growth%20hormone%20deficiency%20(pediatric)
GROWTH HORMONE DEFICIENCY (PEDIATRIC)
Growth hormone deficiency is a congenital or an acquired growth hormone axis disruption in the higher brain, hypothalamus or pituitary which results in short stature.
It may occur at any age.
Short stature is often the only feature present in patients with growth hormone deficiency and other causes of subnormal growth rate.
Etiology may be congenital conditions (eg defective pituitary development that leads to pituitary aplasia, empty sella, encephalocele, midline defects) or acquired conditions (eg tumors of the hypothalamic-pituitary region, cranial irradiation, infiltrative disease).

Diagnosis

  • Short stature is often the only feature present in patients with growth hormone deficiency (GHD) & other causes of subnormal growth rate
    • Exclude other causes of growth failure using appropriate tests
      • Eg hypothyroidism, chronic systemic diseases, skeletal diseases & Turner syndrome
  • Diagnose GHD based on comprehensive clinical & auxological assessment together with laboratory tests [eg, GH-insulin-like growth factor (IGF-1) axis] & radiological evaluation

History

  • Family history of growth hormone deficiency (GHD)
  • Perinatal history (eg difficult labor, traumatic delivery)
  • History of cranial irradiation
  • History of head trauma
  • Growth chart & history of slow or no growth
  • Symptoms of growth hormone deficiency (GHD) in neonates and children

Physical Examination

  • Height and weight evaluation
    • Plot weight and height measurements on growth charts which will graphically depict changes in growth and growth velocity
  • Short stature may suggest growth hormone deficiency (GHD) and immediate investigation should be conducted if any of the following criteria are present:
    • Severe short stature (defined as height >2-3 SD below population mean)
    • Height >2 SD below population mean with 1-year height velocity >1 SD below mean for chronological age or (in child age >2 years), a 1-year decrease of >0.5 SD in height
    • In the absence of short stature, a 1-year height velocity >2 SD below the mean or a 2-years height velocity >1.5 SD below the mean (especially growth hormone manifesting during infancy or in organic acquired GHD
    • Height >1.5 SD below midparental height (average of father’s and mother’s)
    • Signs indicative of an intracranial lesion
    • Signs of multiple pituitary hormone deficiencies (MPHD)
    • Neonatal signs and symptoms of GHD
  • Other manifestations of growth hormone deficiency (GHD) in children
    • Increased subcutaneous fat, especially around the trunk
    • Immature facie, with a prominent forehead & depressed midfacial development
    • Delayed dentition
    • Age of puberty may be delayed
    • In males, the phallus may be small

Laboratory Tests

Serum Growth Hormone (GH) Level

  • In newborns, serum GH level <20 mcg/L is highly suggestive of growth hormone deficiency (GHD)
    • GH level measured in neonates w/ hypoglycemia but no metabolic disorder
  • After the newborn period, random serum GH levels are not reliable indicators of GHD due to the pulsatile nature of GH secretion

Growth Hormone (GH) Stimulation (Provocative) Tests

  • At least 2 provocative tests are ideal to ascertain the diagnosis because of the high frequency of false-negative results
    • Minimum of 2 provocative tests with low peak levels of GH, poor linear growth, & delayed skeletal age is highly indicative of chronic GHD
  • Provocative tests in children with peak GH concentration <10 mcg/L supports GHD diagnosis:
    • Insulin tolerance test (ITT)
      • GH level ≤5.0 mcg/L indicative of GHD
      • Contraindicated in patients with cardiovascular disease, cerebrovascular disease and seizure disorders
    • Growth hormone–releasing hormone (GHRH) with or without arginine
      • GH level <4.1 mcg/L indicates GHD in a GHRH-arginine test
    • Clonidine
    • Levodopa
    • Glucagon with or without beta-blockers
      • Peak GH of ≤3.0 mcg/L indicative of GHD and possible initiation of treatment
    • Propranolol
  • May consider sex steroid priming prior to conducting GH provocative test in prepubertal children (boys >11 years old and girls >10 years old) to improve diagnostic specificity
  • May choose not to proceed with this test if patients have other findings that clearly indicates GHD (pituitary abnormality, newborns with congenital pituitary abnormality, extreme short stature (height <-3 SD), significantly reduced IGF-1 and IGFBP-3 levels, and delayed bone age manifested by an infant or young child with no known nutritional deficiency) 

Insulin-like Growth Factor 1 (IGF-1) or Somatomedin Test & Insulin-like Growth Factor-Binding Protein 3 (IGFBP-3) Test

  • Produced when the liver and other tissues are stimulated by growth hormone (GH)
  • IGF-1 is a direct reflection of the concentrated level of functional GH secretion
    • More stable measurable concentrations compared to the pulsatile secretion of GH 
  • IGFBP-3 is a major serum carrier protein for IGF-I and is GH-dependent
    • Better differentiates low versus low-normal IGFBP-3 levels in young children compared to somatomedin test 
  • Values ≥2 SD below the mean for IGF-1 or IGFBP-3 strongly suggest an abnormality in the GH axis, if other causes of low IGF have been excluded
  • However, normal values for IGF-1 and IGFBP-3 can be found in children with GHD
    • Low levels may be seen in patients with GH insensitivity, hypothyroidism, DM, renal failure, and malignancy

Other Tests

  • Acid-labile subunit test
    • Used to rule-out postreceptor defects, specifically a dysfunction in the acid-labile subunit as a cause of IGF-1 deficiency 
    • Postreceptor defects are more common in patients with GH resistance/insensitivity syndrome and not GHD
    • More studies are needed to establish the use of this test for IGF-1/IGFBP-3 level determination in GHD 
  • Lipid profile
    • Patients with GHD may have increased total cholesterol, low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B and triglyceride (TG) levels and decreased high-density lipoprotein-cholesterol (HDL-C)
  • Thyroxine and thyroid-stimulating hormone (TSH)
  • To rule out hypothyroidism
  • Evaluate for possible causes of GHD: Congenital, genetic or acquired causes
  • Karyotype
    • Perform to evaluate the presence of genetic syndromes (eg Turner syndrome in females)
  • Increased type-1 plasminogen activator inhibitor (PAI-1) activity
  • Increased fibrinogen levels

Imaging

X-ray

  • Assesses the bone age in children
  • Reveals delayed bone age in children with growth hormone deficiency (GHD)
  • Bone age is estimated from a radiograph of the:
    • Left wrist & hand for children 1 year of age or older
    • Knee & ankle for infants <1 year old
  • X-ray of the head may show intracranial calcification in craniopharyngoma

Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) of the Central Nervous System (CNS)

  • Performed to define the anatomy of the hypothalamic-pituitary region & to identify intracranial tumors, optic nerve hypoplasia, septo-optic dysplasia or other structural or developmental anomalies

Differential Diagnosis

Endocrine causes

  • Growth hormone resistance
  • Hypothyroidism
  • Cushing’s syndrome
  • Parathyroid or vitamin D disorders
  • Delayed puberty (GnRH deficiency)

Non-endocrine causes

  • Syndromes (Turner, Noonan, Russell-Silver, etc)
  • Skeletal dysplasia
  • Chronic disease, inflammation
  • Psychosocial short stature
  • Constitutional delay of growth and puberty
  • Malnutrition
  • Intrauterine growth retardation (IUGR), small for gestational age (SGA)

Insulin-like Growth Factor (IGF) deficiency

  • May be caused by GH insensitivity, IGF resistance, growth hormone deficiency (GHD) secondary to hypothalamic dysfunction or pituitary growth hormone deficiency  

Idiopathic short stature (ISS)

  • Genetic and non-genetic short stature manifested as height of >2 SD below the corresponding mean height for age, sex and population group, with constitutional delayed growth and maturation
  • Systemic, endocrine, nutritional & chromosomal abnormalities, especially growth hormone deficiency (GHD) should have been ruled out
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