Mednotes

L3 RDA Growth

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tagsrda, lecture
aliasesL3 RDA Growth

16 min read

Overview

Growth is a defining aspect of childhood, has a wide range of “normal”, and is complex, with both endocrine and non-endocrine drivers. The lecture works from the physiology (the determinants that feed into genetic potential, the growth hormone axis and the growth plate) through the four phases of growth, then to how growth is measured and plotted, and finally to the clinical assessment of short stature, illustrated with a case series and a detailed look at achondroplasia and its emerging therapies.

Determinants of normal growth

  • Growth is a defining aspect of “childhood”, has a wide range of “normal”, is complex, and is both endocrine and non-endocrine.
  • Six determinants converge on genetic potential as the combined determinant of growth: food; psychosocial factors; major systems; perinatal factors; classical hormones (endocrine); growth factors (endocrine, paracrine and autocrine).
  • Underlying endocrinology of growth requires:
    • Normal homeostasis: no hypoxia, no acidosis, no chronic infection or inflammation.
    • A normal endocrine milieu, especially thyroid function, calcium metabolism, cortisol (iatrogenic or endogenous), and sex hormones.
    • Adequate intake of calories, protein, micronutrients and vitamins.

Growth hormone axis

Regulation pathway, in order:

  1. Inputs act on the hypothalamus: nutritional state (hypoglycaemia) and free fatty acids; sleep, exercise and psychological stress; and provocation tests (GHRH, insulin, clonidine, arginine).
  2. Hypothalamic neurosecretory cells (5HT, noradrenaline, dopamine) release somatostatin (inhibitory) and GHRH (stimulatory).
  3. These travel via the portal circulation to the anterior pituitary somatotrophs.
  4. Somatotrophs secrete GH.
  5. GH acts on liver and other tissues to produce somatomedins.
  6. Somatomedins act on chondrocytes (cartilage cells).
  7. GH and somatomedins exert feedback inhibition back on the hypothalamus and pituitary.

Growth hormone itself:

  • A protein from the anterior pituitary.
  • Released in pulses, normally 2 to 4 times per 24 hours.
  • The largest burst is almost always associated with the first episode of stage IV sleep at night. An overnight profile shows a large GH peak (roughly 35 to 40 mU/l) shortly after sleep onset around 2200h, coincident with the first stage IV episode, plus two to three smaller peaks later in the night.
  • Has direct effects on cells, and also acts through stimulating IGF-1 production both locally (autocrine) and from the liver.

IGF-1 and binding proteins:

  • Mediates the anabolic and mitogenic actions of GH.
  • Produced in the liver.
  • Used as a screening test for GH deficiency: stable with minimal variation, but a wide range of normal, influenced by age, puberty and nutrition.
  • Carried in the circulation by at least 5 binding proteins, including IGF-BP3.
  • GH insensitivity produces a severe degree of short stature: Laron syndrome, an autosomal recessive GH receptor mutation, giving a low IGF-1.

Warning

On the GH pathway slide the neurotransmitter key (5-hydroxytryptamine, noradrenaline, dopamine) was faint and only partly confirmable, and a following slide of two extended-family group photographs carried no caption, so its exact teaching point is not stated (it sits after the Laron syndrome content and may be a family case of short stature).

The growth plate

Regions of a long bone end, top to bottom: epiphysis, physis (growth plate), metaphysis, diaphysis.

  • Epiphysis region structures: joint capsule, synovium, lumen, cartilage, bone, epiphyseal vessels.
  • Cells of the physis, in sequence: resting, dividing, proliferating, dying.
  • Metaphysis and diaphysis region: bone formation, nutrient vessels, periosteal vessels.
  • Zonal architecture on histology, top to bottom: resting zone, proliferating zone, hypertrophic zone, ossification zone, trabecular bone.

Phases of growth

The four phases are foetal (intrauterine), infancy, childhood and puberty.

Intrauterine

  • Intrinsic plus extrinsic factors.
  • Extrinsic: maternal size and the placenta.
  • Intrinsic: growth factors and others (possibly leptin).
  • IUGR has lasting consequences.

Infancy

  • Very rapid, with fluctuation.
  • Driven by nutrition, environment and genetics; endocrine factors are less important than at older ages.

Childhood (>2 to 3 years)

  • Growth is more stable, about 5 to 6 cm/year.
  • Deviations from the trend are a concern.
  • Drivers: endocrine (growth hormone dependent), health, and nutrition.

Puberty

  • Accounts for 15% of final adult height.
  • Depends on health and hormones: GH, androgens, oestrogen.
  • Growth velocity peaks then slows (De Montbeillard’s son, 1759 to 1777, shows the velocity peak around age 14).
  • Growth plate fusion around 16 to 18 years in males and around 15 years in females.

Reference lengths and velocities

AgeLength or heightGrowth velocity
Birth50 cm25 cm/year
1 year75 cm10 cm/year
4 years100 cm5 cm/year
8 years125 cm5 cm/year
12 years150 cm

Measurement of growth

  • In utero, growth is best measured by ultrasound.
  • Weight at all ages.
  • In the first 3 years: length (on a measuring table, not standing height) and head circumference. Length rather than height is used for the first 2 to 3 years.
  • Height by standard procedure: head positioned with the outer canthi of the eyes and the ear canal in the horizontal plane, and the child stretched, to get a precision of SD ± 2 mm.

Plotting on a growth chart:

  • A single measure is not as useful as longitudinal measures.
  • Parental heights should be plotted, adjusting approximately 12 cm for the opposite sexed parent.
  • Bone age should be plotted, attached with a dotted line to the chronological age.
  • All children with a chronic illness need a growth chart plotted.
  • Charts carry centile curves expressed as SD bands: 3SD (99.9th), 2SD (97th), 1SD (85th), 0SD (50th), −1SD (15th), −2SD (3rd), −3SD (0.1st). Plotting “actual” points against a “target” point shows whether the trajectory is falling short of genetic height potential.
  • Chart formulae given: centile , where LMS are the parameters published by CDC and is the standard deviation equivalent to the centile required. Body surface area (Mosteller 1987).
  • BMI on the CDC chart: weight (kg) ÷ stature (cm) ÷ stature (cm) × 10,000, or weight (lb) ÷ stature (in) ÷ stature (in) × 703.
  • Puberty is plotted alongside height on Tanner-stage charts for penis stage, pubic hair stage and testes volume (12 mL, 4 mL) against age.
  • Bone age is read from hand and wrist X-rays, which show progressive skeletal maturation through childhood into adolescence (examples at 3y, 4.5y, 13y and 15y).

Short stature

Important

Short stature by itself is not necessarily abnormal: about 3% of the population is normally below the 3rd centile. Conversely, severe growth failure can occur even when height is on the 50th centile. It is the SPEED or TEMPO of growth that is important.

  • Genetic, racial and temporal effects are potentially important, so using the appropriate growth chart matters.
  • Under 3 years this is often called “failure to thrive”.

Causes:

  • Disproportionate: usually caused by skeletal dysplasia.
  • Proportionate: prenatal; emotional deprivation; malnutrition; genetic (familial, chromosomal abnormalities); skeletal (for example rickets); hormonal (GH deficiency, hypothyroidism, Cushing’s syndrome, pubertal delay).

Clinical assessment

History

  • Onset, judged from shoes, clothes, peers and siblings.
  • Other symptoms, with specific inquiry about diet, malabsorption, snoring, headaches, and other endocrine symptoms.
  • Drug exposure, especially steroids.
  • Past history: antenatal, birth weight and early feeding, chronic illness, development.
  • Family history: genetic defects are found in 5 to 30% of GH deficient children, including GHRH receptor and GH-1 gene mutations and abnormal pituitary development (PROP1 and PIT1 genes).
  • Social history: impact, for example teasing; are they worried?; emotional deprivation.

Examination

  • Observation: well or unwell; growth (absolute and proportions); nutrition; dysmorphic signs of face, hands and skin.
  • General systems examination including BP, optic fundi and visual fields.
  • Search for a chronic illness.

Investigations to consider (based on history and examination)

  • FBC/ESR (anaemia, macrocytosis, chronic inflammation).
  • U&Es (renal function).
  • Ca, PO4 and alkaline phosphatase (rickets).
  • Coeliac screening.
  • Thyroid.
  • Bone age.
  • Karyotype or CGH (microarray), especially in girls.
  • Next tier others, for example IGF-1.

Case series

The cases are presented as a photograph plus the same differential checklist each time: skeletal dysplasia? GH deficiency? rickets? hypothyroidism? coeliac disease? PWS? Turner syndrome? (the final adult case adds GH excess?). No answers are given on the slides themselves.

  • A boy with a markedly distended abdomen and thin limbs, a malnutrition or malabsorption appearance.
  • A girl with the same appearance, whose chart is titled “Coeliac disease”: her height tracked below the 3rd centile until a gluten-free diet was started, after which growth accelerated and caught up toward and above the 50th centile, with breast stage 2 and menarche annotated against the curve. Her SD-band chart shows actual points below the −1SD to −2SD band through childhood, converging closer to average by the early teens, with the target well above the plotted trajectory.
  • A boy of thin build measured against a gridded backdrop, whose charts show actual points in the lower percentile bands (roughly 130 to 145 cm between ages 12 and 17) with a target point marked well above.
  • A case of bowed limbs: an infant with enlarged wrist and limb joints, a pelvis and femur X-ray with bowing of the long bones and irregular growth plate margins, and a toddler with visibly bowed legs and a distended abdomen.
  • A stocky, short toddler.
  • An adult male shown front and side against a gridded backdrop.

Warning

Several case slides carry no stated diagnosis, so none is inferred here: the bowed-limb case, an isolated knee X-ray showing irregular, widened and frayed metaphyseal margins with no caption, and a photograph of a very short, elderly-looking person by a height ruler which is unusual for a paediatric case series and may be an adult case or an adult outcome. Handwritten annotations on two of the case charts (“MPH”, and further cursive text near “OH”) are only partly legible.

Achondroplasia

  • The most common short limb skeletal dysplasia, with rhizomelic (proximal) shortening.
  • Affects approximately 250,000 people worldwide, about 1 in 25,000 births.
  • Inheritance: autosomal dominant mutations in the FGFR3 gene, with resultant negative impacts on the growth plate.
  • Complications: short stature; AOM, hyperlordosis and back pain, OSA; spinal and foramen magnum stenosis, hydrocephalus.
  • Growth: the achondroplasia population mean reaches about 130 cm by age 18, well below the normal curves, which reach about 185 cm at the 97th centile by age 18 (chart of male achondroplasia height, n = 189).

FGFR3 mechanism:

  1. Normal signalling through FGFR3 limits chondrocyte proliferation and differentiation within the growth plates.
  2. The pathogenic mutation is a glycine to arginine substitution at nucleotide 1138, in the transmembrane domain.
  3. This is a gain-of-function mutation.
  4. Prolonged FGFR3 signalling inhibits bone growth.

Emerging therapies for achondroplasia

Novel therapies on the horizon:

  • CNP agonist therapy: subcutaneous short acting, and subcutaneous long acting (weekly).
  • Soluble FGFR3 decoy.
  • Tyrosine kinase inhibitors, re-purposed from use in various leukaemias and possibly breast cancer.

Vosoritide, a short acting subcutaneous prodrug of CNP:

  • A CNP analogue, working as a CNP growth agonist pathway against the FGFR3 antagonist pathway.
  • Shown to rescue dwarfism in “achondroplasia” mice; phase 3 trial completed in 5 to 17 year olds.
  • Pathway: FGF binds FGFR3, signalling via Ras to Raf-1 to MEK-1/2 to ERK, and via MEK-3/6 to p38, with a branch to STAT1 and other pathways. CNP binds NPR-B, generating cGMP, activating PKD II, which inhibits Raf-1, so CNP inhibits MAPK signalling. Both arms converge on the nucleus to drive mitosis, terminal differentiation and matrix synthesis.
  • Trial result: baseline annualised growth velocity was similar in both arms (median about 4 cm/year; placebo n = 61, 15 μg/kg vosoritide n = 60). At week 52 the placebo group remained around 4 cm/year while the vosoritide group shifted higher, to roughly 5.6 to 6 cm/year.

Key points

  • Growth is a core aspect of childhood.
  • It must always be part of the clinical examination.
  • All children need a growth chart plotted to monitor health, especially those with a chronic illness.
  • Short stature in and of itself is not abnormal: growth velocity, the tempo of growth, is the key.

Self-test

  1. List the six determinants that converge on genetic potential as drivers of growth.
  2. Describe the steps of growth hormone regulation from hypothalamic input through to action on cartilage, including the feedback loop.
  3. State the three general requirements the underlying endocrinology of growth depends on, naming the endocrine axes that matter most.
  4. Describe the pulsatility of GH release and its relationship to sleep.
  5. Explain why IGF-1 is useful as a screening test for GH deficiency, and what limits its interpretation.
  6. Predict the biochemical picture and the phenotype in an autosomal recessive GH receptor mutation, and name the condition.
  7. Name the four regions of the end of a long bone from the joint inward, and list the cells of the physis in sequence.
  8. List the four phases of growth and give the main driver or defining feature of each.
  9. State the approximate height and growth velocity at birth, 1 year and 4 years.
  10. What proportion of final adult height is gained during puberty, and at what ages does growth plate fusion occur in males and females?
  11. Explain why length rather than height is measured in the first 2 to 3 years, and describe the standard positioning and precision for measuring standing height.
  12. List the four rules for plotting a growth chart given in the lecture.
  13. Explain why a child on the 50th centile can still have severe growth failure, and why a child below the 3rd centile may be entirely normal.
  14. Distinguish disproportionate from proportionate short stature and list the categories of proportionate causes.
  15. List the investigations to consider in a child with short stature, with what each is looking for.
  16. A girl has tracked below the 3rd centile for years with thin limbs and a distended abdomen. Which screening test on the investigation list would you prioritise, and what would you expect to see on her growth chart after treatment?
  17. Describe the effect of the FGFR3 mutation in achondroplasia on the growth plate, stating the type of mutation and its molecular nature.
  18. Explain how vosoritide counteracts the FGFR3 defect, and give the effect seen on annualised growth velocity at 52 weeks.
  19. Integrative: a 12 year old with coeliac disease and a chronic inflammatory burden is short. Using the determinants of growth and the assessment framework, explain the several separate ways his growth could be impaired and what single measurement over time would matter most.

Answers

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