SGA infants be screened for GH deficiency if clinically indicated. Baseline IGF-1, IGF-BP3 are low normal in short SGA children and show an increase with high dose GH therapy and decrease with its discontinuation. [17] The goal of GH therapy in SGA children is to accelerate pre-pubertal growth, allowing catch up to normal height in early childhood, maintain normal growth in later childhood, and achieve normal adult height. [15]
GH therapy is US-FDA approved at a dose of 0.48 mg/kg/week for SGA children who fail to achieve catch up growth by two years of age with subsequent dose adjustments to within the 0.24-0.48 mg/kg/week range. The growth response seen in these children is directly proportional to the dose of GH and the individual height deficit, and inversely proportional to the age of the patient with the younger patients showing a greater response. [18] A mathematical model has been developed to help predict the growth response and allow for alterations in GH dose to achieve the desired results. [19] SGA children may have precocious puberty and the concomitant use of GH and GnRH analogue treatment has been reported to result in considerable gain in predicted adult height. [20]
The efficacy of GH for increasing adult height in short adolescents who were born SGA is unclear. Limited potential for spontaneous catch-up growth in this group of patients has been demonstrated. [21] GH treatment in the same dose range should also be initiated at a young age in very short SGA children to enable sufficient catch-up growth before onset of puberty. [22] The issue of SGA itself being associated with long term risk of Type II DM and the metabolic syndrome and the additional adverse effect of GH on glucose metabolism in these children is of potential concern. Baseline fasting glucose, insulin levels and lipid profile should be measured and close monitoring of these parameters along with blood pressure measurements is warranted.[15] The short term effectiveness and safety of GH treatment in children born SGA has been demonstrated. However, the long term risks and benefits of GH treatment and the final adult heights achieved in this subgroup are still not clearly known and long term studies are required for clarifying these issues.
Idiopathic Short Stature (ISS)
The role of GH in ISS (non GH deficient short stature) continues to be a topic of great controversy. ISS was approved as an indication for GH treatment by the US-FDA in July 2003 on the fulfillment of the following criteria[23]:
Height < -2.25 SD or < 3rd percentile for reference standards
Growth velocity unlikely to attain normal adult height
Pediatric patients with open epiphyses
This approval is based on a few studies which have reported an increase in adult height in at least some children with ISS.[24],[25] Children with ISS may exhibit varying degrees of GH resistance, pathology in the GH-IGF-1 axis, GH receptor, or SHOX gene defects, or mutations in the POU1 (Pit1), PROP1 and GHRH. Therefore, establishing a molecular basis for the short stature in ISS may change the whole perception of ISS as a normal variant.[26] The difficulties involved with diagnosis and treatment of this very heterogeneous group are well recognized and the response to GH may vary greatly. Prediction models are available but need to be optimized to improve efficacy and accuracy of treatment. GH therapy should be initiated early as the height at onset of puberty is an important factor for determining the final height. The major impact of rhGH therapy on final height in ISS occurs in the first year and the average gain in final height is dependent on the dosage used. Treatment regimens therefore should be individualized.[27] Considerable gain in predicted adult height has been reported in pubertal children with ISS by using GnRh agonists along with GH. [28]
GH treatment in ISS continues to be a much debated topic among the endocrinologists, pediatricians, parents, as well as the health care payers and insurers, because of multiple implications and ramifications involved. It is important for all these patients to be enrolled in a database since the long term consequences of treating otherwise healthy children with GH remain uncertain. [11]
Treatment in Turner Syndrome
Short stature is the most consistent clinical feature of Turner syndrome (TS). Growth deficit in TS is characterized by mild intrauterine growth retardation, slow growth in infancy and childhood, and growth failure in childhood and adolescence including an absent pubertal growth spurt. This results in a total growth deficit of about 20 cm or 8 inches below the mean for females of the same ethnic group. The final adult height in untreated TS patients correlates with the mid-parental height. [29] The heights of TS girls should be plotted on TS specific growth charts, specific for ethnic background wherever possible. Girls below -2 SD on normal female growth charts with clinical features of TS, or below -2.5 SD without clinical features of TS should have a peripheral blood karyotype analysis done. A karyotype analysis in fibroblasts should be ordered if there is a strong suspicion of TS in spite of a normal blood karyotype.[29] Provocative GH testing is not recommended in TS if the growth is consistent with that expected for the syndrome. Although TS girls are not GH deficient, GH therapy results in growth acceleration resulting in increased final height. A target of 150 cm final height is a realistic goal in most girls with TS. The number of years of GH therapy (age at initiation of therapy) as well as the GH dose are predictive of final gain in height. The US-FDA approved dose of GH for TS is 0.35 mg/kg/wk but it may need to be individualized. The initiation of GH therapy is recommended as soon as the patient with TS starts to fall below the 5th percentile of the normal female growth curve and treatment is continued till completion of linear growth. Therefore, GH may be initiated as early as two years of age, with close supervision and follow-up by a pediatric endocrinologist.[29],[30] Initiation as well as dosing of estrogen therapy for induction of pubertal development needs to be closely coordinated with GH and individualized to optimize growth and pubertal development. Estrogen replacement needs to be delayed if a wider window of prepubertal growth period is desired to ensure adequate gain in final adult height further height. [31]
Prader Willi Syndrome (PWS)
PWS is a chromosomal disorder characterized by deletion of the paternal alleles at chromosome 15q 11-13 with an estimated prevalence of about 1:15,000 live births. It is characterized by hypotonia, obesity, short stature, hyperphagia, hypogonadism and mental retardation. Short stature in PWS begins in early childhood and average adult height is about 2 SD below the general population average. [32] The cause of short stature in PWS has been a topic of long standing debate especially in the setting of associated obesity. Although contradictory reports exist, there is evidence suggestive of GH deficiency in PWS. [33] Multiple studies have looked into the effect of GH on height as well as obesity and body composition in PWS. Controlled studies have shown decrease in fat mass and improvement in growth velocity and muscle mass when PWS patients are treated with GH. A study involving 25 pre-pubertal PWS children on GH showed improvement in growth velocity as well as decrease in fat mass along with an increase in free fat mass.[33] A four year study in 46 PWS children has reported sustained improvement in growth, body composition, bone mineral density and physical function on a dose of >1.0 mg/m2/day versus 0.3 mg/m2/day. However, this dose was found to be insufficient to sustain improvements in body composition. [35] Body composition improvements along with increased linear growth may be important reason to offer early GH treatment to PWS patients, thereby reducing future morbidity and mortality. In view of reports of mortality associated with severe obesity and respiratory improvement in PWS patients on GH, extreme caution is warranted.
Chronic Renal Failure (CRF)
Growth failure is a common feature in children with CRF and depends on the underlying renal disease, age at onset, nutritional status, and presence of renal osteodystrophy, metabolic acidosis and associated alterations in the GH-IGF-I growth axis. Height measurements of less than -2 SD have been reported in 60-70 percent of patients with CRF.[36] The GH-IGF-1-IGFBP axis is implicated at multiple levels in CRF. A decrease in the number of GH receptors, reduced IGF-1 secretion and increase in IGFBP3 leading to decreased levels of free IGF-1 have been suggested.[37] The rhGH treatment causes accelerated growth resulting in significant and sustained improvement in the standardized height.[38],[39] The rhGH is US-FDA approved for the treatment of growth failure in pre-transplant patients with CRF at a dose of 0.05 mg/kg/day. GH stimulation testing is not required in these patients. The growth response may be affected by the severity of the underlying renal disease and early treatment of rhGH is most effective.[11] Other therapeutic options in the form of rhIGF-1 (recombinant human IGF1), rhIGFBP3 (recombinant human IGFBP3), and their combinations with rhGH are being currently investigated. The concept of IGF-1 displacers to increase the bioavailability of IGF-I also seems promising. [40] Supportive care in the form of adequate nutrition and appropriate medical care are essential for maximum benefit.
MULTIPLE PITUITARY HORMONE DEFICIENCIES (MPHD)
The management of GH therapy in patients with MPHD is similar to that of isolated GH deficiency. There should be a high index of suspicion for other pituitary hormone deficits (thyroid, adrenal, sex steroids, and diabetes insipidus) in the presence of GH deficiency.
Transition to adult management
Patients with documented GH deficiency in childhood, receiving GH for the purpose of growth need reassessment upon attainment of final adult height. Following completion of growth, GH is important for maintaining normal body composition, increasing bone density, normal cardiac function as well as for psychological well being.[41] GH deficiency of childhood may or may not persist into adulthood. Repeat testing for GH deficiency in patients with multiple pituitary hormone deficiencies, severe organic GH deficiency, or those with genetic defects of GH synthesis is not required. Other patients should be retested one to three months after cessation of GH therapy using the criteria for adult GH deficiency (GH peak < 5mg/ml). About 70% of patients who met criteria for GH deficiency in childhood do not do so when retested by adult standards.[1] Younger patients require higher doses than older patients and women require higher doses than men. Average GH dose in adult male is 0.2-0.5 mg/day and in adult female is 0.4-1.0 mg/day, the dose being titrated to achieve a normal IGF-1 for age. [11]
HIV/AIDS
GH is approved for treatment of AIDS wasting in adults. However, it is still not approved for use in children with HIV. A state of GH resistance has been suggested with low IGFI and high IGFBP3 levels in children with HIV disease and growth failure, which is seen to normalize during treatment with protease inhibitors containing regimen. [42] Studies are underway to determine the use of GH in children with HIV. [11], [42]
FOLLOW-UP ON GH THERAPY
Children receiving GH should be followed every 3-6 months by their pediatricians/pediatric endocrinologists to monitor their linear growth and growth velocity. Increase in linear growth velocity is evident within the first three to six months as compared to the pretreatment growth velocity. Improvement in height standard deviation score is evident after one year of GH therapy and IGF-1 levels age seem to normalize. IGF-1 and IGFBP3 levels should be monitored and may be helpful for assurance of compliance and regulating GH dose. Free T4 and TSH should be evaluated for early detection of hypothyroidism. Fasting blood sugar and hemoglobin A1C may be measured in patients at risk of developing impaired carbohydrate tolerance. [11] Other parameters such as complete blood counts, bone markers, insulin levels, lipid profile may need monitoring in specific clinical scenarios. Serial bone ages are helpful in assessing advancement of skeletal age for calculating predicted adult height. Maximum growth promoting effect is seen in the first year of GH treatment, after which it decreases to the normal growth velocity for age. Inadequate growth may be due to compliance issues, inappropriate GH dose, inaccurate GH administration concomitant hypothyroidism or glucocorticoid therapy or an underlying yet undiagnosed disorder. Treatment with GH is usually continued until the completion of linear growth or when growth velocity is less than 2.5 cm per year. The decision to continue GH therapy after completion of linear growth requires reassessment.
Side effects of gh therapy
Recombinant GH is a relatively safe medication. Nevertheless all patients receiving GH are closely followed in a database to monitor for any possible side effects table8.
Investigational uses of gh
There is a suggestion of the potential role of GH to promote growth in a number of other clinical conditions aside from the above US-FDA approved indications. These include chondrodysplasias, Down's syndrome, Russel Silver syndrome, familial dysautonomia and cystic fibrosis as well as chronic gastrointestinal conditions such as Crohn's disease and celiac disease.[43],[44],[45],[46] The role of GH in improving glucocorticoid induced growth suppression is being investigated. GH is also used to promote growth in patients with precocious puberty on GnRh analogues, showing growth suppression and poor growth velocity. Patients with neurofibromatosis, Noonan Syndrome, familial hypophosphatemic rickets and thalassemias have all been shown to have a positive short term growth response to GH therapy as well.
Novel modalities for gh treatment
There has been a great advancement in the availability of different types of GH preparations. New pen devices and delivery systems facilitate administration and improve compliance. Other novel approaches in the form of orally inhaled or intranasal preparations are also being investigated. Several other alternative treatment modalities are under investigation. Although, GH releasing hormone, IGF-1 and oral secretagogues are available but their definitive role in specific clinical scenarios needs to be defined.
GH INSENSITIVITY SYNDROME (GHIS)
GHIS encompasses a group of heritable disorders in which patients have a phenotype of GH deficiency but have normal or high levels of GH. GHIS may result primarily from GH receptor abnormalities, post receptor GH signal transduction problems, defective IGF-1 biosynthesis or secondarily from antibodies to GH or GH receptor, malnutrition, or liver disease.[7] Laron Syndrome is the classic prototype of GH insensitivity. Since these patients exhibit extreme resistance to GH, IGF-1 seems to offer potential for therapy but further studies are needed before final recommendations can be made.
Conclusion
Recombinant DNA technology has made it possible to produce GH in sufficient quantities to treat children with various growth disorders. There are many clinical scenarios with short stature beside GH deficiency in which the benefits of GH can be exploited. Although generally considered to be a safe modality of treatment, great caution must be exercised in ensuring the judicious use of GH in these situations. Any benefits of GH must be weighed against the risk of adverse events, the discomfort of daily injections, as well as the cost involved. Maintaining data base registry for all patients treated with GH is very helpful in the long term follow-up.
Acknowledgement
I thank Dr. Martin Draznin and Dr. Dilip Patel for their critical review of the manuscript and to Mrs. Amy Esman for her expert administrative assistance.
References
1. Lifshitz F, Botero D. Worrisome Growth in Pediatric. In Lifshitz F, ed. Pediatric Endocrinology; 4th edn. New York, U.S.A. Marcel Dekker 2003; 1-46.
2. Tanner JM, Whitehouse RH. Clinical longitudinal standard for height, weight, height velocity, weight velocity and stages of puberty. Arch Dis Child 1976; 51: 170-171.
3. Tanner JM, Whitehouse RH, Marshall WA, Carter BS. Prediction of adult height from height, bone age, and occurrence of menarche, at ages 4 to 16, with allowance for midparent height. Arch Dis Child 1975; 50: 14-26.
4. Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standard. J Pediatr 1952; 40: 423-441.
5. Tanner JM, Whitehouse RH, Cameron N et al. Assessment of skeletal maturity and prediction of adult height (TW2 Method). London: Academic Press, 1983.
6. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd edn. Stanford, CA, Stanford University Press, U.S.A. 1959.
7. Rosenfeld RG, Cohen P. Disorders of GH/insulin-like growth factor secretion and action. In Sperling MA, ed. Pediatric Endocrinology; 2nd edn. Saunders, U.S.A. 2002.
8. Rosenfeld RG, Albertsson-Wikland K, Cassorla F et al. Diagnostic controversy: The diagnosis of childhood GH deficiency revisited. J Clin Endocrinol Metab 1995; 80(5): 1532-1540.
9. GH Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 2000; 85(11): 3990-3993.
10. Maghnie M, Strigazzi C, Tinelli C et al. Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab 1999; 84(4): 1324-1328.
11. Wilson TA, Rose SR, Cohen P et al. Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr 2003; 143(4): 415-421.
12. MacGillivray MH. The basics for the diagnosis and management of short stature: a pediatric endocrinologist's approach. Pediatr Annals 2000; 29(9): 570-575.
13. Cohen P, Bright GM, Rogol AD et al. Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety. J Clin Endocrinol Metab 2002; 87(1): 90-98.
14. Reiter EO, Attie KM, Moshang T Jr et al. A multicenter study of the efficacy and safety of sustained release GH in the treatment of nave pediatric patients with GH deficiency. J Clin Endocrinol Metab 2001; 86(10): 4700-4706.
15. Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P. International Small for Gestational Age Advisory Board. International small for gestational age advisory board consensus development conference statement: Management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics 2003; 111(6): 1253-1261.
16. Abuzzahab MJ, Schneider A, Goddard A et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003; 349(23): 2211-2212.
17. de Zegher F, Du Caju MV, Heinrichs C et al. Early, discontinuous, high dose growth hormone treatment to normalize height and weight of short children born small for gestational age: results over 6 years. J Clin Endocrinol Metab 1999; 845): 1558-1561.
18. Boguszewski M, Albertsson-Wikland K, Aronsson S et al. Growth hormone treatment of short children born small-for-gestational-age: The Nordic Multicentre Trial. Acta Paediatr 1998; 87(3): 257-263.
19. Ranke MB, Lindberg A, Cowell CT et al. Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab 2003; 88(1): 125-131.
20. Kamp GA, Mul D, Waelkens JJ et al. A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation. J Clin Endocrinol Metab 2001; 86(7): 2969-2975.
21. Carel JC, Chatelain P, Rochiccioli P, Chaussain JL. Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study. Endocrinol Metab 2003; 88(4): 1587-1593.
22. Arends NJ, Boonstra VH, Mulder PG et al. GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial. Clin Endocrinol 2003; 59(6): 779-787.
23. Cuttler l, Silver JB. Growth hormone treatment for idiopathic short stature implications for practice and policy. Arch Pediatr Adolesc Med 2004; 158(2): 108-110.
24. Endocrinologic and Metabolic Drugs Advisory Committee. Humatrope for Non-Growth Hormone Deficient Short Stature. Indianapolis, Indiana: Lilly Research Laboratories, U.S.A.; 2003. Briefing Document.
25. Finkelstein B, Imperiale T, Speroff T, Marrero U, Radcliffe DJ, Cuttler L. Effects of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med 2002; 156(2): 230-240.
26. Rosenfeld R, Hwa V. Toward a molecular basis for idiopathic short stature. J Clin Endocrinol Metab 89(3): 1066-1067.
27. Wit JM, Rekers-Mombarg LT. Dutch Growth Hormone Advisory Group. Final height gain by GH therapy in children with idiopathic short stature is dose dependent. J Clin Endocrinol Metab 87(2): 604-611.
28. Kamp GA, Mul D, Waelkens JJ et al. A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation. Endocrinol Metab 2001; 86(7): 2969-2975.
29. Saenger P, Wikland KA, Conway GS et al. Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metab 2001; 86(7): 3061-3069.
30. Frias JL, Davenport ML. Committee on Genetics and Section on Endocrinology. Health supervision for children with Turner syndrome. Pediatrics 2003; 111(3): 692-702.
31. Chernausek SD, Attie KM, Cara JF, Rosenfeld RG, Frane J. Growth hormone therapy of Turner syndrome: the impact on final height Genetech, Inc., Collaborative Study Group. J Clin Endocrinol Metab 2000; 85(7): 2439-2445.
32. Lee PDK, Allen DB, Angulo MA et al. Consensus statement - Prader-Willi Syndrome: growth hormone (GH)/ insulin-like growth factor axis deficiency and GH treatment. The Endocrinologist 10(4): 71-73.
33. Angulo M, Castro-Magana M, Mazur B, Canas JA, Vitollo PM, Sarrantonio M. Growth hormone secretion and effects of growth hormone therapy on growth velocity and weight gain in children with Prader-Willi Syndrome. J Pediatr Endocrinol Metab 1996; 9(3): 393-400.
34. Davies PS, Evans S, Broomhead S et al. Effect of growth hormone on height, weight and body composition in Prader-Willi Syndrome. Arch Dis Child 1998; 78(5): 474-476.
35. Carrel AL, Myers SE, Whitman BY, Allen DB. Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study. J Clin Endocrinol Metab 2002; 87(4): 1581-1585.
36. Warady BA, Jabs K. New hormones in the therapeutic arsenal of chronic renal failure: growth failure and erythropoietin. Pediatr Clin North Am 1995; 42(6): 1551-1577.
37. Rosenfeld R, Allen DB, MacGillivray MH, et al. Growth hormone use in pediatric growth hormone deficiency and other pediatric growth disorders. Am J Managed Care 2000; 6(15): 805-816.
38. Fine RN. Growth hormone in children with chronic renal insufficiency and end-stage renal disease. The Endocrinologist 1998; 8: 160-169.
39. Haffner D, Schaefer F, Nissel R, Wuhl E, Tonshoff B, Mehls O. Effect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure. N Engl J Med 2000; 343(13): 923-930.
40. Roelfsema V, Clark RG. The growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure. J Am Soc Nephrol 2001; 12(6): 1297-1306.
41. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998; 83 (2): 379-381.
42. Van Rossum AM, Gaakeer MI, Verweel S et al. Endocrinologic and immunologic factors associated with recovery of growth in children with human immunodeficiency virus type I infection treated with protease inhibitors. Pediatr Infect Dis J 2003; 22(1): 70-76.
43. Kamboj MK, Axelrod FB, David R et al. Growth hormone treatment in children with familial dysautonomia. J Pediatr 2004; 144(1): 63-67.
44. Shohat M, Tick D, Barakat S, Bu X, Melmed S, Rimoin DL. Short term recombinant growth hormone treatment increases growth rate in achondroplasia. J Clin Endocrinol Metab 1996; 81(11): 4033-4037.
45. Anneren G, Tuvemo T, Carlsson-Skwirut C et al. Growth treatment in young children with Down's syndrome: effects on growth and psychomotor development. Arch Dis Child 1999; 80(4): 334-338.
46. Hardin DS, Stratton R, Kramer JC, de la Rocha RS, Govaerts K, Wilson DP. Growth hormone improves weight velocity and growth velocity in prepubertal children with cystic fibrosis. Horm Metab Res 1998; 30(10): 636-641.(Kamboj Manmohan)
Abstract
Normal growth and development is a prime concern during childhood. Accurate assessment is essential for differentiating between normal and abnormal growth. Increased accessibility to growth hormone has equipped the pediatrician and pediatric endocrinologist to treat and improve growth in many clinical scenarios. At the same time, there is added responsibility to use this tool judiciously. This review summarizes the basics of proper growth assessment, differentiation of normal and abnormal growth causes of and works up of short stature, and delineation of indications for growth hormone treatment.
Keywords: Short stature; Growth hormone (GH); Insulin like growth factor 1 (IGF-1); Idiopathic short stature (ISS); Small for gestational age (SGA)
Growth is a complex process and represents an integration of the genetic potential, appropriately functioning endocrine system, nutritional status, effect of any chronic illness or diseases, and level of physical activity. A disorder at any of these levels may potentially cause significant growth deficit resulting in short stature. Short stature per se is not an illness but may be a manifestation of a multitude of underlying problems. Short stature is arbitrarily defined as height below the 3rd percentile or two standard deviations below the mean for that age and sex in the same ethnic group (a similar reference group); therefore, 3% of all children would be essentially classified as short. The common causes of short stature are listed in table1.[1]
The concept of following children for appropriate growth and development is familiar to all pediatricians. Short stature in children becomes the primary focus of concern for parents as well as their pediatricians. It is of the utmost importance to define the underlying factors responsible for short stature on an individual basis to be able to delineate patients requiring growth hormone (GH) therapy versus others who may not require any medical intervention. The widespread availability of GH albeit at a considerable expense has brought on great debate about the clinical scenarios in which GH should be used.
Assessment of growth
There is great variability in the rate of growth at different periods of childhood table2.[2] accurate height and weight measurements are essential for proper assessment of growth. The height measurements are preferably obtained using a Harpenden stadiometer. A minimum interval of six months is generally recommended between height measurements for a reliable evaluation and extrapolations regarding growth velocity. Accurate growth assessment can be made by comparing data using standard reference growth charts. The mid-parental target height is calculated for obtaining the genetic potential of the individual table3.[3] An estimation of skeletal age/bone age is traditionally done by assessing the skeletal maturation on a left hand and wrist radiograph using the Greulich and Pyle methods or Tanner-Whitehouse technique. The Bayley-Pinneau method is most commonly used for calculating the predicted adult height.[4],[5],[6] Dental development is helpful in assessing the skeletal maturation as well. A number of auxologic abnormalities may be suggestive of GH deficiency table4.[7]
History and Physical Examination
Detailed dietary history is important to rule out malnutrition as a cause of growth retardation. Malnutrition may also give falsely low levels of insulin like growth factor 1 (IGF-1). The nutritional status of the patient should preferably be restored to normal before testing for GH deficiency. History of consanguinity, intrauterine infections, medications, maternal pre-eclampsia, smoking, alcohol, and exposure to toxins in-utero are important determinants of intrauterine growth. An accurate assessment of birth weight, birth length, gestational age at birth, and type of delivery are essential. Presence of midline craniofacial abnormalities, microphallus, septo-optic dysplasia, neonatal hypoglycemia, and prolonged jaundice may be early indicators for presence of GH deficiency.
The patient should be evaluated for the presence of chronic illnesses such as pulmonary, cardiac, renal, gastrointestinal diseases, malabsorption, celiac disease or HIV. Past history of intracranial tumors, leukemia or signs and symptoms suggestive of the same need to be ruled out. Treatment modalities in the form of chemotherapy, cranio-spinal irradiation, bone marrow transplantation, immuno-suppressive therapy, and high dose steroid regimens may lead to growth deficits. A note should be made of complaints of anorexia, nausea, vomiting, and diarrhea along with a detailed dietary history. Effort should be made to detect any psychosocial stress factors at home or school that may impact the child's growth. Family history of short stature and mid-parental target height calculation is helpful for categorization into familial short stature. However, it is important to remember that several conditions associated with growth hormone deficiency may be familial as well.
Detailed physical examination including assessment of body proportions in addition to the auxological data is helpful in the differential diagnosis of the underlying disorder. Specific syndromic stigmata may help identify Turner syndrome, Russel Silver syndrome, Prader Willi syndrome, Albright's hereditary osteodystrophy, and pseudohypoparathyroidism. The simple most useful parameter in the assessment of the child with growth retardation is the clinical evaluation with emphasis placed on serial measurements of height and determination of the height velocity.[8] Children with auxologic parameters and risk factors suggestive of pathology in the hypothalamo- pituitary-GH-IGF-1 axis should be screened with appropriate laboratory evaluation table5.
GH Stimulation Tests
GH stimulation tests are performed generally using at least two sequential stimuli. The commonly used secretagogues are arginine, clonidine, levodopa, insulin, glucagon, and rGHRH (Geref). The insulin induced hypoglycemia test for GH stimulation probably remains the most reliable test and is still considered the gold standard. However, it is unpleasant for the patient, requires very close medical supervision and hence not commonly undertaken in pediatrics. Serum levels of GH are measured at baseline and then serially after each secretagogue. Levels of GH above 10 ng/ml are considered normal, and levels less than 10 ng/ml are consistent with GH deficiency. Random measurements of GH are not helpful because of the diurnal variation and pulsatility of GH secretion. Twenty four hour spontaneous GH measurements may give more accurate and useful information about the GH profile of a child with short stature. However, the test is more tedious, needs hospitalization for close monitoring and thus not feasible for routine use. The practice of sex steroid priming before GH stimulation tests is still debated. However, it is well recognized that unprimed GH stimulation tests done in the peri-pubertal periods may give subnormal results.[9] It is also important to correct hypothyroidism adequately before GH stimulation testing because GH secretion may be subnormal due to hypothyroidism itself. Although widely used, GH stimulation tests are by themselves of limited accuracy as they rely on arbitrary cutoff values for a normal or subnormal response. These tests have poor reproducibility, are uncomfortable, expensive, and also carry some risk of side effects. In addition, the response varies with age as well as sexual development.
A more reliable comprehensive assessment for GH deficiency may be made based on history, physical examination, auxologic assessment in association with IGF-1, IGF-BP3 and GH stimulation test results. MRI or CT scan with and without contrast offers the best visualization for the identification of pituitary tumors or anatomical abnormalities of the pituitary associated with GH deficiency. It is recommended that patients diagnosed with severe GH deficiency, visual disturbances, signs of increased intracranial pressure or acquired growth failure should have an MRI study. An MRI may also be helpful in prediction of permanent GH deficiency.[10]
Testing in the Neonate
A random GH level of less than 20 ng/ml in the presence of neonatal hypoglycemia is suggestive of GH deficiency. IGF-BP3 is more helpful than IGF-1 in this age group. GH stimulation tests are usually not advised in neonates although a glucagon stimulation test is generally considered safe. Any newborn with history of significant birth trauma, hypoglycemia, prolonged hyperbilirubinemia, or micropenis should be investigated for GH deficiency.[7]
Treatment of growth disorders
After an assessment of short stature has been made, appropriate therapy may be instituted. Treatment must be directed initially and primarily towards correction of any underlying condition such as malabsorption, celiac disease, inflammatory bowel disease, malnutrition, chronic renal insufficiency, cystic fibrosis or chronic pulmonary conditions requiring specific medical intervention. GH therapy may help in accelerating growth in some of these patients but adequate catch up growth is unlikely unless the underlying disorder has been corrected. Any concurrent endocrine deficits such as hypothyroidism or adrenal insufficiency also need adequate hormone replacement. table6 summarizes the conditions for which GH has been approved by the United States Food and Drug Administration (US-FDA).[11]
Constitutional Delay in Growth
The growth pattern in constitutional delay involves slow growth in the first few years of life followed by normal growth velocity after three to four years of age. These children thus grow along or even below the normal lower growth percentiles. They have a delayed skeletal age versus genetic/familial short stature where the bone age is consistent with chronological age. Constitutional growth delay is characterized by a positive family history of the same and the predicted adult height falls within range of mid parental target height. In the absence of any medical intervention, patients with constitutional delay of growth and puberty will reach a final height which is consistent with their genetic potential. Growth and development can be followed by assessing serial bone ages while providing ample reassurance to the family. Most endocrinologists advocate no medical intervention. If reassurance does not suffice and there are issues of poor self image, growth can be accelerated in boys with testosterone injections (50 - 100 mg every 4 weeks for 3 to 6 months). New forms of testosterone supplementation such as testosterone gel are now available but their efficacy in boys with constitutional delay has not been well documented. Girls seem to be referred less commonly than boys for constitutional delay; short term estrogen therapy may be helpful in these cases. In cases of severe short stature resulting from genetic short stature and constitutional delay, a six month trial of GH therapy can be initiated and continued if growth velocity is increased to 7 to 10 cm/year.[12]
GH Deficiency
There is no controversy about starting GH therapy with recombinant human GH (rhGH) once the diagnosis of GH deficiency is made irrespective of the underlying cause. The aim is to normalize growth and growth velocity in order to achieve normal final adult height.[9] Formal recommendations are still not available about oral GH secretagogues and rGHRH (Geref) which is now available but not thought to be as effective.[11]
The majority of children with GH deficiency are diagnosed based on auxologic criteria, poor growth velocity, low IGF-1 and IGF- BP3 levels and failure of adequate response on GH stimulation testing. The Lawson Wilkins Pediatric Endocrine Society (LWPES) also recommends GH treatment in the following clinical scenarios:[11]
Children who meet all the above criteria but have a normal response on GH stimulation tests should be given a trial of GH therapy for 6 months. This treatment may be continued further if there is an adequate clinical response.
It should not be compulsory to order GH stimulation test if empty sella, pituitary stalk agenesis, sellar on suprasellar mass lesions, or ectopic pituitary is seen on MRI/CT scan in the clinical scenario suggestive of GH deficiency.
GH Dosing
Dosage recommendations for GH in GH deficiency in children are 0.17-0.30 mg/kg/week table7. It has been demonstrated that the efficacy and safety of GH can be optimized by modulating the dose of GH dose in a gender specific manner by following the growth response and levels of serum IGF-1.[13] Sustained release preparations of GH were marketed but have been recently discontinued. The dosing convenience offered by such formulations, when available, may promote long term compliance. [14]
GH therapy for children born small for gestational age (SGA)
SGA is defined as birth weight and/or length at least 2 SD below the mean for gestational age, based on appropriate reference population criteria.[15] Therefore the accurate identification of gestational age, birth weight, and length measurements becomes essential. The etiology of SGA may be multifactorial including maternal, fetal or placental factors. Mutations in the IGF-1 receptor gene have also being implicated in intrauterine and post natal growth deficits. [16] Most children with SGA exhibit catch-up growth by 2 years of age and failure to do so by 3 years of age warrants comprehensive evaluation and assessment. These children may exhibit classical GH deficiency or mild neurosecretory dysfunction. [16] The diagnosis of SGA does not exclude GH deficiency, and bone age estimation may not be a reliable predictor of adult height. Thus, it is recommended that the SGA infants be screened for GH deficiency if clinically indicated. Baseline IGF-1, IGF-BP3 are low normal in short SGA children and show an increase with high dose GH therapy and decrease with its discontinuation. [17] The goal of GH therapy in SGA children is to accelerate pre-pubertal growth, allowing catch up to normal height in early childhood, maintain normal growth in later childhood, and achieve normal adult height. [15]
GH therapy is US-FDA approved at a dose of 0.48 mg/kg/week for SGA children who fail to achieve catch up growth by two years of age with subsequent dose adjustments to within the 0.24-0.48 mg/kg/week range. The growth response seen in these children is directly proportional to the dose of GH and the individual height deficit, and inversely proportional to the age of the patient with the younger patients showing a greater response. [18] A mathematical model has been developed to help predict the growth response and allow for alterations in GH dose to achieve the desired results. [19] SGA children may have precocious puberty and the concomitant use of GH and GnRH analogue treatment has been reported to result in considerable gain in predicted adult height. [20]
The efficacy of GH for increasing adult height in short adolescents who were born SGA is unclear. Limited potential for spontaneous catch-up growth in this group of patients has been demonstrated. [21] GH treatment in the same dose range should also be initiated at a young age in very short SGA children to enable sufficient catch-up growth before onset of puberty. [22] The issue of SGA itself being associated with long term risk of Type II DM and the metabolic syndrome and the additional adverse effect of GH on glucose metabolism in these children is of potential concern. Baseline fasting glucose, insulin levels and lipid profile should be measured and close monitoring of these parameters along with blood pressure measurements is warranted.[15] The short term effectiveness and safety of GH treatment in children born SGA has been demonstrated. However, the long term risks and benefits of GH treatment and the final adult heights achieved in this subgroup are still not clearly known and long term studies are required for clarifying these issues.
Idiopathic Short Stature (ISS)
The role of GH in ISS (non GH deficient short stature) continues to be a topic of great controversy. ISS was approved as an indication for GH treatment by the US-FDA in July 2003 on the fulfillment of the following criteria[23]:
Height < -2.25 SD or < 3rd percentile for reference standards
Growth velocity unlikely to attain normal adult height
Pediatric patients with open epiphyses
This approval is based on a few studies which have reported an increase in adult height in at least some children with ISS.[24],[25] Children with ISS may exhibit varying degrees of GH resistance, pathology in the GH-IGF-1 axis, GH receptor, or SHOX gene defects, or mutations in the POU1 (Pit1), PROP1 and GHRH. Therefore, establishing a molecular basis for the short stature in ISS may change the whole perception of ISS as a normal variant.[26] The difficulties involved with diagnosis and treatment of this very heterogeneous group are well recognized and the response to GH may vary greatly. Prediction models are available but need to be optimized to improve efficacy and accuracy of treatment. GH therapy should be initiated early as the height at onset of puberty is an important factor for determining the final height. The major impact of rhGH therapy on final height in ISS occurs in the first year and the average gain in final height is dependent on the dosage used. Treatment regimens therefore should be individualized.[27] Considerable gain in predicted adult height has been reported in pubertal children with ISS by using GnRh agonists along with GH. [28]
GH treatment in ISS continues to be a much debated topic among the endocrinologists, pediatricians, parents, as well as the health care payers and insurers, because of multiple implications and ramifications involved. It is important for all these patients to be enrolled in a database since the long term consequences of treating otherwise healthy children with GH remain uncertain. [11]
Treatment in Turner Syndrome
Short stature is the most consistent clinical feature of Turner syndrome (TS). Growth deficit in TS is characterized by mild intrauterine growth retardation, slow growth in infancy and childhood, and growth failure in childhood and adolescence including an absent pubertal growth spurt. This results in a total growth deficit of about 20 cm or 8 inches below the mean for females of the same ethnic group. The final adult height in untreated TS patients correlates with the mid-parental height. [29] The heights of TS girls should be plotted on TS specific growth charts, specific for ethnic background wherever possible. Girls below -2 SD on normal female growth charts with clinical features of TS, or below -2.5 SD without clinical features of TS should have a peripheral blood karyotype analysis done. A karyotype analysis in fibroblasts should be ordered if there is a strong suspicion of TS in spite of a normal blood karyotype.[29] Provocative GH testing is not recommended in TS if the growth is consistent with that expected for the syndrome. Although TS girls are not GH deficient, GH therapy results in growth acceleration resulting in increased final height. A target of 150 cm final height is a realistic goal in most girls with TS. The number of years of GH therapy (age at initiation of therapy) as well as the GH dose are predictive of final gain in height. The US-FDA approved dose of GH for TS is 0.35 mg/kg/wk but it may need to be individualized. The initiation of GH therapy is recommended as soon as the patient with TS starts to fall below the 5th percentile of the normal female growth curve and treatment is continued till completion of linear growth. Therefore, GH may be initiated as early as two years of age, with close supervision and follow-up by a pediatric endocrinologist.[29],[30] Initiation as well as dosing of estrogen therapy for induction of pubertal development needs to be closely coordinated with GH and individualized to optimize growth and pubertal development. Estrogen replacement needs to be delayed if a wider window of prepubertal growth period is desired to ensure adequate gain in final adult height further height. [31]
Prader Willi Syndrome (PWS)
PWS is a chromosomal disorder characterized by deletion of the paternal alleles at chromosome 15q 11-13 with an estimated prevalence of about 1:15,000 live births. It is characterized by hypotonia, obesity, short stature, hyperphagia, hypogonadism and mental retardation. Short stature in PWS begins in early childhood and average adult height is about 2 SD below the general population average. [32] The cause of short stature in PWS has been a topic of long standing debate especially in the setting of associated obesity. Although contradictory reports exist, there is evidence suggestive of GH deficiency in PWS. [33] Multiple studies have looked into the effect of GH on height as well as obesity and body composition in PWS. Controlled studies have shown decrease in fat mass and improvement in growth velocity and muscle mass when PWS patients are treated with GH. A study involving 25 pre-pubertal PWS children on GH showed improvement in growth velocity as well as decrease in fat mass along with an increase in free fat mass.[33] A four year study in 46 PWS children has reported sustained improvement in growth, body composition, bone mineral density and physical function on a dose of >1.0 mg/m2/day versus 0.3 mg/m2/day. However, this dose was found to be insufficient to sustain improvements in body composition. [35] Body composition improvements along with increased linear growth may be important reason to offer early GH treatment to PWS patients, thereby reducing future morbidity and mortality. In view of reports of mortality associated with severe obesity and respiratory improvement in PWS patients on GH, extreme caution is warranted.
Chronic Renal Failure (CRF)
Growth failure is a common feature in children with CRF and depends on the underlying renal disease, age at onset, nutritional status, and presence of renal osteodystrophy, metabolic acidosis and associated alterations in the GH-IGF-I growth axis. Height measurements of less than -2 SD have been reported in 60-70 percent of patients with CRF.[36] The GH-IGF-1-IGFBP axis is implicated at multiple levels in CRF. A decrease in the number of GH receptors, reduced IGF-1 secretion and increase in IGFBP3 leading to decreased levels of free IGF-1 have been suggested.[37] The rhGH treatment causes accelerated growth resulting in significant and sustained improvement in the standardized height.[38],[39] The rhGH is US-FDA approved for the treatment of growth failure in pre-transplant patients with CRF at a dose of 0.05 mg/kg/day. GH stimulation testing is not required in these patients. The growth response may be affected by the severity of the underlying renal disease and early treatment of rhGH is most effective.[11] Other therapeutic options in the form of rhIGF-1 (recombinant human IGF1), rhIGFBP3 (recombinant human IGFBP3), and their combinations with rhGH are being currently investigated. The concept of IGF-1 displacers to increase the bioavailability of IGF-I also seems promising. [40] Supportive care in the form of adequate nutrition and appropriate medical care are essential for maximum benefit.
MULTIPLE PITUITARY HORMONE DEFICIENCIES (MPHD)
The management of GH therapy in patients with MPHD is similar to that of isolated GH deficiency. There should be a high index of suspicion for other pituitary hormone deficits (thyroid, adrenal, sex steroids, and diabetes insipidus) in the presence of GH deficiency.
Transition to adult management
Patients with documented GH deficiency in childhood, receiving GH for the purpose of growth need reassessment upon attainment of final adult height. Following completion of growth, GH is important for maintaining normal body composition, increasing bone density, normal cardiac function as well as for psychological well being.[41] GH deficiency of childhood may or may not persist into adulthood. Repeat testing for GH deficiency in patients with multiple pituitary hormone deficiencies, severe organic GH deficiency, or those with genetic defects of GH synthesis is not required. Other patients should be retested one to three months after cessation of GH therapy using the criteria for adult GH deficiency (GH peak < 5mg/ml). About 70% of patients who met criteria for GH deficiency in childhood do not do so when retested by adult standards.[1] Younger patients require higher doses than older patients and women require higher doses than men. Average GH dose in adult male is 0.2-0.5 mg/day and in adult female is 0.4-1.0 mg/day, the dose being titrated to achieve a normal IGF-1 for age. [11]
HIV/AIDS
GH is approved for treatment of AIDS wasting in adults. However, it is still not approved for use in children with HIV. A state of GH resistance has been suggested with low IGFI and high IGFBP3 levels in children with HIV disease and growth failure, which is seen to normalize during treatment with protease inhibitors containing regimen. [42] Studies are underway to determine the use of GH in children with HIV. [11], [42]
FOLLOW-UP ON GH THERAPY
Children receiving GH should be followed every 3-6 months by their pediatricians/pediatric endocrinologists to monitor their linear growth and growth velocity. Increase in linear growth velocity is evident within the first three to six months as compared to the pretreatment growth velocity. Improvement in height standard deviation score is evident after one year of GH therapy and IGF-1 levels age seem to normalize. IGF-1 and IGFBP3 levels should be monitored and may be helpful for assurance of compliance and regulating GH dose. Free T4 and TSH should be evaluated for early detection of hypothyroidism. Fasting blood sugar and hemoglobin A1C may be measured in patients at risk of developing impaired carbohydrate tolerance. [11] Other parameters such as complete blood counts, bone markers, insulin levels, lipid profile may need monitoring in specific clinical scenarios. Serial bone ages are helpful in assessing advancement of skeletal age for calculating predicted adult height. Maximum growth promoting effect is seen in the first year of GH treatment, after which it decreases to the normal growth velocity for age. Inadequate growth may be due to compliance issues, inappropriate GH dose, inaccurate GH administration concomitant hypothyroidism or glucocorticoid therapy or an underlying yet undiagnosed disorder. Treatment with GH is usually continued until the completion of linear growth or when growth velocity is less than 2.5 cm per year. The decision to continue GH therapy after completion of linear growth requires reassessment.
Side effects of gh therapy
Recombinant GH is a relatively safe medication. Nevertheless all patients receiving GH are closely followed in a database to monitor for any possible side effects table8.
Investigational uses of gh
There is a suggestion of the potential role of GH to promote growth in a number of other clinical conditions aside from the above US-FDA approved indications. These include chondrodysplasias, Down's syndrome, Russel Silver syndrome, familial dysautonomia and cystic fibrosis as well as chronic gastrointestinal conditions such as Crohn's disease and celiac disease.[43],[44],[45],[46] The role of GH in improving glucocorticoid induced growth suppression is being investigated. GH is also used to promote growth in patients with precocious puberty on GnRh analogues, showing growth suppression and poor growth velocity. Patients with neurofibromatosis, Noonan Syndrome, familial hypophosphatemic rickets and thalassemias have all been shown to have a positive short term growth response to GH therapy as well.
Novel modalities for gh treatment
There has been a great advancement in the availability of different types of GH preparations. New pen devices and delivery systems facilitate administration and improve compliance. Other novel approaches in the form of orally inhaled or intranasal preparations are also being investigated. Several other alternative treatment modalities are under investigation. Although, GH releasing hormone, IGF-1 and oral secretagogues are available but their definitive role in specific clinical scenarios needs to be defined.
GH INSENSITIVITY SYNDROME (GHIS)
GHIS encompasses a group of heritable disorders in which patients have a phenotype of GH deficiency but have normal or high levels of GH. GHIS may result primarily from GH receptor abnormalities, post receptor GH signal transduction problems, defective IGF-1 biosynthesis or secondarily from antibodies to GH or GH receptor, malnutrition, or liver disease.[7] Laron Syndrome is the classic prototype of GH insensitivity. Since these patients exhibit extreme resistance to GH, IGF-1 seems to offer potential for therapy but further studies are needed before final recommendations can be made.
Conclusion
Recombinant DNA technology has made it possible to produce GH in sufficient quantities to treat children with various growth disorders. There are many clinical scenarios with short stature beside GH deficiency in which the benefits of GH can be exploited. Although generally considered to be a safe modality of treatment, great caution must be exercised in ensuring the judicious use of GH in these situations. Any benefits of GH must be weighed against the risk of adverse events, the discomfort of daily injections, as well as the cost involved. Maintaining data base registry for all patients treated with GH is very helpful in the long term follow-up.
Acknowledgement
I thank Dr. Martin Draznin and Dr. Dilip Patel for their critical review of the manuscript and to Mrs. Amy Esman for her expert administrative assistance.
References
1. Lifshitz F, Botero D. Worrisome Growth in Pediatric. In Lifshitz F, ed. Pediatric Endocrinology; 4th edn. New York, U.S.A. Marcel Dekker 2003; 1-46.
2. Tanner JM, Whitehouse RH. Clinical longitudinal standard for height, weight, height velocity, weight velocity and stages of puberty. Arch Dis Child 1976; 51: 170-171.
3. Tanner JM, Whitehouse RH, Marshall WA, Carter BS. Prediction of adult height from height, bone age, and occurrence of menarche, at ages 4 to 16, with allowance for midparent height. Arch Dis Child 1975; 50: 14-26.
4. Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standard. J Pediatr 1952; 40: 423-441.
5. Tanner JM, Whitehouse RH, Cameron N et al. Assessment of skeletal maturity and prediction of adult height (TW2 Method). London: Academic Press, 1983.
6. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd edn. Stanford, CA, Stanford University Press, U.S.A. 1959.
7. Rosenfeld RG, Cohen P. Disorders of GH/insulin-like growth factor secretion and action. In Sperling MA, ed. Pediatric Endocrinology; 2nd edn. Saunders, U.S.A. 2002.
8. Rosenfeld RG, Albertsson-Wikland K, Cassorla F et al. Diagnostic controversy: The diagnosis of childhood GH deficiency revisited. J Clin Endocrinol Metab 1995; 80(5): 1532-1540.
9. GH Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 2000; 85(11): 3990-3993.
10. Maghnie M, Strigazzi C, Tinelli C et al. Growth hormone (GH) deficiency (GHD) of childhood onset: reassessment of GH status and evaluation of the predictive criteria for permanent GHD in young adults. J Clin Endocrinol Metab 1999; 84(4): 1324-1328.
11. Wilson TA, Rose SR, Cohen P et al. Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr 2003; 143(4): 415-421.
12. MacGillivray MH. The basics for the diagnosis and management of short stature: a pediatric endocrinologist's approach. Pediatr Annals 2000; 29(9): 570-575.
13. Cohen P, Bright GM, Rogol AD et al. Effects of dose and gender on the growth and growth factor response to GH in GH-deficient children: implications for efficacy and safety. J Clin Endocrinol Metab 2002; 87(1): 90-98.
14. Reiter EO, Attie KM, Moshang T Jr et al. A multicenter study of the efficacy and safety of sustained release GH in the treatment of nave pediatric patients with GH deficiency. J Clin Endocrinol Metab 2001; 86(10): 4700-4706.
15. Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P. International Small for Gestational Age Advisory Board. International small for gestational age advisory board consensus development conference statement: Management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics 2003; 111(6): 1253-1261.
16. Abuzzahab MJ, Schneider A, Goddard A et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003; 349(23): 2211-2212.
17. de Zegher F, Du Caju MV, Heinrichs C et al. Early, discontinuous, high dose growth hormone treatment to normalize height and weight of short children born small for gestational age: results over 6 years. J Clin Endocrinol Metab 1999; 845): 1558-1561.
18. Boguszewski M, Albertsson-Wikland K, Aronsson S et al. Growth hormone treatment of short children born small-for-gestational-age: The Nordic Multicentre Trial. Acta Paediatr 1998; 87(3): 257-263.
19. Ranke MB, Lindberg A, Cowell CT et al. Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab 2003; 88(1): 125-131.
20. Kamp GA, Mul D, Waelkens JJ et al. A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation. J Clin Endocrinol Metab 2001; 86(7): 2969-2975.
21. Carel JC, Chatelain P, Rochiccioli P, Chaussain JL. Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study. Endocrinol Metab 2003; 88(4): 1587-1593.
22. Arends NJ, Boonstra VH, Mulder PG et al. GH treatment and its effect on bone mineral density, bone maturation and growth in short children born small for gestational age: 3-year results of a randomized, controlled GH trial. Clin Endocrinol 2003; 59(6): 779-787.
23. Cuttler l, Silver JB. Growth hormone treatment for idiopathic short stature implications for practice and policy. Arch Pediatr Adolesc Med 2004; 158(2): 108-110.
24. Endocrinologic and Metabolic Drugs Advisory Committee. Humatrope for Non-Growth Hormone Deficient Short Stature. Indianapolis, Indiana: Lilly Research Laboratories, U.S.A.; 2003. Briefing Document.
25. Finkelstein B, Imperiale T, Speroff T, Marrero U, Radcliffe DJ, Cuttler L. Effects of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med 2002; 156(2): 230-240.
26. Rosenfeld R, Hwa V. Toward a molecular basis for idiopathic short stature. J Clin Endocrinol Metab 89(3): 1066-1067.
27. Wit JM, Rekers-Mombarg LT. Dutch Growth Hormone Advisory Group. Final height gain by GH therapy in children with idiopathic short stature is dose dependent. J Clin Endocrinol Metab 87(2): 604-611.
28. Kamp GA, Mul D, Waelkens JJ et al. A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation. Endocrinol Metab 2001; 86(7): 2969-2975.
29. Saenger P, Wikland KA, Conway GS et al. Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metab 2001; 86(7): 3061-3069.
30. Frias JL, Davenport ML. Committee on Genetics and Section on Endocrinology. Health supervision for children with Turner syndrome. Pediatrics 2003; 111(3): 692-702.
31. Chernausek SD, Attie KM, Cara JF, Rosenfeld RG, Frane J. Growth hormone therapy of Turner syndrome: the impact on final height Genetech, Inc., Collaborative Study Group. J Clin Endocrinol Metab 2000; 85(7): 2439-2445.
32. Lee PDK, Allen DB, Angulo MA et al. Consensus statement - Prader-Willi Syndrome: growth hormone (GH)/ insulin-like growth factor axis deficiency and GH treatment. The Endocrinologist 10(4): 71-73.
33. Angulo M, Castro-Magana M, Mazur B, Canas JA, Vitollo PM, Sarrantonio M. Growth hormone secretion and effects of growth hormone therapy on growth velocity and weight gain in children with Prader-Willi Syndrome. J Pediatr Endocrinol Metab 1996; 9(3): 393-400.
34. Davies PS, Evans S, Broomhead S et al. Effect of growth hormone on height, weight and body composition in Prader-Willi Syndrome. Arch Dis Child 1998; 78(5): 474-476.
35. Carrel AL, Myers SE, Whitman BY, Allen DB. Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study. J Clin Endocrinol Metab 2002; 87(4): 1581-1585.
36. Warady BA, Jabs K. New hormones in the therapeutic arsenal of chronic renal failure: growth failure and erythropoietin. Pediatr Clin North Am 1995; 42(6): 1551-1577.
37. Rosenfeld R, Allen DB, MacGillivray MH, et al. Growth hormone use in pediatric growth hormone deficiency and other pediatric growth disorders. Am J Managed Care 2000; 6(15): 805-816.
38. Fine RN. Growth hormone in children with chronic renal insufficiency and end-stage renal disease. The Endocrinologist 1998; 8: 160-169.
39. Haffner D, Schaefer F, Nissel R, Wuhl E, Tonshoff B, Mehls O. Effect of growth hormone treatment on the adult height of children with chronic renal failure. German Study Group for Growth Hormone Treatment in Chronic Renal Failure. N Engl J Med 2000; 343(13): 923-930.
40. Roelfsema V, Clark RG. The growth hormone and insulin-like growth factor axis: its manipulation for the benefit of growth disorders in renal failure. J Am Soc Nephrol 2001; 12(6): 1297-1306.
41. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endocrinol Metab 1998; 83 (2): 379-381.
42. Van Rossum AM, Gaakeer MI, Verweel S et al. Endocrinologic and immunologic factors associated with recovery of growth in children with human immunodeficiency virus type I infection treated with protease inhibitors. Pediatr Infect Dis J 2003; 22(1): 70-76.
43. Kamboj MK, Axelrod FB, David R et al. Growth hormone treatment in children with familial dysautonomia. J Pediatr 2004; 144(1): 63-67.
44. Shohat M, Tick D, Barakat S, Bu X, Melmed S, Rimoin DL. Short term recombinant growth hormone treatment increases growth rate in achondroplasia. J Clin Endocrinol Metab 1996; 81(11): 4033-4037.
45. Anneren G, Tuvemo T, Carlsson-Skwirut C et al. Growth treatment in young children with Down's syndrome: effects on growth and psychomotor development. Arch Dis Child 1999; 80(4): 334-338.
46. Hardin DS, Stratton R, Kramer JC, de la Rocha RS, Govaerts K, Wilson DP. Growth hormone improves weight velocity and growth velocity in prepubertal children with cystic fibrosis. Horm Metab Res 1998; 30(10): 636-641.(Kamboj Manmohan)