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Pituitary Gland: Growth and Growth Failure
Pituitary Gland: Growth and Growth Failure G Oppizzi, Ospedale Niguarda Ca’ Granda, Milan, Italy M Rondinelli, IRCCS MultiMedica, Milan, Italy ã 2014 Elsevier Inc. All rights reserved.
Auxology Apparatus Parental Height Standard Deviation Score Growth Velocity Diagnostic Approach to Short Children Bone Age Growth Charts Clinical Evaluation GH Deficiency Clinical Aspects Causes of GH Deficiency Hypothalamic–pituitary dysfunctions Congenital malformations of the hypothalamic–pituitary region Trauma of the brain and/or the hypothalamus Inflammation Tumors Psychosocial dwarfism GH neurosecretory dysfunction GH Resistance or Insensitivity Syndromes A Short Review of GH and IGF-I Physiology Assessment of GH Secretion Imaging Treatment Safety
Glossary Dwarfism A severe height defect possibly due to one of several medical or endocrine diseases. Growth charts Standard reference tables in which height and age or height velocity and age are plotted; used to compare to normal values the data of a given child.
1 2 3 3 3 3 3 4 4 4 4 4 4 5 5 5 5 5 5 6 6 7 8 8 8
Recombinant hGH Growth hormone obtained by bacteria into which the gene coding for human growth hormone has been inserted.
Growth is a very sensitive accomplishment that can be easily disrupted in pediatric patients due to many medical conditions, from psychological disturbances to the more severe kidney, liver, or heart diseases; whenever “something goes wrong,” this is reflected by the slowing or even the cessation of the process of growth. Endocrine derangements are frequently the final common mechanism that mediates the observed growth failure; however, there are conditions in which the lack of growth hormone secretion or activity is the primary cause of dwarfism. In the third millennium, recombinant growth hormone is available in virtually unlimited amounts, but its use must be directed only where it can be of help. A careful diagnostic workout, with the aim of addressing the treatments in the appropriate direction, underlying remediable causes, is mandatory. This article summarizes the clinical approach to patients with pathologically short statures, with particular focus on the auxological and endocrinological aspects that reflect the most rationale assessment to be recommended.
Auxology The term “auxology” derives from the Greek verb auxano (meaning “to grow”). It refers to the body of science of assessing growth, including aspects such as weight, head circumference, height, bone maturation, and changes in body aspect secondary to sexual
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.04100-3
1
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Pituitary Gland: Growth and Growth Failure
maturation. The term Short Stature defines children whose stature is lower than two standard deviations (SD) from the mean height for age, sex, and racial origin. Some authors prefer to use percentiles, instead of SD; the 3rd centile is considered the lower limit of the normal range. There is, obviously, a mathematical relationship between stature measurements reported in centiles and those in SD of the mean, the 3rd centile being approximately 2 SD (see Figure 1). The measurement of a child’s height is not as trivial as it may appear; some important rules concerning equipment, dedicated technique, and reporting should be followed.
Apparatus In children younger than 2 years supine length is considered: a rigid board against which the head lies with a movable footboard on which the feet are placed perpendicular to the horizontal plane. For children older than 2 years, standing height should be measured, ideally using a piece of equipment (such as the Harpenden’s stadiometer) fixed to the wall, thus allowing reliable and repeatable measurements. The positioning technique is of utmost relevance. The same basic technique should be followed regardless of the apparatus used to avoid faulty or inaccurate data: the child’s feet (without shoes and socks) should be placed together with the heels touching the backboard (or wall), and the legs should be straight with arms loose at the sides. The head should be in the Frankfurt plane (Figure 2): lateral margin of the eyelid horizontally aligned with the meatus acusticus. The child must take a deep breath while the observer exerts a firm but gentle upward pressure on the mastoids to extend the cervical spine, then the child must breathe out and relax while the pressure is maintained and the measurement is taken, reading the lower complete millimeter (no roundings). All measurements at subsequent visits of a given child must be taken by the same observer in order to minimize reading error, but even in the best trained hands the error between subsequent measurements is rarely less than 0.4–0.5 cm. Moreover, one should take into account that due to softness of
Figure 1 Relationship between heights expressed as percentiles and standard deviations of the mean.
Figure 2 Correct handling of patient’s head to obtain precise and repeatable measurements.
Pituitary Gland: Growth and Growth Failure
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intervertebral disks and heel pads the real difference of height in the same child varies from morning to evening and also according to the degree of physical activity and hours spent in standing position; therefore, repeated visits should be scheduled approximately at the same hour (morning is recommended).
Parental Height Parental height is also essential to assess a child’s stature; real measures are much better than self-reported heights. Target height can then be estimated by simply averaging the parents’ height (adding 13 cm to the mother’s stature for males or by subtracting these 13 cm from the father’s height for females). The resulting “midparental height” represents the target height for the a given child within a 10 cm range; there is a 95% probability the child will reach that height.
Standard Deviation Score When reporting a child’s stature simply as “below the 3rd centile” one does not provide any information on how far his or her stature deviates from normal; furthermore, in clinical studies one could not group patients as simply “below the xth centile” or directly compare different statures of patients of different heights. Therefore the best way of representing stature data is the worldwide adopted standard deviation score (SDS): SDS ¼ x Y^ =SD where x is the child’s height (in cm), Yˆ is the mean stature for age, and SD is the standard deviation of mean stature for age. With this simple method one can very easily appreciate changes in growth (either spontaneous or due to treatment). For example, when a child’s stature changes from a score of 3.4 to a score of 2.9 in a 6-month period, this means that the child is gaining centimeters toward the normal range. With this method, patients with different ages and degrees of short stature can be grouped and their SDS treated statistically.
Growth Velocity The precise measurement of height is the first step of the assessment of growth pattern, which is an important parameter. In fact, the current stature could simply reflect a slowed growth during intrauterine life or early years that has not yet been recovered. A better source of information on growth is provided by assessing growth rate: changes in height plotted versus time. Considering the intrinsic error in measurements and the expected changes in growth for a given age, the minimum interval between two subsequent measures should be 3 months; however, the minimal length of time to extrapolate yearly growth velocity should be at least 6 months (the ideal would be an entire year of observation with four measurements at 3-month intervals). Height velocity, expressed in centimeter per year, can be estimated by plotting longitudinal measurements of stature on the appropriate growth chart. It varies with age and sex: in the first 6 months of life a boy can grow 15 cm (i.e., 30 cm year1); this gradually slows down to about 9 cm year1 at 2 years, and to 5 cm year1 of mean velocity at 10 years. Within the next 2–3 years the pubertal spurt re-accelerates to a maximal growth velocity of 12–14 cm year1, this however almost closes the epiphyseal cartilages, leaving only a few centimeters to be gained until growth is completed. According to the mathematical model of growth elaborated by J. Karlberg, one can distinguish three different phases of growth: infancy, childhood, and puberty. They are integrated to accomplish a nonlinear pattern; they also reflect different underlying biological mechanisms: during infancy, as well as during fetal life, nutritional and metabolic factors play the major role, while growth hormone (GH) comes into play mostly during the second phase; both GH and sex hormones interact during pubertal growth. Estrogens are particularly involved: even in males estradiol is the most active steroid acting on hypothalamic centers responsible for growth hormone secretory peaks that are particularly elevated in pubertal subjects.
Diagnostic Approach to Short Children Once stature has been accurately determined and found to be pathological, and growth rate has also been recorded as slower than expected for age and sex, the diagnostic approach implies further steps. Physical examination could have already shown possible dysmorphic features such as those of Down’s and Turner’s syndromes, Noonan syndrome, etc.; hypothyroidism and rickets also exhibit typical body disproportions. Maternal medical history is very important as far as ascertaining exposure to alcohol, smoking, or other toxins during pregnancy.
Bone Age Bone age reflects the biological maturation of the child. Different techniques exist to assess skeletal maturation; the most widely used is an X-ray of the left hand and wrist. The Greulich and Pyle method consists of matching the overall appearance of the bones to the standards shown on the atlas and consequently to assign the closest age. The Tanner–Whitehouse technique (known as TW2)
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Pituitary Gland: Growth and Growth Failure
is relatively more complex: it assigns a score to each of 20 bones of the wrist so that all contribute to the final calculation of bone age. Bone age is delayed in most growth disorders and in itself it has no diagnostic value, although it can be used together with chronological age and height to predict final height more accurately than by simple midparental stature. Equations that incorporate height velocity and the occurrence of menarche (for pubertal girls) can also be used for this purpose. Children with delayed bone maturation and short stature have a larger chance of recovering from growth defects (either spontaneously or following therapy) than those in whom bone age and chronological age are similar.
Growth Charts The standard reference charts on which a child’s height should be plotted vary from country to country; in U.K. and other European countries, the Tanner and Whitehouse charts are commonly used, while in the United States the CDC growth charts and (for children under 2 years of age) the WHO tables are more common. Country specific tables for South American, Asian and African countries are now also available. When considering children of different ethnic or racial origin, standards charts for these groups should be consulted whenever possible. Distance charts (i.e., stature plotted against age) can be either cross-sectional or longitudinal: the former are built from data collected in large samples of children of an entire age range at the same time, whereas the latter are based on measurements collected from smaller samples of the same children that have been followed for several years until complete bone maturation. If the purpose is simply to screen a population or to search for differences between two different populations the cross-sectional charts are suitable. On the contrary, if one wants to follow the growth pattern of a single patient, the longitudinal type charts are more appropriate. It must be taken into account that growth velocity might be in the normal range in two of the most common causes of short stature: genetic short stature (also called familial short stature) and in constitutional delay of growth. Therefore, not only could stature per se be insufficient for a diagnosis, but in some cases even growth rate may not be enough for the complex assessment of growth failure.
Clinical Evaluation Children growing at a rate lower than the 5th centile for their age should undergo a careful overall medical investigation taking into consideration all possible causes starting from malnutrition (in turn secondary to malabsorption, celiac disease, etc.), lung and heart diseases, renal failure, etc. (Table 1) reports the most frequently observed causes of growth failure; it should be stressed that the endocrine diseases represent only a small percentage of the affected patients. The endocrine assessment should consider, for instance, hypothyroidism, Cushing’s disease, and GH deficiency in all its variants. Hypothyroidism can easily be ruled out by measuring FT4 and TSH plasma levels, while Cushing’s disease can be suggested on the basis of the three most common symptoms reported in affected children: typical body features, weight gain, and short stature; the diagnosis can be confirmed by hormonal tests and imaging procedures.
GH Deficiency Clinical Aspects GH deficiency (see Table 2 for classification) can be attributed to either congenital or acquired forms. All the forms have in common the most relevant clinical sign: growth defect. In both in the United States and Europe the prevalence appears to be 1:4000 children of school age. A severe form of congenital GH deficiency can be suspected at birth by the association of small birth size and micropenis; in patients with multiple pituitary deficiencies (in particular the association of GH and ACTH deficiency), postnatal spontaneous hypoglycemia might be a relevant symptom. In congenital forms the growth rate remains low and, within the first year, the patient’s length can already be 3–4 standard deviations below the expected mean values. In the acquired forms (which represent about 25% of all the patients with GH deficiency), both stature and growth rate can be normal until the appearance of the underlying disease, then they fall to lower percentile lines and other clinical features such as obesity, delayed puberty, and visual field defects may appear. In the complete (congenital) form, the triad of short stature, bone age retardation, and absent growth hormone response to provocative test is of diagnostic relevance. Low levels of insulin-like growth factor-1 (IGF-I), the main peripheral effector of growth promoting action of GH, frequently accompany this triad.
Causes of GH Deficiency Hypothalamic–pituitary dysfunctions Because many hypothalamic dysfunctions disturb pituitary function, it is frequently impossible to distinguish between the two locations of the defect. Several genetic causes such as errors of Pit1 gene and Prop-1 mutations (the transcription factors responsible for the control of the genes of GH and other pituitary hormones) have been reported (see Table 2). GHRH receptor gene defects located on chromosome 7 may induce GH unresponsiveness, and, finally, mutations of the GH-1 gene (the one encoding for growth hormone) have been described.
Pituitary Gland: Growth and Growth Failure
Table 1
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General causes of short stature
Primary growth defects (intrinsic growth plate defects) • Chondrodysplasias • Chromosomal short stature Turner syndrome Down syndrome 18 q deletions • Genetic short stature Familial short stature • Intrauterine growth retardation/small for gestational age (SGA) Intrinsic fetal abnormalities Maternal abnormalities Placental disorders Secondary growth defects (low growth velocity) • Severe malnutrition • Renal diseases • Chronic liver diseases • Hematologic disorders • Diabetes mellitus • Chronic pulmonary diseases • Cardiac diseases • Gastrointestinal diseases (inflammatory and celiac disease) • Malignancies and/or chemotherapy and/or radiotherapy • Corticosteroid treatment • Immunological diseases (AIDS) • Vitamin D deficiency or resistance • Endocrine diseases (GH deficiency and related disorders, Cushing’s syndrome, hypothyroidism) Delayed growth • Constitutional delay of growth and puberty • Malnutrition of moderate degree • Mild underlying medical disease Final short stature due to early accelerated growth • Precocious puberty • Virilizing forms of congenital adrenal hyperplasia
Congenital malformations of the hypothalamic–pituitary region The septo-optical displasia is one example in which anatomical abnormalities of this region are accompanied by GH, ACTH, and other pituitary deficiencies. This is due to mutations in the HESX1 gene.
Trauma of the brain and/or the hypothalamus Trauma of the brain and/or the hypothalamus may cause multiple pituitary insufficiencies; difficult delivery or hypoxemia in the perinatal period are also part of this condition.
Inflammation Fungal, viral, and bacterial infections as well as granulomatous diseases involving this area may lead to pituitary insufficiency.
Tumors In addition to tumors of this brain area (meningiomas, gliomas, ependymomas, etc.), craniopharyngiomas are rather frequent in children. Radiation therapy, used on some of these tumors or in hematologic disorders, may determine GH deficiency.
Psychosocial dwarfism Psychosocial dwarfism is the consequence of a severe form of emotional deprivation frequently ascribed to a familiar or to social inadequate conditions in which GH secretion is low and behavioral abnormalities of eating habits are also common. The reversibility to a condition of normal GH secretion in these children may confirm the diagnosis.
GH neurosecretory dysfunction In affected patients, GH responses to provocative tests are normal but IGF-I is low; the diagnostic clue is the greatly decreased spontaneous peaks of GH secretion observed during a 24 h continuous sampling.
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Pituitary Gland: Growth and Growth Failure
Table 2
GH deficiency and related disorders
Congenital hypothalamic–pituitary abnormalities • Genetic defects GH-IGF axis Isolated GH deficiency: type I A, type I B, type II, type III Transcription factors abnormalities determining multiple hormone deficiencies : POU1F1/Pit-1 (pituitary hypoplasia), PROP1 (combined pituitary deficiency); HESX1 (associated with septo-optic dysplasia), PITX2 (associated with Rieger syndrome), and other (Lhx3, Lhx4, SIX6, OTX2, SOX2, SOX3, GLI2) Molecular defects of GH-RH Molecular defects of the GH-RH receptor Bio-inactive growth hormone • Malformations: holoprosencephaly; septo-optic dysplasia; midbrain defects including corpus callosum and hippocampus Acquired hypothalamic–pituitary abnormalities • Trauma (perinatal or post-natal) • CNS infections (viral, bacterial or fungal) • Inflammatory disorders: histiocytosis X, sarcoidosis, tubercolosis, hypophysitis • Tumors involving hypothalamus or pituitary and their therapy (surgery and/or radiation): Pituitary adenomas Craniopharyngiomas Meningiomas Gliomas/astrocytomas Germinomas Metastases (or local extension of craniopharyngeal carcinoma) Growth hormone insensitivity • Abnormalities of GH receptor and postreceptor defects • Primary defects of IGF-1 biosynthesis • Genetic insensitivity to IGF-1 Other causes • Idiopatic GHD • Psychosocial dwarfism • GH neurosecretory dysfunction • Prader–Willi syndrome
GH Resistance or Insensitivity Syndromes In GH resistance syndromes, the common feature is represented by lack of GH action in spite of elevated plasma levels of the hormone; IGF-I is frequently low in these forms and the growth defect is particularly severe. Zvi Laron first described such a syndrome in 1965, years before the somatomedin hypothesis was presented. Laron syndrome (MIM# 262500) It is caused by homozygous or compound heterozygous mutations in the extracellular domain of the GH receptor gene. Several hundred patients have been worldwide reported thus far, mainly in the Mediterranean area, Middle East and Ecuador. In GH resistance (or insensitivity), IGF-I is also unresponsive to induction test with hGH; there are studies under way showing positive growth acceleration in these patients during treatment with human recombinant IGF-I.
A Short Review of GH and IGF-I Physiology GH, a polypeptide hormone of 191 amino acids with molecular weight of about 22 000, is produced by specific cells of the anterior pituitary and is released in bursts lasting only minutes, followed by long periods during which plasma levels are almost undetectable. The most frequently observed peaks are those following meals and those in the first part of slow-wave sleep. The physiological basis for this pulsatile secretory pattern is found in the hypothalamic nuclei (in particular the ventromedial nucleus) where the two main hypothalamic factors controlling GH are produced: growth hormone-releasing hormone (GHRH, positive regulator) is mainly responsible for the secretory peaks, but its activity is evident only when the other factor, somatotrophin-release inhibiting factor (SRIF, negative regulator), is inhibited. These two hormones, together with other hypothalamic factors such as GH-releasing peptides and neurosecreted amines interplay with each other: GH released, in every minute, is then the algebraical result of these opposite forces (Figure 3). Feedback mechanisms also play a role both at hypothalamic and at pituitary level controlling plasma GH levels and IGF-I values. Moreover, ultrashort feedback mechanisms are also exerted by the levels of the two neuroregulatory hormones GHRH and SRIF, which influence each other, acting back on hypothalamic neurosecretory amines. GH in itself has little effect on bone and cartilage development, but its growth-promoting activity is mediated by substances that are induced by the hormone: GH-free serum has mitogenic properties in cell cultures and insulin-like activity in adipose tissue and promotes the incorporation of amino acids and sulfate into the cartilage. In 1972, W. H. Daughaday proposed the somatomedin hypothesis to explain these effects. It is now recognized that the most important of these substances is IGF-I, produced in the liver and kidney as well as in the growing cartilages. What is actually measured in the plasma is mostly the IGF-I coming from the liver
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Figure 3 Regulation of growth hormone secretion and interplay among the main influences.
and kidney, although IGF-I mediating the growth effect of GH is mainly the amount locally generated by chondrocytes under stimulation by GH. However, plasma IGF-I levels provide a reliable indicator of the effective amount of GH produced, since it is found to be very low in almost all the conditions of endocrine-mediated growth defect. When measured in a given patient after a short cycle (2 days) of exogenous hGH administration (induction test) it also provides relevant information about sensitivity to GH. In conclusion, IGF-I reflects the integrated concentrations of the previously secreted GH (i.e., in the preceding 24–36 h); at variance with the pulsatility of GH, their levels are quite stable during the day. Although IGF-I levels may be low even in conditions different from GH deficiency (hypothyroidism, renal diseases, malnutrition, etc.), they reflect GH spontaneous secretion much better than the provocative tests. At present, however, these tests remain the gold standard for the diagnosis of GH deficiency.
Assessment of GH Secretion From the previously discussed considerations, and due to the pulsatile nature of GH secretion, it emerges that baseline plasma GH levels are very frequently found undetectable if single random samples are taken, even in normal subjects. Therefore, to confirm a diagnosis of GH deficiency, blood samples must be obtained in standard conditions and appropriate stimulation tests should be performed. Some of the following standardized tests are considered useful for initial screening purpose: (1) a post-prandial (3–4 h after a protein-rich meal) or (2) a post-exercise sample (30 min after a strenuous exercise) that shows GH levels above the cutoff value of 10 mg l1 could rule out GH deficiency and avoid further testing. These procedures, however, are not commonly used in clinical practice, and consequently the most widely used tests have been: (1) arginine infusion (0.5 g kg1 by slow i.v. infusion within 30 min) and (2) insulin-induced hypoglycemia (0.1 U kg1 as i.v. bolus). These tests are not devoid of side effects and should be performed by trained personnel in appropriately equipped centers. The main defect of these two tests is their high false positive rate: from 10 to 20% of normal children fail to respond to these tests and would then be wrongly diagnosed as GH deficient. Moreover, approximately 30% of normal children will show discordant responses to the two tests. The basis for interpreting this discrepancy is to be found in the interplay between the two neurohormones GHRH and SRIF: a GH response to the stimulations mentioned above would be possible only when the stimulus reaches the hypothalamic region during a decreasing phase of SRIF (and the reciprocal GHRH increase). One of the main problems common to the various provocative tests resides in the interpretation of the results: different countries have adopted different cutoff levels to separate normal from pathological responses. Cutoff values ranging from 5 to 10 mg l1 of GH at the peak are widely accepted. It must also be considered that the commercial kits used for the assay of GH in plasma with monoclonal antibodies have reached a level of sensitivity much higher than that obtained at the time when the set
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Pituitary Gland: Growth and Growth Failure
points of these test were established. Some authors have proposed a provocative test based on the administration of arginine infusion (0.5 g kg1 i.v. in 30 min) supposed to act by shutting off the endogenous SRIF tone, together with an intravenous injection of synthetic GHRH (1 mg kg1). This double test is a very potent GH secretory stimulus, with high sensitivity and specificity; the cutoff limit for normal subjects has been set to 19 mg l1. The main advantage of this test is its greater capability of discriminating normal from pathological responses (GH deficiency) due to the minimal number of false positives, moreover it avoids the risks of hypoglycemia. In conclusion, it is recommended that each Pediatric Endocrinology Center should adopt two or three provocative tests, and use always the same tests, after having established it own limits of normal responses. Baseline IGF-I levels are also of great help: GH-deficient patients generally have very low levels (i.e., IGF-I levels 2 SDS below the mean for age and sex). While a normal or elevated IGF-I level strongly points against the diagnosis of GH deficiency, the contrary is not true: in the presence of very low IGF-I levels other clinical conditions such as undernutrition etc, should be excluded before considering GH deficit. However, the provocative tests for GH secretion retain some limits: they are not physiological, they are poorly reproducible, and the normal range of responses is arbitrary. These reasons emphasize the recommendation that the poorly growing child should undergo a complete examination, including psychological, medical, and hormonal aspects. GH deficiency remains a clinical diagnosis, corroborated by auxological data concerning the growth pattern, by medical history, and by biochemical tests; it is not the simple observation of hormonal levels below a set value.
Imaging Once this clinical diagnosis is obtained a high quality magnetic resonance imaging of the pituitary and hypothalamic area (with contrast medium) is mandatory. T1 weighted images can show morphological abnormalities: pituitary stalk agenesis or interruption, pituitary hypoplasia, or other lesions. In acquired forms it will show the cystic or solid lesion damaging pituitary/ hypothalamic function.
Treatment The starting dose of hGH to be used in children with GH deficiency is in the range from 30 to 70 mg kg1 body weight per day. It must be administered in the evening at bedtime, in order to mimic the nocturnal spontaneous GH secretory peaks. Daily subcutaneous injections are recommended, although different devices for administration (such as needle-free percutaneous jet injector system) and long acting intramuscular preparations requiring only fortnightly injections have been used. Pen devices (either with almost painless needles or the new needle-free devices) have almost completely replaced the old use of syringes; they are accurate and easily used by the children themselves. The treatment efficacy is monitored by regular assessment of growth rate at 3–6 month intervals. The growth-promoting effects observed with the treatment are mainly a function of the administered doses: increased doses lead to accelerated growth rates. Moreover, the younger the patient age at the beginning of treatment, the better the final results that will be obtained. The administered doses must be regularly re-set according to the effects on weight/height obtained. Until about 1990, GH therapy was generally discontinued after growth rate was observed to be greatly decreased and cartilages closed, but now that metabolic effects of GH are better understood the treatment regimen has gradually changed to “adult” doses (such as 0.04–0.06 mg kg1 week1; given daily or on alternate days). In the “transition” age from adolescence to adulthood the dose is gradually decreased and a wash-out trimester is recommended before re-test for the persistence of GH deficiency. Those patients with genetic or organic GH deficiency have an elevated chance to be reconfirmed deficient and should restart treatment (at the much lower adult range doses). On the contrary patients previously labeled as “isolated or idiopathic” GH deficiency have a high chance to result normal at retesting. Reports confirming preliminary positive effects on bone mineral density, muscle strength, exercise performance, cardiovascular function, and body composition are encouraging to continue replacement therapy in adulthood. It is to be noted that, besides true GH deficiency, hGH treatment in pediatric age is now approved also for other indications: chronic renal failure, Idiopathic short stature, SGA children, and other syndromes such as Turner, Noonan, Prader–Willi and SHOX deficiency.
Safety The preliminary data from an ongoing study on safety of GH therapy (The Safety and Appropriateness of Growth hormone treatments in Europe: SAGhE study) had apparently indicated little increase in Standardized Mortality Rate in patients treated versus controls in the French cohort. On the contrary in The Netherlands, Sweden and Belgium with a more accurate verification of the data, no increased risk was found. We have to wait for the full group of 30 000 children to be evaluated, before a final conclusion will be reached.
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Further Reading Cohen P, Rogol AD, Deal CL, et al. (2008) Consensus statement on the diagnosis and treatment of children with idiopathic short stature: A summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. Journal of Clinical Endocrinology and Metabolism 93: 4210–4217. Cook DW, Divall SA, and Radovick S (2011) Normal and aberrant growth. In: Kronenberg HM, Melmed S, Larsen PR, and Polonsky KS (eds.) Williams Textbook of Endocrinology, 12th edn., pp. 935–1053. Philadelphia: Saunders. GH Research Society (2000) Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: Summary statement of the GH Research Society. Journal of Clinical Endocrinology and Metabolism 85: 3990–3993. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, Frasier SD, Hasegawa Y, Hintz RL, Lafranchi S, Lippe B, Loriaux L, and Melmed S (1995) Diagnostic controversy: The diagnosis of childhood growth hormone deficiency revisited. Journal of Clinical Endocrinology and Metabolism 80: 1532–1540. Sa¨vendahl L, Maes M, Albertsson-Wikland K, Borgstro¨m B, Carel JC, Henrard S, Speybroeck N, Thomas M, Zandwijken G, and Hokken-Koelega A (2012) Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: Preliminary report of 3 countries participating in the EU SAGhE Study. Journal of Clinical Endocrinology and Metabolism 97: E213–E217. Wilson TA, Rose SR, Cohen P, et al. (2003) Update of guidelines for the use of growth hormone in children: The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. Journal of Pediatrics 143: 415–421.
Relevant Websites http://www.cdc.gov/growthcharts/. http://www.who.int/childgrowth/.
Auxology Apparatus Parental Height Standard Deviation Score Growth Velocity Diagnostic Approach to Short Children Bone Age Growth Charts Clinical Evaluation GH Deficiency Clinical Aspects Causes of GH Deficiency Hypothalamic–pituitary dysfunctions Congenital malformations of the hypothalamic–pituitary region Trauma of the brain and/or the hypothalamus Inflammation Tumors Psychosocial dwarfism GH neurosecretory dysfunction GH Resistance or Insensitivity Syndromes A Short Review of GH and IGF-I Physiology Assessment of GH Secretion Imaging Treatment Safety
Glossary Dwarfism A severe height defect possibly due to one of several medical or endocrine diseases. Growth charts Standard reference tables in which height and age or height velocity and age are plotted; used to compare to normal values the data of a given child.
1 2 3 3 3 3 3 4 4 4 4 4 4 5 5 5 5 5 5 6 6 7 8 8 8
Recombinant hGH Growth hormone obtained by bacteria into which the gene coding for human growth hormone has been inserted.
Growth is a very sensitive accomplishment that can be easily disrupted in pediatric patients due to many medical conditions, from psychological disturbances to the more severe kidney, liver, or heart diseases; whenever “something goes wrong,” this is reflected by the slowing or even the cessation of the process of growth. Endocrine derangements are frequently the final common mechanism that mediates the observed growth failure; however, there are conditions in which the lack of growth hormone secretion or activity is the primary cause of dwarfism. In the third millennium, recombinant growth hormone is available in virtually unlimited amounts, but its use must be directed only where it can be of help. A careful diagnostic workout, with the aim of addressing the treatments in the appropriate direction, underlying remediable causes, is mandatory. This article summarizes the clinical approach to patients with pathologically short statures, with particular focus on the auxological and endocrinological aspects that reflect the most rationale assessment to be recommended.
Auxology The term “auxology” derives from the Greek verb auxano (meaning “to grow”). It refers to the body of science of assessing growth, including aspects such as weight, head circumference, height, bone maturation, and changes in body aspect secondary to sexual
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.04100-3
1
2
Pituitary Gland: Growth and Growth Failure
maturation. The term Short Stature defines children whose stature is lower than two standard deviations (SD) from the mean height for age, sex, and racial origin. Some authors prefer to use percentiles, instead of SD; the 3rd centile is considered the lower limit of the normal range. There is, obviously, a mathematical relationship between stature measurements reported in centiles and those in SD of the mean, the 3rd centile being approximately 2 SD (see Figure 1). The measurement of a child’s height is not as trivial as it may appear; some important rules concerning equipment, dedicated technique, and reporting should be followed.
Apparatus In children younger than 2 years supine length is considered: a rigid board against which the head lies with a movable footboard on which the feet are placed perpendicular to the horizontal plane. For children older than 2 years, standing height should be measured, ideally using a piece of equipment (such as the Harpenden’s stadiometer) fixed to the wall, thus allowing reliable and repeatable measurements. The positioning technique is of utmost relevance. The same basic technique should be followed regardless of the apparatus used to avoid faulty or inaccurate data: the child’s feet (without shoes and socks) should be placed together with the heels touching the backboard (or wall), and the legs should be straight with arms loose at the sides. The head should be in the Frankfurt plane (Figure 2): lateral margin of the eyelid horizontally aligned with the meatus acusticus. The child must take a deep breath while the observer exerts a firm but gentle upward pressure on the mastoids to extend the cervical spine, then the child must breathe out and relax while the pressure is maintained and the measurement is taken, reading the lower complete millimeter (no roundings). All measurements at subsequent visits of a given child must be taken by the same observer in order to minimize reading error, but even in the best trained hands the error between subsequent measurements is rarely less than 0.4–0.5 cm. Moreover, one should take into account that due to softness of
Figure 1 Relationship between heights expressed as percentiles and standard deviations of the mean.
Figure 2 Correct handling of patient’s head to obtain precise and repeatable measurements.
Pituitary Gland: Growth and Growth Failure
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intervertebral disks and heel pads the real difference of height in the same child varies from morning to evening and also according to the degree of physical activity and hours spent in standing position; therefore, repeated visits should be scheduled approximately at the same hour (morning is recommended).
Parental Height Parental height is also essential to assess a child’s stature; real measures are much better than self-reported heights. Target height can then be estimated by simply averaging the parents’ height (adding 13 cm to the mother’s stature for males or by subtracting these 13 cm from the father’s height for females). The resulting “midparental height” represents the target height for the a given child within a 10 cm range; there is a 95% probability the child will reach that height.
Standard Deviation Score When reporting a child’s stature simply as “below the 3rd centile” one does not provide any information on how far his or her stature deviates from normal; furthermore, in clinical studies one could not group patients as simply “below the xth centile” or directly compare different statures of patients of different heights. Therefore the best way of representing stature data is the worldwide adopted standard deviation score (SDS): SDS ¼ x Y^ =SD where x is the child’s height (in cm), Yˆ is the mean stature for age, and SD is the standard deviation of mean stature for age. With this simple method one can very easily appreciate changes in growth (either spontaneous or due to treatment). For example, when a child’s stature changes from a score of 3.4 to a score of 2.9 in a 6-month period, this means that the child is gaining centimeters toward the normal range. With this method, patients with different ages and degrees of short stature can be grouped and their SDS treated statistically.
Growth Velocity The precise measurement of height is the first step of the assessment of growth pattern, which is an important parameter. In fact, the current stature could simply reflect a slowed growth during intrauterine life or early years that has not yet been recovered. A better source of information on growth is provided by assessing growth rate: changes in height plotted versus time. Considering the intrinsic error in measurements and the expected changes in growth for a given age, the minimum interval between two subsequent measures should be 3 months; however, the minimal length of time to extrapolate yearly growth velocity should be at least 6 months (the ideal would be an entire year of observation with four measurements at 3-month intervals). Height velocity, expressed in centimeter per year, can be estimated by plotting longitudinal measurements of stature on the appropriate growth chart. It varies with age and sex: in the first 6 months of life a boy can grow 15 cm (i.e., 30 cm year1); this gradually slows down to about 9 cm year1 at 2 years, and to 5 cm year1 of mean velocity at 10 years. Within the next 2–3 years the pubertal spurt re-accelerates to a maximal growth velocity of 12–14 cm year1, this however almost closes the epiphyseal cartilages, leaving only a few centimeters to be gained until growth is completed. According to the mathematical model of growth elaborated by J. Karlberg, one can distinguish three different phases of growth: infancy, childhood, and puberty. They are integrated to accomplish a nonlinear pattern; they also reflect different underlying biological mechanisms: during infancy, as well as during fetal life, nutritional and metabolic factors play the major role, while growth hormone (GH) comes into play mostly during the second phase; both GH and sex hormones interact during pubertal growth. Estrogens are particularly involved: even in males estradiol is the most active steroid acting on hypothalamic centers responsible for growth hormone secretory peaks that are particularly elevated in pubertal subjects.
Diagnostic Approach to Short Children Once stature has been accurately determined and found to be pathological, and growth rate has also been recorded as slower than expected for age and sex, the diagnostic approach implies further steps. Physical examination could have already shown possible dysmorphic features such as those of Down’s and Turner’s syndromes, Noonan syndrome, etc.; hypothyroidism and rickets also exhibit typical body disproportions. Maternal medical history is very important as far as ascertaining exposure to alcohol, smoking, or other toxins during pregnancy.
Bone Age Bone age reflects the biological maturation of the child. Different techniques exist to assess skeletal maturation; the most widely used is an X-ray of the left hand and wrist. The Greulich and Pyle method consists of matching the overall appearance of the bones to the standards shown on the atlas and consequently to assign the closest age. The Tanner–Whitehouse technique (known as TW2)
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Pituitary Gland: Growth and Growth Failure
is relatively more complex: it assigns a score to each of 20 bones of the wrist so that all contribute to the final calculation of bone age. Bone age is delayed in most growth disorders and in itself it has no diagnostic value, although it can be used together with chronological age and height to predict final height more accurately than by simple midparental stature. Equations that incorporate height velocity and the occurrence of menarche (for pubertal girls) can also be used for this purpose. Children with delayed bone maturation and short stature have a larger chance of recovering from growth defects (either spontaneously or following therapy) than those in whom bone age and chronological age are similar.
Growth Charts The standard reference charts on which a child’s height should be plotted vary from country to country; in U.K. and other European countries, the Tanner and Whitehouse charts are commonly used, while in the United States the CDC growth charts and (for children under 2 years of age) the WHO tables are more common. Country specific tables for South American, Asian and African countries are now also available. When considering children of different ethnic or racial origin, standards charts for these groups should be consulted whenever possible. Distance charts (i.e., stature plotted against age) can be either cross-sectional or longitudinal: the former are built from data collected in large samples of children of an entire age range at the same time, whereas the latter are based on measurements collected from smaller samples of the same children that have been followed for several years until complete bone maturation. If the purpose is simply to screen a population or to search for differences between two different populations the cross-sectional charts are suitable. On the contrary, if one wants to follow the growth pattern of a single patient, the longitudinal type charts are more appropriate. It must be taken into account that growth velocity might be in the normal range in two of the most common causes of short stature: genetic short stature (also called familial short stature) and in constitutional delay of growth. Therefore, not only could stature per se be insufficient for a diagnosis, but in some cases even growth rate may not be enough for the complex assessment of growth failure.
Clinical Evaluation Children growing at a rate lower than the 5th centile for their age should undergo a careful overall medical investigation taking into consideration all possible causes starting from malnutrition (in turn secondary to malabsorption, celiac disease, etc.), lung and heart diseases, renal failure, etc. (Table 1) reports the most frequently observed causes of growth failure; it should be stressed that the endocrine diseases represent only a small percentage of the affected patients. The endocrine assessment should consider, for instance, hypothyroidism, Cushing’s disease, and GH deficiency in all its variants. Hypothyroidism can easily be ruled out by measuring FT4 and TSH plasma levels, while Cushing’s disease can be suggested on the basis of the three most common symptoms reported in affected children: typical body features, weight gain, and short stature; the diagnosis can be confirmed by hormonal tests and imaging procedures.
GH Deficiency Clinical Aspects GH deficiency (see Table 2 for classification) can be attributed to either congenital or acquired forms. All the forms have in common the most relevant clinical sign: growth defect. In both in the United States and Europe the prevalence appears to be 1:4000 children of school age. A severe form of congenital GH deficiency can be suspected at birth by the association of small birth size and micropenis; in patients with multiple pituitary deficiencies (in particular the association of GH and ACTH deficiency), postnatal spontaneous hypoglycemia might be a relevant symptom. In congenital forms the growth rate remains low and, within the first year, the patient’s length can already be 3–4 standard deviations below the expected mean values. In the acquired forms (which represent about 25% of all the patients with GH deficiency), both stature and growth rate can be normal until the appearance of the underlying disease, then they fall to lower percentile lines and other clinical features such as obesity, delayed puberty, and visual field defects may appear. In the complete (congenital) form, the triad of short stature, bone age retardation, and absent growth hormone response to provocative test is of diagnostic relevance. Low levels of insulin-like growth factor-1 (IGF-I), the main peripheral effector of growth promoting action of GH, frequently accompany this triad.
Causes of GH Deficiency Hypothalamic–pituitary dysfunctions Because many hypothalamic dysfunctions disturb pituitary function, it is frequently impossible to distinguish between the two locations of the defect. Several genetic causes such as errors of Pit1 gene and Prop-1 mutations (the transcription factors responsible for the control of the genes of GH and other pituitary hormones) have been reported (see Table 2). GHRH receptor gene defects located on chromosome 7 may induce GH unresponsiveness, and, finally, mutations of the GH-1 gene (the one encoding for growth hormone) have been described.
Pituitary Gland: Growth and Growth Failure
Table 1
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General causes of short stature
Primary growth defects (intrinsic growth plate defects) • Chondrodysplasias • Chromosomal short stature Turner syndrome Down syndrome 18 q deletions • Genetic short stature Familial short stature • Intrauterine growth retardation/small for gestational age (SGA) Intrinsic fetal abnormalities Maternal abnormalities Placental disorders Secondary growth defects (low growth velocity) • Severe malnutrition • Renal diseases • Chronic liver diseases • Hematologic disorders • Diabetes mellitus • Chronic pulmonary diseases • Cardiac diseases • Gastrointestinal diseases (inflammatory and celiac disease) • Malignancies and/or chemotherapy and/or radiotherapy • Corticosteroid treatment • Immunological diseases (AIDS) • Vitamin D deficiency or resistance • Endocrine diseases (GH deficiency and related disorders, Cushing’s syndrome, hypothyroidism) Delayed growth • Constitutional delay of growth and puberty • Malnutrition of moderate degree • Mild underlying medical disease Final short stature due to early accelerated growth • Precocious puberty • Virilizing forms of congenital adrenal hyperplasia
Congenital malformations of the hypothalamic–pituitary region The septo-optical displasia is one example in which anatomical abnormalities of this region are accompanied by GH, ACTH, and other pituitary deficiencies. This is due to mutations in the HESX1 gene.
Trauma of the brain and/or the hypothalamus Trauma of the brain and/or the hypothalamus may cause multiple pituitary insufficiencies; difficult delivery or hypoxemia in the perinatal period are also part of this condition.
Inflammation Fungal, viral, and bacterial infections as well as granulomatous diseases involving this area may lead to pituitary insufficiency.
Tumors In addition to tumors of this brain area (meningiomas, gliomas, ependymomas, etc.), craniopharyngiomas are rather frequent in children. Radiation therapy, used on some of these tumors or in hematologic disorders, may determine GH deficiency.
Psychosocial dwarfism Psychosocial dwarfism is the consequence of a severe form of emotional deprivation frequently ascribed to a familiar or to social inadequate conditions in which GH secretion is low and behavioral abnormalities of eating habits are also common. The reversibility to a condition of normal GH secretion in these children may confirm the diagnosis.
GH neurosecretory dysfunction In affected patients, GH responses to provocative tests are normal but IGF-I is low; the diagnostic clue is the greatly decreased spontaneous peaks of GH secretion observed during a 24 h continuous sampling.
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Table 2
GH deficiency and related disorders
Congenital hypothalamic–pituitary abnormalities • Genetic defects GH-IGF axis Isolated GH deficiency: type I A, type I B, type II, type III Transcription factors abnormalities determining multiple hormone deficiencies : POU1F1/Pit-1 (pituitary hypoplasia), PROP1 (combined pituitary deficiency); HESX1 (associated with septo-optic dysplasia), PITX2 (associated with Rieger syndrome), and other (Lhx3, Lhx4, SIX6, OTX2, SOX2, SOX3, GLI2) Molecular defects of GH-RH Molecular defects of the GH-RH receptor Bio-inactive growth hormone • Malformations: holoprosencephaly; septo-optic dysplasia; midbrain defects including corpus callosum and hippocampus Acquired hypothalamic–pituitary abnormalities • Trauma (perinatal or post-natal) • CNS infections (viral, bacterial or fungal) • Inflammatory disorders: histiocytosis X, sarcoidosis, tubercolosis, hypophysitis • Tumors involving hypothalamus or pituitary and their therapy (surgery and/or radiation): Pituitary adenomas Craniopharyngiomas Meningiomas Gliomas/astrocytomas Germinomas Metastases (or local extension of craniopharyngeal carcinoma) Growth hormone insensitivity • Abnormalities of GH receptor and postreceptor defects • Primary defects of IGF-1 biosynthesis • Genetic insensitivity to IGF-1 Other causes • Idiopatic GHD • Psychosocial dwarfism • GH neurosecretory dysfunction • Prader–Willi syndrome
GH Resistance or Insensitivity Syndromes In GH resistance syndromes, the common feature is represented by lack of GH action in spite of elevated plasma levels of the hormone; IGF-I is frequently low in these forms and the growth defect is particularly severe. Zvi Laron first described such a syndrome in 1965, years before the somatomedin hypothesis was presented. Laron syndrome (MIM# 262500) It is caused by homozygous or compound heterozygous mutations in the extracellular domain of the GH receptor gene. Several hundred patients have been worldwide reported thus far, mainly in the Mediterranean area, Middle East and Ecuador. In GH resistance (or insensitivity), IGF-I is also unresponsive to induction test with hGH; there are studies under way showing positive growth acceleration in these patients during treatment with human recombinant IGF-I.
A Short Review of GH and IGF-I Physiology GH, a polypeptide hormone of 191 amino acids with molecular weight of about 22 000, is produced by specific cells of the anterior pituitary and is released in bursts lasting only minutes, followed by long periods during which plasma levels are almost undetectable. The most frequently observed peaks are those following meals and those in the first part of slow-wave sleep. The physiological basis for this pulsatile secretory pattern is found in the hypothalamic nuclei (in particular the ventromedial nucleus) where the two main hypothalamic factors controlling GH are produced: growth hormone-releasing hormone (GHRH, positive regulator) is mainly responsible for the secretory peaks, but its activity is evident only when the other factor, somatotrophin-release inhibiting factor (SRIF, negative regulator), is inhibited. These two hormones, together with other hypothalamic factors such as GH-releasing peptides and neurosecreted amines interplay with each other: GH released, in every minute, is then the algebraical result of these opposite forces (Figure 3). Feedback mechanisms also play a role both at hypothalamic and at pituitary level controlling plasma GH levels and IGF-I values. Moreover, ultrashort feedback mechanisms are also exerted by the levels of the two neuroregulatory hormones GHRH and SRIF, which influence each other, acting back on hypothalamic neurosecretory amines. GH in itself has little effect on bone and cartilage development, but its growth-promoting activity is mediated by substances that are induced by the hormone: GH-free serum has mitogenic properties in cell cultures and insulin-like activity in adipose tissue and promotes the incorporation of amino acids and sulfate into the cartilage. In 1972, W. H. Daughaday proposed the somatomedin hypothesis to explain these effects. It is now recognized that the most important of these substances is IGF-I, produced in the liver and kidney as well as in the growing cartilages. What is actually measured in the plasma is mostly the IGF-I coming from the liver
Pituitary Gland: Growth and Growth Failure
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Figure 3 Regulation of growth hormone secretion and interplay among the main influences.
and kidney, although IGF-I mediating the growth effect of GH is mainly the amount locally generated by chondrocytes under stimulation by GH. However, plasma IGF-I levels provide a reliable indicator of the effective amount of GH produced, since it is found to be very low in almost all the conditions of endocrine-mediated growth defect. When measured in a given patient after a short cycle (2 days) of exogenous hGH administration (induction test) it also provides relevant information about sensitivity to GH. In conclusion, IGF-I reflects the integrated concentrations of the previously secreted GH (i.e., in the preceding 24–36 h); at variance with the pulsatility of GH, their levels are quite stable during the day. Although IGF-I levels may be low even in conditions different from GH deficiency (hypothyroidism, renal diseases, malnutrition, etc.), they reflect GH spontaneous secretion much better than the provocative tests. At present, however, these tests remain the gold standard for the diagnosis of GH deficiency.
Assessment of GH Secretion From the previously discussed considerations, and due to the pulsatile nature of GH secretion, it emerges that baseline plasma GH levels are very frequently found undetectable if single random samples are taken, even in normal subjects. Therefore, to confirm a diagnosis of GH deficiency, blood samples must be obtained in standard conditions and appropriate stimulation tests should be performed. Some of the following standardized tests are considered useful for initial screening purpose: (1) a post-prandial (3–4 h after a protein-rich meal) or (2) a post-exercise sample (30 min after a strenuous exercise) that shows GH levels above the cutoff value of 10 mg l1 could rule out GH deficiency and avoid further testing. These procedures, however, are not commonly used in clinical practice, and consequently the most widely used tests have been: (1) arginine infusion (0.5 g kg1 by slow i.v. infusion within 30 min) and (2) insulin-induced hypoglycemia (0.1 U kg1 as i.v. bolus). These tests are not devoid of side effects and should be performed by trained personnel in appropriately equipped centers. The main defect of these two tests is their high false positive rate: from 10 to 20% of normal children fail to respond to these tests and would then be wrongly diagnosed as GH deficient. Moreover, approximately 30% of normal children will show discordant responses to the two tests. The basis for interpreting this discrepancy is to be found in the interplay between the two neurohormones GHRH and SRIF: a GH response to the stimulations mentioned above would be possible only when the stimulus reaches the hypothalamic region during a decreasing phase of SRIF (and the reciprocal GHRH increase). One of the main problems common to the various provocative tests resides in the interpretation of the results: different countries have adopted different cutoff levels to separate normal from pathological responses. Cutoff values ranging from 5 to 10 mg l1 of GH at the peak are widely accepted. It must also be considered that the commercial kits used for the assay of GH in plasma with monoclonal antibodies have reached a level of sensitivity much higher than that obtained at the time when the set
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Pituitary Gland: Growth and Growth Failure
points of these test were established. Some authors have proposed a provocative test based on the administration of arginine infusion (0.5 g kg1 i.v. in 30 min) supposed to act by shutting off the endogenous SRIF tone, together with an intravenous injection of synthetic GHRH (1 mg kg1). This double test is a very potent GH secretory stimulus, with high sensitivity and specificity; the cutoff limit for normal subjects has been set to 19 mg l1. The main advantage of this test is its greater capability of discriminating normal from pathological responses (GH deficiency) due to the minimal number of false positives, moreover it avoids the risks of hypoglycemia. In conclusion, it is recommended that each Pediatric Endocrinology Center should adopt two or three provocative tests, and use always the same tests, after having established it own limits of normal responses. Baseline IGF-I levels are also of great help: GH-deficient patients generally have very low levels (i.e., IGF-I levels 2 SDS below the mean for age and sex). While a normal or elevated IGF-I level strongly points against the diagnosis of GH deficiency, the contrary is not true: in the presence of very low IGF-I levels other clinical conditions such as undernutrition etc, should be excluded before considering GH deficit. However, the provocative tests for GH secretion retain some limits: they are not physiological, they are poorly reproducible, and the normal range of responses is arbitrary. These reasons emphasize the recommendation that the poorly growing child should undergo a complete examination, including psychological, medical, and hormonal aspects. GH deficiency remains a clinical diagnosis, corroborated by auxological data concerning the growth pattern, by medical history, and by biochemical tests; it is not the simple observation of hormonal levels below a set value.
Imaging Once this clinical diagnosis is obtained a high quality magnetic resonance imaging of the pituitary and hypothalamic area (with contrast medium) is mandatory. T1 weighted images can show morphological abnormalities: pituitary stalk agenesis or interruption, pituitary hypoplasia, or other lesions. In acquired forms it will show the cystic or solid lesion damaging pituitary/ hypothalamic function.
Treatment The starting dose of hGH to be used in children with GH deficiency is in the range from 30 to 70 mg kg1 body weight per day. It must be administered in the evening at bedtime, in order to mimic the nocturnal spontaneous GH secretory peaks. Daily subcutaneous injections are recommended, although different devices for administration (such as needle-free percutaneous jet injector system) and long acting intramuscular preparations requiring only fortnightly injections have been used. Pen devices (either with almost painless needles or the new needle-free devices) have almost completely replaced the old use of syringes; they are accurate and easily used by the children themselves. The treatment efficacy is monitored by regular assessment of growth rate at 3–6 month intervals. The growth-promoting effects observed with the treatment are mainly a function of the administered doses: increased doses lead to accelerated growth rates. Moreover, the younger the patient age at the beginning of treatment, the better the final results that will be obtained. The administered doses must be regularly re-set according to the effects on weight/height obtained. Until about 1990, GH therapy was generally discontinued after growth rate was observed to be greatly decreased and cartilages closed, but now that metabolic effects of GH are better understood the treatment regimen has gradually changed to “adult” doses (such as 0.04–0.06 mg kg1 week1; given daily or on alternate days). In the “transition” age from adolescence to adulthood the dose is gradually decreased and a wash-out trimester is recommended before re-test for the persistence of GH deficiency. Those patients with genetic or organic GH deficiency have an elevated chance to be reconfirmed deficient and should restart treatment (at the much lower adult range doses). On the contrary patients previously labeled as “isolated or idiopathic” GH deficiency have a high chance to result normal at retesting. Reports confirming preliminary positive effects on bone mineral density, muscle strength, exercise performance, cardiovascular function, and body composition are encouraging to continue replacement therapy in adulthood. It is to be noted that, besides true GH deficiency, hGH treatment in pediatric age is now approved also for other indications: chronic renal failure, Idiopathic short stature, SGA children, and other syndromes such as Turner, Noonan, Prader–Willi and SHOX deficiency.
Safety The preliminary data from an ongoing study on safety of GH therapy (The Safety and Appropriateness of Growth hormone treatments in Europe: SAGhE study) had apparently indicated little increase in Standardized Mortality Rate in patients treated versus controls in the French cohort. On the contrary in The Netherlands, Sweden and Belgium with a more accurate verification of the data, no increased risk was found. We have to wait for the full group of 30 000 children to be evaluated, before a final conclusion will be reached.
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Further Reading Cohen P, Rogol AD, Deal CL, et al. (2008) Consensus statement on the diagnosis and treatment of children with idiopathic short stature: A summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. Journal of Clinical Endocrinology and Metabolism 93: 4210–4217. Cook DW, Divall SA, and Radovick S (2011) Normal and aberrant growth. In: Kronenberg HM, Melmed S, Larsen PR, and Polonsky KS (eds.) Williams Textbook of Endocrinology, 12th edn., pp. 935–1053. Philadelphia: Saunders. GH Research Society (2000) Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: Summary statement of the GH Research Society. Journal of Clinical Endocrinology and Metabolism 85: 3990–3993. Rosenfeld RG, Albertsson-Wikland K, Cassorla F, Frasier SD, Hasegawa Y, Hintz RL, Lafranchi S, Lippe B, Loriaux L, and Melmed S (1995) Diagnostic controversy: The diagnosis of childhood growth hormone deficiency revisited. Journal of Clinical Endocrinology and Metabolism 80: 1532–1540. Sa¨vendahl L, Maes M, Albertsson-Wikland K, Borgstro¨m B, Carel JC, Henrard S, Speybroeck N, Thomas M, Zandwijken G, and Hokken-Koelega A (2012) Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: Preliminary report of 3 countries participating in the EU SAGhE Study. Journal of Clinical Endocrinology and Metabolism 97: E213–E217. Wilson TA, Rose SR, Cohen P, et al. (2003) Update of guidelines for the use of growth hormone in children: The Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. Journal of Pediatrics 143: 415–421.
Relevant Websites http://www.cdc.gov/growthcharts/. http://www.who.int/childgrowth/.