Growth Retardation

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Growth Retardation

• 96/10/12
• Data from Up To Date
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INTRODUCTION

• Short stature is not a disease it is a term
  applied to a child who is 2 standard deviations
  (SD) or more below the mean height for children
  of that sex and chronologic age (and ideally of
  the same racial-ethnic group).
• This translates into being below the third
  percentile for height.
• A single measurement of height is much less
  useful in assessing growth than is the pattern of
  growth over a period of time.

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• Growth curve in a male with intrinsic shortness.
  The growth velocity is normal from age 5 onward
  with the height being below, but parallel to, the
  third percentile.

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• To define any growth point, one must measure
  children accurately and plot each point (height,
  weight, and head circumference) precisely.
• One of the more common causes of apparent growth
  failure (and short stature) is mismeasurement or
  aberrant plotting of the data.

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Prediction of height potential

• Somatic growth and biologic maturation are
  influenced by many factors that act independently
  or in concert to modify a child's genetic
  potential for growth.
• Although the precise contribution of heredity
  cannot be quantitated, an estimate of a child's
  adult height potential can be obtained by
  calculation of the midparental height, adjusted
  for the sex of the child
•   For girls, 13 cm is subtracted from the
  father's height and averaged with the mother's
  height.
• For boys, 13 cm is added to the mother's height
  and averaged with the father's height.

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VARIATIONS OF NORMAL GROWTH

• A normal pattern of growth is evidence that the
  general health of a child or adolescent is good.
• On the other hand, children with just about any
  subacute or chronic illness may grow slowly.
• Statural growth is a continuous but not linear
  process. There are three phases of postnatal
  growth infantile, childhood, and pubertal.
• Each has its own distinctive pattern.

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• The infantile phase is characterized by rapid but
  decelerating growth during the first two years of
  life overall growth during this period is about
  30 to 35 cm.
• Infants often cross percentile lines in the first
  24 months as they grow toward their genetic
  potential and get further away from the excesses
  or constraints of the intrauterine environment.

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• The childhood phase is characterized by growth at
  a relatively constant velocity of 5 to 7 cm per
  year there is often slight slowing later in
  childhood.
• The pubertal phase is characterized by a growth
  spurt of 8 to 14 cm per year because of the
  synergistic effects of increasing gonadal steroid
  and growth hormone secretion.

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Idiopathic short stature

• There are certain children whose stature falls
  below 2 SD of the mean for age, and for whom no
  endocrine, metabolic or other diagnosis can be
  made.
• Such children are considered to have idiopathic
  short stature.

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• They have normal (often at the lower limit)
  growth velocity, no biochemical or other evidence
  for a specific growth retarding condition, normal
  serum concentrations of insulin-like growth
  factor-I (IGF-I) and IGF binding protein-3, and
  normal growth hormone responses to pharmacologic
  agents that lead to growth hormone release.

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PATTERNS OF ABNORMAL GROWTH

• The most common causes of short stature beyond
  the first year or two of life are familial
  (genetic) short stature and delayed
  (constitutional) growth.
• The latter may have a genetic basis, because
  there is often another close family member in
  whom growth was delayed.
• The shortest children often have both of these
  variants of normal growth.

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• Although there is considerable individual
  variability, the size at birth in children with
  these disorders is usually normal.
• However, a downward shift in growth begins at
  three to six months that is often
  indistinguishable from that in normal children
  (lag-down growth) but tends to be more severe and
  more prolonged .
• Many of these children have normal growth
  velocity by the third or fourth year, and then
  continue to grow below, but parallel to, the
  third percentile .

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• There are multiple ways in which to categorize
  slow growth and the resulting short stature, but
  it is the abnormal growth rate (the trajectory
  along the growth chart) that is more relevant
  than the issue of whether a child is short or not
  (see above).
• I use a classification based upon the
  relationship between chronologic age, height age,
  weight age, bone age, and growth rate.

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• Intrinsic shortness Intrinsic shortness is
  characterized by inherent limitations of bone
  growth and predicts adult short stature.
• Delayed growth Delayed growth is defined as a
  bone age closer to height age than chronologic
  age and predicts "normal" adult stature.

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• Attenuated growth Attenuated growth is
  characterized by a growth rate that is so slow
  that the child progressively deviates from a
  previously defined growth channel (or
  percentile).
• Because the height age approximates the bone age,
  adult height potential is often normal, but only
  after remedial action is taken for one of the
  many possible causes.

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DISEASES THAT MAY CAUSE GROWTH FAILURE AND SHORT
STATURE

• Renal disease
• Metabolic acidosis
• Cancer
• Glucocorticoid therapy
• Pulmonary disease
• Cardiac disease
• Gastrointestinal disease
• Immunologic disease
• Metabolic and endocrine diseases

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• Renal disease Growth failure in children with
  renal disease is multifactorial.
• Implicated factors include metabolic acidosis,
  uremia, poor nutrition secondary to dietary
  restrictions, anorexia of chronic illness,
  anemia, calcium and phosphorus imbalance, renal
  osteodystrophy and potential adverse effects on
  the serum concentrations of growth factors and
  their binding proteins.

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• Metabolic acidosis alone can also impair growth,
  as occurs in children with renal tubular acidosis
  .
• Alkali therapy may lead to attainment and
  maintenance of normal stature.

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• Cancer Children with cancer may grow poorly
  before diagnosis because of poor food intake,
  nausea, vomiting, and increased caloric
  utilization.
• After diagnosis, anorexia, nausea, and vomiting
  induced by chemotherapy and radiotherapy also can
  contribute to impaired growth.
• These effects of treatment often subside by one
  to two years, and some children then have
  catch-up growth.

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• Late growth failure is common in children who
  received cranial radiotherapy (and perhaps
  chemotherapy), because it causes growth hormone
  (GH), gonadotropin, and sometimes thyrotropin
  deficiency .
• In younger children, especially girls, cranial
  radiotherapy can cause precocious puberty and
  adult short stature.
• Primary hypothyroidism also can occur if the
  thyroid gland was in the radiation field. Spinal
  irradiation may result in slow growth of the
  spine, with relative sparing of limb growth.

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• Glucocorticoid therapy Glucocorticoids exert
  multiple growth-suppressing effects, interfering
  with endogenous growth hormone secretion, bone
  formation, nitrogen retention, and collagen
  formation .
• The impairment in growth is most pronounced with
  daily therapy, may be less pronounced with an
  alternate-day regimen, and even can occur with
  inhaled glucocorticoids .

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• As an example, one report evaluated the effect of
  seven months of relatively low-dose inhaled
  beclomethasone dipropionate (400 mcg/day) in 7-
  to 9-year-old children with mild asthma .
• Treatment had no effect on overnight urinary
  cortisol excretion, but did reduce growth
  velocity (0.79 versus 1.14 mm/week).
• At the end of the seven months of therapy,
  children receiving beclomethasone had grown 1 cm
  less than those in the placebo group.

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• The growth-impairing effects of glucocorticoids
  may persist after therapy is discontinued.
• In a study of 224 children with cystic fibrosis
  who previously had been treated for up to four
  years with either alternate-day prednisone or
  placebo, mean height after age 18 years (on
  average six to seven years after cessation of
  therapy) was significantly lower in boys who had
  received either high- or low-dose prednisone
  (170.5 and 170.7 versus 174.6 cm with placebo p
  0.03) .
• This effect was most pronounced in boys who had
  started taking prednisone at 6 to 8 years of age.
  
• In contrast, there was no persistent growth
  impairment in girls treated similarly.

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• Pulmonary disease Asthma is the most common
  chronic pulmonary disease in children. Severe
  asthma alone probably results in slow growth, but
  it is slowed more by treatment, especially with
  glucocorticoids.
• Cystic fibrosis is both a pulmonary and
  gastrointestinal disease. Growth failure is
  multifactor in this disorder as poor food intake,
  increased fecal losses becuase of maldigestion or
  malabsorption, chronic infection, and increased
  energy requirements (work of breathing) can all
  contribute.

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• Cardiac disease Growth failure is common in
  children with severe heart disease of any cause.
  The major pathogenetic factors are thought to be
  anorexia and increased basal energy requirements
  .

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• Gastrointestinal disease Celiac disease is a
  prime example of a remediable cause of short
  stature, especially in younger children .
• Children with growth failure resulting from
  gastrointestinal disease have a greater deficit
  in weight than height (ie, they are
  underweight-for-height) in contrast to those with
  endocrine disorders who are often
  overweight-for-height .
• Older children with inflammatory bowel disease,
  especially Crohn's disease, may present with
  growth failure before the onset of
  gastrointestinal symptoms.

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• Immunologic disease Renewed interest in
  immunologic causes of growth retardation has come
  with the AIDS epidemic. However, it is difficult
  to attribute growth failure to the infection or
  its immunologic consequences, because anorexia,
  malabsorption, diarrhea, severe infections, and
  failure of one or more organ systems are so
  common in these patients .
• Growth failure also can occur with other
  immunological deficiencies such as the severe
  combined immunodeficiency syndrome. As with HIV
  infection, multiple factors are probably
  involved.

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• Metabolic and endocrine diseases Growth failure
  is common in children and adolescents with many
  of the inborn disorders of metabolism.
• Among acquired metabolic diseases, the most
  common is autoimmune diabetes mellitus.
• Diabetes was, in the past, an important cause of
  short stature and attenuated growth because of
  caloric deficit resulting from severe glucosuria
  .
• However, it is now rare because of improvements
  in therapy.
• Although children with fair-to-good metabolic
  control have some decrease in insulin-like growth
  factor-1 (IGF-1) production or action, their
  growth is usually normal.

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• Any disorder associated with vitamin D deficiency
  or decreased vitamin D action can cause
  hypophosphatemia and rickets, which is
  characterized by abnormal epiphyseal development,
  bowing of the extremities, and poor growth.
• Other common endocrine causes of growth failure
  and short stature are hypothyroidism,
  hypopituitarism (isolated GH deficiency or
  multiple anterior pituitary hormone
  deficiencies), and hypercortisolism (Cushing's
  syndrome, exogenous and endogenous).

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• GH deficiency usually results from deficiency of
  growth hormone-releasing hormone (GHRH), but can
  be because of sellar and parasellar tumors (eg,
  germinoma ) that destroy the pituitary gland
  itself.
• These children can have striking catch-up growth
  after surgical treatment or during GH replacement
  therapy .
• A rare cause is an inactivating mutation of the
  GHRH receptor that is inherited in an autosomally
  recessive manner .

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• Hypothyroidism is a well-recognized cause of
  growth failure that may be an early or the major
  manifestation of hypothyroidism in children.
• The skeletal age is usually as delayed as the
  height age as a result, many children with
  hypothyroidism have a reasonably normal growth
  potential.

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• Cushing's syndrome in children is most often
  iatrogenic, because of glucocorticoid therapy for
  asthma, inflammatory bowel disease, or
  immunologic renal disease.
• Endogenous Cushing's syndrome is uncommon in
  children, but should be considered if the child
  has both weight gain and growth retardation, ie,
  is overweight-for-height .

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DIAGNOSIS OF ENDOCRINE CAUSES OF GROWTH FAILURE

• Hypothyroidism Thyroid function should always
  be evaluated, because growth failure may be the
  first or even the only manifestation of
  hypothyroidism.
• The evaluation should include measurements of
  both serum thyrotropin (TSH) and thyroxine both
  primary and central hypothyroidism can cause
  growth failure, and measurement of serum TSH
  alone will not detect central hypothyroidism.

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• Cushing's syndrome Cushing's syndrome is rare
  in children except when due to the toxicity of
  glucocorticoid therapy.
• It is initially a clinical diagnosis that is
  suggested by the clinical findings and then
  confirmed by biochemical and imaging tests.
• The following findings were noted in a review of
  59 patients with Cushing's syndrome who were
  between the ages of 4 and 20 years

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• A corticotropin (ACTH)-secreting pituitary
  adenoma (Cushing's disease) is by far the most
  common cause, accounting for 50 cases.
• The two major findings are weight gain (90
  percent) and growth retardation (83 percent)
  bone age was normal at diagnosis in most
  patients.

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• Growth hormone deficiency If growth hormone
  deficiency is congenital and complete, the
  diagnosis is relatively easy to confirm.
• Affected children present with severe growth
  failure, delayed bone age, and very low serum
  concentrations of growth hormone, IGF-I, and its
  major binding protein, IGF-binding protein-3.

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• The rare children with growth hormone
  insensitivity have high serum growth hormone
  concentrations but low serum IGF-I and IGF
  binding-protein-3 concentrations.
• In its complete form, this condition is called
  Laron-type dwarfism (complete growth hormone
  insensitivity).

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Treatment of growth hormone deficiency in
children

• PREPARATIONS OF GROWTH HORMONE FOR THERAPY
  Seven pharmacologic preparations are approved for
  treatment of growth hormone deficiency in
  children, and others are still being tested

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• Aqueous solutions of growth hormone for
  subcutaneous administration.
• Several brands of growth hormone have been
  available for subcutaneous administration for
  many years, and most information about growth
  hormone treatment comes from these preparations.
• Most are available in multiple-dose pen devices
  that materially aid in administration.
• Daily therapy is more effective than three times
  a week at the same dose .
• The recommended dose of growth hormone in
  children with growth hormone deficiency is 0.04
  mg/kg per day.
• Children with chronic kidney disease or Turner's
  syndrome are given slightly higher doses because
  they have a degree of growth hormone resistance.

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• Growth hormone encapsulated in biodegradable
  glycolide microspheres for deep subcutaneous
  administration.
• This formulation was approved by the United
  States Food and Drug Administration in January
  2000.
• In a study of 74 children with growth hormone
  deficiency, either 1.5 mg/kg body weight once a
  month or 0.75 mg/kg twice a month significantly
  increased linear growth compared with the
  pretreatment rate, but this formulation was not
  compared with a subcutaneous formulation .
• Local reactions at the injection site were
  common 60 percent of injections resulted in
  subcutaneous nodules and 36 percent in
  postinjection pain.
• This product has been removed from the market.

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• Synthetic growth hormone-releasing hormone
  (sermorelin, Geref) is an approved treatment for
  children whose pituitaries are capable of
  releasing growth hormone .
• It is about one-half as expensive as growth
  hormone but, in the recommended doses, may be
  somewhat less effective .
• This product has been removed from the market.

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• Several growth hormone-releasing peptides (GHRP)
  or nonpeptide analogs (some active orally) are
  being evaluated in growth hormone-deficient
  children and adults .
• It is too early to determine their long-term
  efficacy and safety.

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The End

• Thank for your attention.