Growth Hormone Deficiency

Vijayakumar Madhava
Additional Professor, Department of Pediatrics,
Government Medical College, Kozhikode, India.

First Created: 04/04/2016  Last Updated: 04/04/2016

Growth Hormone Deficiency - Abstract

Growth hormone deficiency is one of the common causes of short stature in children. The incidence of this condition is between 1in 3000-4000 live births. Diagnosis is often delayed because of the lack of importance given to the art of accurate and serial measurement of height and plotting those observations in a growth chart. There is no “gold standard test” for diagnosis and clinicians have to depend upon a careful history and accurate auxological measurements for early detection. Before doing specific tests, nutritional, systemic, and familial causes should be ruled out. Growth hormone replacement therapy is the treatment of choice. With the advent of recombinant technology, the availability of growth hormones is not a problem but its exorbitant cost prevents many needy patients from taking this medicine.

Introduction

The growth hormone is secreted by the pituitary gland, which is located at the base of the skull, in a bony cavity situated in the sphenoid bone called sella turcica. It is attached to the hypothalamus by infundibulum and consists of two parts namely anterior adenohypophysis (anterior lobe) and posterior neurohypophysis (posterior lobe). Developmentally, the anterior pituitary gland develops from Rathke’s pouch, as an invagination of the oral ectoderm and posterior pituitary from neural ectoderm. The anterior pituitary gland produces 6 hormones from the 5 cell types. They are:

  • Somatotrope - Growth hormone (GH)
  • Lactotrope - Prolactin (PRL)
  • Thyrotrope - Thyroid-stimulating hormone (TSH)
  • Corticotrope - Pro opio melanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH)
  • Gonadotrope - leutinizing hormone (LH), follicle-stimulating hormone (FSH)

Hormones secreted by the posterior lobe of the pituitary gland are produced in the supraoptic and paraventricular nuclei of the hypothalamus. They are oxytocin and vasopressin. The hypothalamus controls the hormonal secretion by the pituitary gland by producing various inhibitory and releasing hormones. Major hormones secreted by the hypothalamus are:

  • Growth hormone-releasing hormone (GHRH)
  • Corticotropin-releasing hormone (CRH)
  • Thyrotropin-releasing hormone (TRH)
  • Gonadotropin-releasing hormone (GnRH)
  • Growth hormone inhibiting hormone (somatostatin)
  • Dopamine

Growth hormone

The growth hormone is a 191 amino acid single-chain polypeptide synthesized from the somatotropes. The gene responsible for its production (GH1) is situated in the long arm of chromosome 17 (q 22-24). It is secreted in a pulsatile fashion which is controlled by the alternating secretion of GHRH and somatostatin. Ghrelin, a hormone produced from the stomach and arcuate nucleus of the hypothalamus also stimulates GH secretion. Various physiologic factors influencing GH synthesis and release are sleep, exercise, stress, trauma, hypoglycemia, fasting, and puberty, which stimulate and hyperglycemia which inhibits its secretion and/or release. Pharmacological agents used to increase GH secretion include insulin, glucagon, clonidine, levodopa, and propranolol. Peak serum GH concentrations are achieved during sleep.

The growth hormone acts by stimulating the synthesis of insulin-like growth factor (IGF-1). IGF-1 is a single chain polypeptide containing 70 amino acids, synthesized mainly from the liver and circulates binding to several binding proteins of which IGFBP3 is the most important one. The secretion of both IGF1 and IGFBP3 are regulated by GH. Hence estimation of these proteins are widely used in the diagnosis oh GH deficiency

Growth Hormone Deficiency

Growth hormone deficiency is not a single disease but is a group of different disorders with different causes. It can present as isolated GH deficiency or associated with other anterior and posterior pituitary hormone deficiencies. Some may have various extra pituitary features like optic nerve hypoplasia and midline defects. The majority remains as idiopathic but more and more cases are being diagnosed as due to genetic defects. Mutations of the genes encoding the transcriptional factors cause the major bulk of GH deficiencies.

As per the current studies, the incidence varies from 1 in 4000 to 1 in 10000 live births. Familial cases account for 5- 30% of all cases. (Table 1)

Table 1: Genetic disorders presenting with growth hormone deficiency

Genetic forms Hormones affected Other features Inheritance
POU1F1 (PIT1) GH,TSH,PRL Manifestations limited to pituitary gland AR
PROP1 GH,TSH,PRL,LH,FSH,ACTH Manifestations limited to pituitary gland AR
LHX3 GH,TSH,PRL,LH,FSH Short neck, limited neck rotation AR
LHX4 GH,TSH,ACTH, Arnold chiari malformation, cerebellar abnormalities AD
HESX1 Variable deficiencies Septo optic dysplasia AR,AD
SOX2 GH Anophthalmia, learning difficulties, esophageal atresia  
SOX3 Variable deficiencies Mental retardation XR
GLI2 Variable deficiencies Holoprosencephaly, midline defects AD
GLI3   Pallister-Hall syndrome AD
SHH   Single central incisor AD
Isolated Growth hormone deficiencies (IGHD)
GHRHR GH   AR
GH1 defects
Type 1 A
GH- severe short stature Anti GH antibodies on treatment AR
GH1-type 1B GH-less severe short stature Good response to treatment AR
GH1- type ii GH- less severe short stature   AD
GH 1-type iii GH hypogammaglobulinemia XL

Acquired causes of GH deficiency (Table 2)

  • Any lesion that damages the pituitary gland, pituitary stalk, and/or hypothalamus can cause hypopituitarism. They usually cause multiple pituitary hormone deficiencies. Posterior pituitary gland involvement leading to diabetes insipidus is more common in acquired hypopituitarism. Somatotropes are most vulnerable to radiation injury and pressure effects, followed by gonadotropes and thyrotropes. Hence growth failure is the commonest endocrine manifestation followed by pubertal disorders and hypothyroidism in such cases.
  • Traumatic brain injury:

    Brain trauma causes pituitary hormone deficiency by hampering the blood supply to the pituitary stalk or causing direct injury to the pituitary gland, stalk or hypothalamus. Perinatal trauma results in isolated or multiple pituitary hormone deficiencies. Hypopituitarism is more commonly seen in children born after breech extraction, forceps deliveries, prolonged labor, and babies who have suffered hypoxic attacks. In children, GH deficiency is reported following child abuse, road traffic accidents and after intracranial bleeds.
  • CNS tumors:

    midline brain tumors like craniopharyngioma, germinoma, glioma, and meningioma produce hypothalamic or pituitary insufficiency. They will have associated features of raised intracranial tension, visual defects, and visual field defects. Craniopharyngioma produces panhypopituitarism.
  • Cranial irradiation:

    cranial irradiation directly impairs hypothalamic or pituitary functions. Irradiation at a low dose of radiation results in isolated growth hormone deficiency and high doses produce multiple pituitary hormone deficiencies. After 5 years of radiotherapy, almost all children who received >3000 cGy over three weeks have developed growth hormone deficiency.
  • CNS infections:

    inflammation of the brain resulting from bacterial, viral or fungal infections can produce hypopituitarism. Among bacteriae, Mycobacterium tuberculosis, H- influenza, and Group-B - Streptococcus predominate.
  • Systemic diseases:

    Various systemic diseases like sarcoidosis, SLE, autoimmune thyroiditis and Langerhans cell histiocytosis (LCH) can produce hypophysitis leading to hypopituitarism. Diabetes insipidus is the commonest endocrinopathy caused by LCH.
  • Hemolytic anemia:

    Iron overload in hemolytic anemia like thalassemia causes hypopituitarism leading to growth delay and pubertal development.

Table 2: Causes of acquired hypopituitarism

Lesions Examples
Tumors Craniopharyngioma, germinoma, optic glioma, dysgerminoma, ependymoma, meningioma, pituitary adenoma
Radiotherapy Radiotherapy of CNS tumors, cranial irradiation in hematological malignancies, BMT
Brain Trauma Birth injuries(breech extraction, forceps), Traumatic brain injuries (Road traffic accidents, child abuse), subarachnoid hemorrhage, post neurosurgery
Infection & inflammation Pyogenic meningitis, tuberculous meningitis, viral encephalitis, sarcoidosis, autoimmune conditions (SLE, thyroiditis)
Infiltration Langerhans cell histiocytosis
Iron overload: thalassemia, hemochromatosis
Psychosocial deprivation Cause functional but reversible pituitary deficiency

Clinical Features - Neonatal Period

A neonate with hypopituitarism presents with non-specific features like poor feeding, lethargy, apnea, poor weight gain, jitteriness, or seizures. Useful clinical features are as follows (TABLE 3):

Table 3: Common clinical features of Hypopituitarism in a neonate

Clinical presentation Possible cause
Hypoglycemia Associated ACTH deficiency
Temperature instability TSH deficiency
Prolonged unconjugated hyperbilirubinemia TSH deficiency
Conjugated hyperbilirubinemia Cortisol deficiency
Microphallus GH deficiency, Gonadotropin (LH) deficiency
Undescended testes Gonadotropin deficiency
Diabetes insipidus (rare) Associated midline defects

Clinical features- Childhood

Majority of affected children present with short stature. Most of the babies have normal birth weight and length. By 6 months of age, clinically appreciable growth faltering is seen, and by the age of 2 years, they will be shorter than their peers, severity increases as the age advances. Their body proportions are normal for age. The following axiological criteria warrant investigations for GH deficiency:

  • Severe short stature (height more than3 SD below the mean) for the population
  • Height more than 2 SD below the mean for a population with a growth velocity over 12 months more than 1 SD (25th percentile) below the mean
  • Height SD more than 1.5 SD below the mid parental height
  • Height velocity more than 2SD below the mean over 1 year or more than 1.5 SD below the mean for 2 years
  • Other anterior pituitary hormone deficiencies (central hypothyroidism, DI, micropenis)
  • Neonatal symptoms and signs of growth hormone deficiency
  • Signs indicative of an intracranial lesion

Boys usually present with micropenis even in isolated GH deficiency. Some may have associated gonadotropin deficiency. The latter also present with arrested pubertal growth and delayed puberty. Delayed development and mental retardation are rare manifestations of GH deficiency. They denote associated central hypothyroidism, prolonged untreated neonatal hypoglycemia, or a birth injury. Prolonged DI with electrolyte imbalances also produces brain damage. Infants have poor development of musculature, resulting in some delay in attaining gross motor milestones. Facial bone growth is retarded (midfacial hypoplasia) and the nasal bridge is underdeveloped. Fontanels close late. Growth of the skull is normal in relation to the face resulting in cephalofacial disproportion and the appearance of a relatively large head. Voice remains infantile (high pitched) because of the hypoplasia of the larynx. Eyes are prominent and often protuberant. Teeth are crowded and erupt late. Hands and feet are small. The characteristic facial appearance is often called “doll-like appearance”. Features of diabetes insipidus, presenting as polyuria and polydipsia are rare, and they will have associated midline defects such as septic-optic dysplasia or holoprosencephaly. Occasionally these symptoms may be an initial manifestation of LCH. Even though many cases are described with truncal obesity, such a presentation is rare in the Indian scenario. The presence of midline abnormalities like single upper central incisor, cleft palate, impaired vision, and nystagmus are features of genetic forms of GH deficiency. Please refer to table 1.

Diagnostic Evaluation

A careful history and auxological measurements help to differentiate pathological short stature from genetic & constitutional delay in growth and puberty. Wasting will be more pronounced in undernutrition. Carefully rule out any systemic organic diseases or chronic infections before doing investigations for growth hormone deficiency. Hypothyroidism is a more common endocrine cause in our country where newborn screening program is not practiced. (Table 4) Bone age is characteristically delayed in congenital GH deficiency. Typically radiology of hand bones are used for calculating bone age

Table 4 : Investigations to rule out systemic diseases

Investigation Disease screened
Hemoglobin, peripheral smear Chronic anemias (iron deficiency anemia, hemolytic anemia, chronic infections)
ESR Chronic infection, inflammation
Blood urea, serum creatinine Chronic kidney disease
Calcium, phosphorous, alkaline phosphatase Rickets, pseudo hypoparathyroidism
SGPT, serum proteins Chronic liver diseases
ABG, Venous PCO2, bicarbonates Renal tubular acidosis
Blood glucose Diabetes Mellitus
Thyroid function tests Hypothyroidism
Tissue transglutaminase Celiac disease
Urine microscopy RTA, Chronic glomerulonephritis, chronic pyelonephritis
Stool-cysts Giardiasis
X-ray Hand-rickets, skull-supracellar calcifications, craniopharyngioma

Assessment of Pituitary Growth hormone production

Accurate assessment of growth hormone production is not easy owing to the pulsatile nature of growth hormone secretion. Between normal pulses of secretion, serum levels of growth hormone are very low. Hence measurement of random GH estimation is useless. Measurement of growth hormone reserve is done by using physiological and pharmacological stimuli. These tests called “provocative tests” or “stimulation tests” are the basic tests for diagnosing GH deficiency. Stimulation tests include using physiologic stimuli like fasting, sleep, and exercise or pharmacologic stimuli like levodopa, clonidine, glucagon, propranolol, arginine, and insulin. For a child to be diagnosed as having growth hormone deficiency if he/she fails stimulation tests with at least 2 separate stimuli. (Table 5)

Table 5: Growth hormone stimulation tests (Modified from Pediatric Endocrinology : Mark A Sperling: 4th edition)

Stimulus Dosage Samples (minutes) Comments
Levodopa (PO) < 15 kg-125 mg
15- 30 kg-250 mg
>30 kg-500 mg
0,60,90 Nausea, vomiting, headache
Clonidine (PO) 0.15 mg/m2 0,30,60,90 Tiredness, postural hypotension
Arginine HCL (IV) 0.5 g/kg (max 30 g) 10% arginine HCL in 0.9% saline over 30 minutes 0,15,30,45,60 Late hypoglycemia
Insulin (IV) 0.05-0.1 IU/kg 0,15,30,45,60,75,90,120 Hypoglycemia
Glucagon (IM) 0.03 mg/kg (max 1 mg) 0,30,60,90,120,150,180 Nausea
Procedure
  • Euthyroid state is essential before testing
  • Test should be done after an overnight fast
  • Peripubertal children (bone age > 10 years) should be primed with sex steroids. Premarin 5 mg PO, the night before and the morning of the test in girls and depot testosterone 100 mg 3 days before testing in boys
  • Close monitoring with BP, heart rate and IV saline administration in case of hypotension if clonidine is used. Monitoring blood sugars and administering 10% dextrose and glucagon in case of hypoglycemia if insulin is used
  • 2 standard stimulation tests are usually recommended

Disadvantages of provocative tests

None of the provocative tests mimics the normal secretory pattern of growth hormone. They have poor reproducibility.

Interpretation of results

In general, the results are interpreted as follows

  • Severe deficiency: GH stimulated levels <5 ng/ml
  • Mild to moderate deficiency: GH levels 5-10 ng/ml
  • Severe deficiency: GH levels >10 ng/ml

Measurement Of Igf1 and Igfbp3

Measurement of IGF1 and IGFBP3 can reflect the growth hormone status of the patient. Their serum levels remain constant throughout the day hence a single reading suffices. But these measurements have some limitations. IGF-1 concentrations are age-dependent. (Table 6) They are the lowest in young children. Their serum concentration will be affected by various conditions. Malnutrition, malabsorption (e.g.; Celiac disease), type 1 diabetes, etc will cause a reduction in serum IGF-1 levels. Age-dependent variations in the levels of IGFBP3 are less marked; hence it is a more dependable marker of GH deficiency at a young age including infants. (Table 7) Moreover, its levels are not much affected by nutritional status, unlike the levels of IGF-1. IGFBP3 levels are clearly growth hormone-dependent.

Table 6: Serum levels of IGF-1 in different age groups (adapted from Harriet Lane 19th Ed: 2012:267-268)

Age Boys (male) ng/ml Girls (females) ng/ml
2 months-6 years 17-248 17-248
6-9 years 88-474 88-474
9-12 years 110-565 117-771
12-16 years 202-957 g 261-1096
16-26 years 18-780 182-780

Table 7: Serum levels of IGF-BP3 in different age groups (adapted from Harriet Lane 19th ed :2012 :267-268)

Age Boys (male) ng/ml Girls (females) ng/ml
0-2 0.94-1.76 0.66-2.51
2-4 1.12-2.33 0.84-3.77
4-6 1.16-3.13 1.32-3.60
6-8 1.32-3.38 1.21-4.66
8-10 1.35-3.94 1.58-3.99
10-12 1.53-5.02 1.93-6.46
12-14 1.73-5.11 1.78-6.08
14-16 1.90-6.40 2.02-5.44
16-18 1.70-6.04 1.88-5.29

Role of imaging

An MRI of the brain with particular emphasis on the hypothalamus and pituitary gland should be done in all children diagnosed as having growth hormone deficiency. In children <10 years a normal pituitary gland has a length of 5-6 mm in the vertical axis. In hypopituitarism in addition to a small pituitary gland absence of a pituitary stalk and ectopic position of the posterior pituitary bright spot may be seen. Imaging also helps to find out intracranial tumors or congenital anomalies like septo-optic dysplasia

Assessment of other pituitary hormonal status

Low T4 or free T4 and low/low normal TSH levels are suggestive of central hypothyroidism. A prolonged response to TRH is seen in this situation. Low basal cortisol and poor cortisol response to ACTH is suggestive of a defect in cortisol production. Unless cortisol is supplemented, it results in an adrenal crisis. LH, FSH, testosterone/estradiol estimation is done if they present with pubertal delay. Low ADH levels denoted by high sodium levels, high plasma, and low urine osmolality warrant further investigations for posterior pituitary function. Low prolactin levels are seen in some forms of Growth hormone deficiency disorders (PIT-1 gene defect). Its levels are high in intracranial tumors.

Testing a neonate

Presence of micropenis, midline defects, or resistant hypoglycemia warrants evaluation for the growth hormone axis. GH stimulation testing can’t be done in a neonate. In the presence of hypoglycemia, the measurement of GH from a critical sample almost mimics a GH stimulation test. A Growth hormone level less than 20 ng/ml is suggestive of Growth hormone deficiency in a neonate.

Growth hormone insensitivity

A combination of normal growth hormone levels in stimulation tests combined with low serum IGF-1 and IGF BP3 levels in a short child (in whom nutritional and systemic disorders are ruled out) is suggestive of growth hormone insensitivity. The levels of IGF-1 will remain low even after growth hormone supplementation for one week (IGF-1 generation test). The treatment option for GH insensitivity is IGF1.

Evaluation for genetic disorders

Recently detection of a correct genetic cause for short stature is possible in research laboratories. Pointers to a possible genetic etiology are:

  • Early onset of growth failure
  • Positive family history
  • Consanguinity
  • Associated congenital anomalies (septo -optic dysplasia, midline defects, single central incisor)
  • Severe short stature height >3 SD below mean)
  • Very low GH response to provocation, very low IGF-1 and IGF-BP3 levels

Treatment

The treatment option available for growth hormone deficiency is recombinant human growth hormone. Normalization of height in a child with GH deficiency is the primary objective of the treatment. Normally growing children with craniopharyngioma should also be considered for GH therapy. Daily depot preparations are commonly in use at present.

Dosing: GH is administered as subcutaneous injection in the evening. It is commonly used in the range of 25- 50 µg/kg/day (1 mg = 3 IU). A higher dose may be required in special conditions (Turner’s syndrome)

Monitoring:

After initiating the treatment, the patient should be followed up at regular intervals. He should be recalled after a week of initiation of therapy to look for any adverse effects of injections. Thereafter regular monitoring should be done once in 4-6 months. The most important parameter for assessing the response to treatment is the demonstration of an increase in height and height velocity, plotted in a growth chart. Serial assessment of serum IGF-1 and IGF-BP3 levels are done but they do not always correlate well with the growth response. Yearly monitoring of thyroid hormone status (free T4 and TSH) and adrenal status (morning serum cortisol) as well as bone age estimation is a must.

Factors affecting the response:

Younger the age of initiation of treatment, the greater will be the response. If the child is entering puberty with an unsatisfactory height, GH dose escalation or combined GH and GnRH agonist therapy are tried.

Multiple pituitary hormone deficiencies (MPHD):

in these children, in addition to GH therapy, monitoring of other pituitary hormonal deficiencies should be done regularly since they may manifest at a later age. If detected, supplementation (thyroxine, hydrocortisone, sex steroids, DDAVP) should be carried out.

Transition to adult management:

GHD may persists into adult life. Other than promoting linear growth, GH has important metabolic actions which are important for maintaining adult body compositions and health. After the final height is achieved, as suggested by closed sutures in a hand x-ray and other parameters, a retesting of the GH- IGF axis is done by doing a GH stimulation test after stopping GH therapy for 3 months. Measurements of other pituitary hormones, IGF-1, and in selected cases, insulin tolerance tests, bone mineral density, fasting lipid levels also should be done. Continuation of growth hormone treatment is advocated if adult GH deficiency is diagnosed.

Conclusion:

Growth hormone deficiency is not a rare disease. Since recombinant human growth hormone is available, even though costly, treatment is a reality and the response is excellent once the treatment is initiated sufficiently early. The only way to identify this disease sufficiently early is to have his/her growth standards plotted in a growth chart.

Figure 1: A case of growth hormone deficiency, diagnosed at age of 8 year. Note the typical “Doll like face” with prominent forehead, protruding eyes, and mid facial hypoplasia

growth-hormone-deficiency

Figure 2: Same girl after treatment for 2 years ( at the age of 10 years)

growth-hormone-deficiency

Figure 3: After treatment for 5years (at age 13 years of age)

growth-hormone-deficiency

Complications

GH is a well-tolerated drug and side effects are rare. Complications include benign intracranial hypertension, edema, slipped capital femoral epiphysis, pre-pubertal gynecomastia, and arthralgia. Treatment may unmask underlying hypothyroidism or adrenal insufficiency (hence their serial monitoring is very important.


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