Endocrine Aspects of 11q: Is there a role for GH?
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Endocrine Aspects of 11q: Is there a role for GH?






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  • Short stature is not a disease, but it can make a person stand out. Even though short stature is a normal phenomenon among varied ethnic groups, to an affected individual, shortness can sometimes be an overwhelming handicap in everyday life. It can be a positive attribute for jockeys or gymnasts, but it can also have a significant negative effect on a patient’s well-being. Lifshitz F, Botero D. Worrisome growth. In: Lifshitz F, ed. Pediatric Endocrinology. 4th ed. New York: Marcel Dekker; 2003:1-35.
  • When interpreting growth chart data, assess the quality of the plot: Determine the methods used in height measurements Understand that the plot may be affected by the different techniques used by different staff members For very young children, make sure the appropriate chart is used for standing vs lying measurements Accuracy of the plot (yearly, birthday plot) Duration/completeness of the data Lipman TH, Hench KD, Benyi T, et al. A multicentre randomised controlled trial of an intervention to improve the accuracy of linear growth measurement . Arch Dis Child. 2004:89:342-346.
  • List 5 common errors in measuring: Doctor’s line of sight is not at eye level with the child Use of floppy arm devices Child’s back not against the board; body alignment incorrect Child’s hairpiece (caps, ponytail holders, etc.) not removed Child’s shoes and socks still on Care should be taken in teaching staff how to measure height. If the practitioner is following growth patterns, then any deviation showing poor growth should be double-checked.
  • This chart summarizes the normal, expected growth rates achieved during childhood. During the first year of life, growth is rapid, with most infants doubling their birth weight and adding as much as 26 cm in length. Thereafter, growth slows down. The typical child will increase in height by 10-13 cm during the second year of life and then slow to a rate of approximately 5-7 cm per year until puberty begins. During the pubertal growth spurt, these growth rates increase substantially. Growth is usually finished by the late teens. Adapted from: National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion. Clinical growth charts. Available at: www.cdc.gov/nchs/about/major/nhase/growthchart/clinical_charts.htm. Accessed August 24, 2004.
  • In many cases, a suspicion of GHD arises when children fail to grow at an age-appropriate pace. Standard height velocity charts exist for boys and for girls; these charts are constructed by measuring the height gained per year for many boys and girls at various ages and breaking the range of their growth rate into percentiles. The percentiles are represented by the curved lines. The mean height gained per year at any age is considered normal and marks the 50th percentile of height gained per year for age. On this slide, a girls’ height velocity chart is shown with solid lines (click for animation). At age 12.5 years, the average age of menarche, the girls’ growth spurt is on the wane. (Click for animation.) In contrast, the boys’ growth spurt is just beginning. Adapted from: National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion. Available at: www.cdc.gov/nchs/about/major/nhase/growthchart/clinical_charts.htm. Accessed August 24, 2004. Chart based on data from Tanner JM, Davies PS. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr. 1985;107:317-329 .
  • Genetic factors also can influence growth. Midparental height provides a good estimate of a child’s final height, as given by the formulas on this slide for boys and girls. Familial timing of puberty and growth can affect when a child enters this important developmental stage, which in turn influences his or her final height. Finally, different ethnic groups demonstrate wide variations in the average heights of their respective populations. Lifshitz F, Botero D. Worrisome growth. In: Lifshitz F, ed. Pediatric Endocrinology. 4th ed. New York: Marcel Dekker; 2003:1-35.
  • This slide shows a sample hand and wrist x-ray that is taken to determine bone age. The bones indicated in the white box are those used in the determination of bone age, including the phalanges, where the epiphysis can be seen.
  • The determination of bone age is important to assess the growth potential of a child. In addition, bone age can be informative of growth rate. Bone age is determined by x-ray of the hand and wrist. (Click for animation.) Shown within the yellow circles is the epiphyseal plate of a male subject at 8 and 14 years of age. At the younger age, the epiphysis has not closed, indicating further growth potential. By 14 years of age, the epiphyses have begun to close, signaling the impending completion of this boy’s growth.
  • For all children, growth is influenced by genetics, environment, nutrient intake, and economics.
  • Google family picture. Note the remarkable preservation of familial height.
  • For all children, growth is influenced by genetics, environment, nutrient intake, and economics.
  • For all children, growth is influenced by nutrient intake, genetics and environmental circumstances. For the child with special health care needs, other factors such as medication, medical condition, congenital abnormalities, and impaired motor skills may have an impact on growth
  • Remember that insulin is the most important factor in fetal growth. Thyroid hormone is important during infancy and childhood. GH doesn’t become important till childhood.
  • From 1995 to 2002, a lower percentage of GHD cases were classified as organic in nature, as compared to the period between 1986 and 1994. However, of the organic cases reported from the later period, far more were of other/unknown origin, compared to the earlier period. Accordingly, fewer cases of organic GHD due to CNS irradiation, other CNS tumor, or craniopharyngioma were reported in the later period. Levy RA, Connelly K. Diagnostic growth hormone deficiency testing practices among patients in the NCGS/NCSS databases. J Pediatr Endocrinol Metab . 2003;16(suppl 3):619-624.

Endocrine Aspects of 11q: Is there a role for GH? Endocrine Aspects of 11q: Is there a role for GH? Presentation Transcript

  • Endocrine Aspects of 11q Is there a role for GH? …no issue Thomas G. Kelly, MD, FAAP Pediatric Endocrinology UC San Diego / Rady Children’s Hospital San Diego small
  • Short Stature Can Be a Stigma
  • Goals
    • Review the process of growth
    • Promote an understanding of factors that are critical to this process.
    • Discuss examples of growth failure and discuss how they are treated.
    • Discuss 11q syndrome and what is known about growth and growth hormone.
  • Overview
    • Introduction with Basic Growth Vocabulary
    • How Do We Grow?
    • What can go wrong?
    • How do we fix it?
  • Understanding Your Child’s Growth What you need to know
    • Height and Height %
      • - an assessment of stature and its comparison to the general population
    • Growth Velocity
      • - an assessment of the rate of growth
    • Mid parental height
      • - a calculation of predicted height based on parental heights
    • Bone age
      • - An assessment of the degree of growth plate closure
  • Assessing Stature
    • Current Height
    • Growth Velocity
    • Predicted Height
  • Height
    • Evaluation of height must be done in the context of normal standards
    • Charts compare child’s height with the 3rd-97th% of normal American kids
    • Plotting height and weight provides a useful and objective assessment of the adequacy of growth.
    • SDS score (Ht-mean HT/SD) describes the location of those whose Ht is >97th +2SD and<3rd % (-2SD).
    OK135S057 
  • What creates error in measurement
  • Good Technique = Good Data
      • Method of measurement
      • Staff with different techniques
      • Standing vs lying
      • The “birthday plot”
  • Incorrect Height Measuring Techniques
    • Line of sight not at eye level
    • Using floppy arm device
    • Child’s back not against board
    • Child’s hairpiece not removed
    • Child’s socks still on
  • Scoliosis
  • Rickets
  • Height Velocity
    • Invaluable in assessing a child with growth abnormalities.
    • Kids grow with remarkable fidelity relative to the growth curves from 2yrs to puberty.
    • Any crossing of Ht %’s is a concern.
    • Velocity should be calculated over at least a 6 month period.
      
  • What’s normal ?
  • Normal Growth Rates During Childhood National Center for Health Statistics Age Growth (cm/year) Birth to 1 year 17 – 26 1 to 2 years 10 –13 2 years to puberty 5 –7 Puberty Girls 7 –12 Boys 8 –13
  • Normal Growth Rates During Childhood National Center for Health Statistics. Tanner JM, et al. J Pediatr. 1985. Girls: solid lines Boys: dashed lines Girls’ peak growth rate: 11.5 years Boys’ peak growth rate: 13.5 years Boys: dashed lines Boys’ peak growth rate: 13.5 years Growth rate (cm/y) Age (y) 2 19 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 0 13 12 11 10 9 8 7 6 5 4 3 2 1
  • How tall will I be when I grow up?
  • Height Prediction
    • Midparental height
      • Boys: [(M+F) + 5 inches]/2
      • Girls: [(M+F) – 5 inches]/2
    • Bone Age
  • Mid-Parental Height- An Assessment of Genetic Potential
    • The “mid-parental height” or MPH is a calculation based on parental heights of the expected final height of the child.
    • A useful tool in the assessment of whether a child’s current height percentile is appropriate.
    • MPH is adjusted ± 5 inches to account for the difference between the male and female heights on the growth curve . .
  • Examples of Mid-Parental Height
    • Dad = 66”;
    • Mom = 61”
    • MPH for a girl =
    • Dad’s ht -5 or 66-5= 61”
    • +
    • Mom’s ht = 61
    • Divided by 2
    • (61+61)/2 = 61”
    • MPH for a boy =
      • Dad’s Ht + Mom’s Ht +5
      • 2
    66” 61” 61”
  • A bone age demonstrates growth potential Phalanges (Finger Bones) Epiphysis (Growth Plate) Metacarpal (Hand Bones) Carpal (Wrist Bones) Epiphysis (Growth Plate)
  • Male, 8 years Male, 14 years
  • BA MPH
  • Factors Affecting Growth Growth Environmental Influences Economic Factors Genes Nutrition Biological Factors
  • Genes
    • Although length and weight at birth depend on the intrauterine environment the final height achieved by a child is largely dependent on their genetic endowment.
    • Height is highly heritable!
    • Although this achievable height is limited by genetic factors …
    • up to this limit height potential depends on environmental factors
  • Environment
    • Normal interaction between infants and children and their environment is necessary for normal growth and development.
    • Syndrome of growth failure and weight loss is long recognized in infants separated from their mothers or socially isolated, subject to cruelty, neglect, or institutional upbringing.
  • Economics
    • Socioeconomic Deprivation -Poverty leads to Stunting from:
      • Poor nutrition
      • Increased susceptibility to infections
      • Limited access to health care
      • Recurrent and/or chronic infections
  • Nutrition
    • Adequate Nutrition is essential for good linear growth.
    • Growth Failure may be the direct result of inadequate protein or other essential nutrients.
    • Alternatively, biologic influences such as disturbances of bowel endocrine, or metabolic function may play a role
  • Examples of Feeding Problems that can lead to impaired Nutrition
    • Problems with gastroesophageal reflux (GER) can contribute to problems with feeding. Many children with neurodevelopmental problems have GER
    • Tactile sensitivity or sensory defensiveness, common among children with cerebral palsy, autism, and spina bifida may cause a child to avoid putting things in his/her mouth.
    • Children with feeding problems as a result of behavioral or emotional issues. Or, the result of complex perinatal medical interventions that center around feeding or around the mouth, making subsequent oral experiences, including feeding, unpleasant.
    • Low Birth Weight
    • Intrauterine Growth Retardation (IUGR) is a fetus with an estimated weight < 10th % for gestational age.
    • Small for gestational age (SGA) is an infant with a birthweight <10th%.
    • Depending on the timing, duration and severity of the insult, and success of postnatal intervention, the growth potential of IUGR/SGA children may be permanently adversely affected.
    • IUGR leading to SGA is an approved indication for Growth Hormone if growth deficit is not overcome in the first 3 yrs of life.
    Nutritional/Biologic Factors and Growth
  • Generalizations About Growth
    • Despite all the factors mentioned
      • Genes
      • Environment
      • Nutrition
      • Economics
    • Children normally grow at a remarkably predictable rate.
    • The sequence of growth is usually uncomplicated and orderly, but variations exist and individual growth patterns may be confused with problems of hormonal regulation
  • Normal Growth Patterns associated with Short Stature
    • Two Common Conditions
    • Genetic Short Stature
    • Late Bloomer (Constitutional Delay)
  • Familial Short Stature
    • Diagnosis
      • Growth chart pattern
      • Family history (with accurate family heights)
      • Normal bone age
      • Normal growth velocity
  • Constitutional Delay
    • Late Bloomers
    • Generally refers to a delay in growth as well as pubertal development
    • More common in boys
    • Possibly related to nutrition
  • The Late Bloomer (AKA Constitutional Delay)
    • Not associated with growth failure
    • Adolescents channeled to a curve that may be short for the population and/or family
    • Family history of late puberty with catch-up growth at puberty
  • Pubertal Delay
    • Growth Velocity: prepubertal
    • BA<CA
    • May intervene to initiate puberty
  • What Can Go Wrong? Growth Environmental stressors Economic Stressors Genetic/Chromosomal Abnormalities Malnutrition And Disease
  • Genetic and Chromosomal Abnormalities
    • A genetic disorder is any disorder caused by faults in inherited genetic material within a persons cells.
    • In these conditions there is the potential for altered growth because the affected metabolic pathways disturb energy production and/or the building of body tissue.
      • Examples: Genetic abnormalities of bone, cartilage
  • Genetic and Chromosomal Abnormalities
    • A Chromosomal Abnormality is any change in the normal structure or number of chromosomes.
    • It can be associated with growth patterns that differ from those of children without chromosomal abnormalities.
    • It is assumed that these differing growth patterns represent altered growth potential related to the underlying chromosomal abnormality.
      • Turner’s Syndrome missing an X chromosome or parts of an X.
      • Down’s Syndrome has an extra chromosome.
  • What Can We Do?
    • Evaluate For :
    • Conditions that alter growth
      • Known or suspected Chromosomal disorders.
      • History of IUGR/SGA
      • Genetic Syndrome
    • Conditions that have the potential to alter growth.
    • Metabolic Disorders Renal
    • Endocrine Disorders Cardiac
    • Gastrointestinal Infectious
    • Hematologic Psychosocial
    • Immune Pulmonary
  • Endocrine Causes of Short Stature
    • Low Thyroid Function
        • Decreased appetite
        • Constipation
        • Lethargy
        • Dry skin and hair
    • Growth Hormone Deficiency
        • Decreased lean body mass, increased fat mass
        • Decreased bone mineral content
  • Endocrine Causes of Short Stature
  • Growth Hormone Deficiency
    • Prevalence is 1/4000-1/80000
    • Diagnosis is suspected by poor growth, history of brain irradiation or trauma
    • Since growth hormone secretion is pulsatile so random growth hormone measures are useless.
    • IGF-1 and IGFBP-3 are surrogate markers of GH sufficiency
    • Note that IGF-1 is significantly affected by nutritional status .
  • GH Testing
    • GH deficiency is confirmed using stimulatory tests
      • Arginine, clonidine, L Dopa and insulin
      • Some agents (arginine and clonidine) may act as GHRH agonists in the pituitary
    • Stimulatory tests are not perfect:
      • May miss partially deficient patients
  • Etiologies of Pediatric GHD Levy RA, et al. J Pediatr Endocrinol Metab . 2003. * Percentage of organic GHD cases Early NCGS Pediatric Registry (1986-1994) Later NCGS Pediatric Registry (1995-2002) N % N % Idiopathic GHD 10,106 72.8 9190 81.7 Organic GHD 3767 27.2 2059 18.3 Other/unknown 996 26.4* 955 46.4* CNS irradiation 884 23.5* 317 15.4* Other CNS tumor 799 21.2* 308 15.0* Craniopharyngioma 600 15.9* 214 10.4* Septo-optic dysplasia 413 11.0* 248 12.0* Trauma 75 2.0* 17 0.8*
  • Pediatric Indications For Growth Hormone
    • The FDA has approved GH for the following pediatric conditions associated with short stature:
      • GH deficiency (defined as on the basis of the provocative tests)
      • Turner Syndrome
      • Chronic renal insufficiency
      • SGA or IUGR infants that fail to demonstrate catch-up growth
      • Prader-Willi Syndrome
      • Idiopathic short stature (<2.5 SD below the mean and not expected to meet a normal adult height)
  • Cancer and GH Therapy
    • No definitive link between GH therapy and an increased incidence of leukemia.
    • Currently GH therapy is not recommended in patients with an active malignant condition.
  • Endocrine Abnormalities in 11q- Syndrome
    • 9 children with Jacobsen (11q-) were studied in San Diego with the following findings:
    • 8/9 had short stature (ht<5th%)
        • Six with >-2SD
        • One had IUGR
        • Four had low IGF-1 levels
    • 4/9 males had cryptorchidism (failure of testes to descend).
  • Endocrine Abnormalities in 11q- Syndrome
    • Case Reports suggest an association of 11q deletions or translocations with short stature.
    • 6 publications with 5 single case reports plus the small series from San Diego of 8 affected patients
    • One publication of central GH and TH deficiencies.
    • Studies suggest that genetic information encoded in 11q is important for normal growth.
    • Insufficient data is available to suggest a mechanism for growth failure in these children.
  • Take-away Messages
    • Growth Velocity correlates with good health
    • Abnormal growth velocity merits evaluation
    • A good history and exam are often diagnostic
    • Laboratory and Imaging studies may be helpful
    • Timing is everything
  • Resources For Patients & Families
    • MAGIC Foundation: www.magicfoundation.org
    • Human Growth Foundation:
    • www.hgfound.org