S4: Principles of Growth

Question 1

What four periods can growth be divided into?

Answer 1

1. Intrauterine.
2. Infancy.
3. Childhood.
4. Adolescence.
   Each period as its own characteristic pattern and the mechanisms regulating growth. Growth at differences ages is largely determined by different things at each stage so this is why certain conditions may not be diagnosed until later on, when there is failure of the process to work and this is seen in the phenotype.

Question 2

Describe non pathological influences on growth

Answer 2

Growth and development are continuous, orderly, sequential processes influenced by maturational, environmental and genetic factors. There are many non-pathological factors that influence on growth, these include things like genetics, age, sex, nutrition, socioeconomic status and even things like the season and environmental influences. It isn’t all about endocrine hormones.

Question 3

Describe pattern of growth throughout life

Answer 3

• Growth is a longitudinal concept. Genes influence it at the beginning thus growth is an indicator of development and it involves increases in size and complexity. It also involves changes in body composition and function.
• Genetics and the intrauterine environment will largely determine the size at birth. In terms of intrauterine environment this is the placental function (the nutrient supply!), maternal size and length of gestation.
• After this for the first year of life, environment and nutrition take over as the main determinant of growth.
• Later on in childhood, thyroid and growth hormone will largely determine growth and problems here will be picked up e.g. GH deficiency.
• At puberty and onto adulthood, the sex steroids will shape secondary sexual characteristics and further growth.

Question 4

Describe prenatal growth

Answer 4

• Prenatal growth is the most rapid phase from zygote at fertilisation to birth.
• The first trimester includes rapid growth and differentiation of the organs with the formation of the embryonic disk. The ectoderm becomes the skin, hair, brain, nerves. The endoderm becomes the cardiac, skeletal, renal and bloods. The mesoderm becomes the lungs, gut, thyroid and pancreas.
• Second trimester is where cellular hypertrophy results in a peak foetal length velocity of 2.5 cm per week.
• Third trimester where maturation of organs and maximum weight gain occurs. There is build of subcutaneous fat near term.

Question 5

List extrinsic and intrinsic factors affecting prenatal growth

Answer 5

• Extrinsic factors play a more important part than intrinsic factors.
• Extrinsic factors include: placenta, blood flow and nutrition, maternal anatomy, size nutrition.
• Intrinsic factors: genes, hormone function.

Question 6

Describe the hormones affecting prenatal growth

Answer 6

• Growth hormone (GH): High during foetal life but secretion in utero is a limited influence.
• Insulin like growth factors I and II and IGF receptor: Predominant role in foetal growth and development. IGF-II is more abundantly expressed but IGF-I more closely correlated with foetal growth in a dose related manner, independently of GH.
• Thyroids: Absent thyroid hormone does not appear to affect foetal growth and normal prenatal growth in children born with thyroid agenesis or dysgenesis. Lack of thyroid hormone is more apparent in growth postnatally.
• Foetal glucocorticoid: Needed in tissue differentiation and prenatal development of the organs such as lungs, liver.

Question 7

Describe size at birth

Answer 7

• Birth size is dependent on the in-utero environment.
• Birth sizes: Average length is 48-51 cm and weight is 2.7-4.1 kg (37-41 weeks).
• Variations appropriate for gestational age are usually due to genetics. The terms for variations for size at birth are ‘small for gestational age’ and ‘large for gestational age’.
• Weak correlation between birth and adult size and not all genes expressed at birth.
• Male on average 150 g heavier, 0.9 cm longer and slightly greater lean mass. This may be due to increased testosterone production near term (‘mini adolescence’).

Question 8

Describe post natal growth and Karleberg’s ICP model

Answer 8

• Infancy, childhood and puberty (ICP model) breaks down child growth mathematically.
• The components of the human growth curve from birth to adulthood reflect the different hormonal phases of the growth process. The model provides an improved instrument for detecting and understanding growth failure, as if a child comes in we can look at Karlberg’s ICP and see at which hormonal phase the child is in and if they are lacking.
• Infant expansive growth: mainly nutritional.
• Childhood: Hormonal influence.
• Puberty: Sex steroid.
• Graph: Steep (infancy)–> steady (childhood + prepubertal) –> steep again at puberty.

Question 9

Describe height velocity throughout life

Answer 9

During childhood it plateaus after 1st year of birth. Girls reach their peak height velocity earlier than boys and growth plates fuse first. Boys have a higher peak growth and it is later on, this is why boys are taller than girls.

Question 10

Describe growth of infancy (birth to 1 year)

Answer 10

• Rapid growth 25 cm in first year and a 3 -fold weight gain.
• Marked deceleration of growth rate, height velocity (HV). 20 cm/year at birth and 10–12 cm/year at 12 months.
• Influence shifts from maternal to genetics and environmental (especially nutrition).
• The relative role of genes on size begins to reveal its influence. 2/3 infants demonstrate some shifts across their birth centiles in the first 18 months of life.

Question 11

Describe growth of childhood (1st year to puberty)

Answer 11

• Height velocity HV near constant 4-8 cm/y, mild deceleration towards puberty.
• Influence by hormones (GH, thyroid) > nutrition.
• Girls grows slightly faster than boys until 4 years then few differences in the height velocities between the sexes before puberty.
• Skeletal maturity slightly more advanced in girls than boys..
• Active change in body proportion: Babies have large head compared to body. Legs growing faster than the trunk and head. Upper to lower segment ratio: 1.7 at birth, 1.4 at 2 years, 1.0 by 10 years.

Question 12

Describe hormonal influence to the hypothalamic-pituitary axis on the growth plate

Answer 12

• Hypothalamus releases GnRH.
• Somatostatin regulates GH (-ve).
• GH can act directly on GH receptors at bone leading to skeletal growth (elongation of long bone) or bind to binding factor e.g.
  GHBP which stabilises GH and then acts on growth plate. So GH can either act directly on receptors or form different compounds that then act on receptors.

Question 13

What is canalisation?

Answer 13

• Canalisation is a concept that states that infants and children should stay within one or two growth centiles, any crossing of height centiles warrants further investigation.
• Crossing of centiles is a relatively normal event in child development, but in the clinical setting should be taken seriously.
• Some children may display catch up or catch down growth.

Question 14

Describe catch up growth

Answer 14

• Catch-up growth is where the child’s height velocity is above the limits of normal for his/her age and it has been like that for at least 1yr AND this abnormally high velocity has occurred after a period of transient growth inhibition. Thus catch up occurs after illness or under-nutrition.
• The catch-up growth can be complete i.e. child catches up to normal height for that age or incomplete i.e. target height not has not managed to be reached.
• Examples include the increased growth rate in an infant following IUGR is usually called catch-up growth or a child with hypothyroidism receiving thyroxine.
• Catch up growth typically occurs between birth and 6-18 months of age.

Question 15

Describe catch down growth

Answer 15

• Catch-down growth is seen in children who start of at a high growth percentile in early infancy. Then these children show a fall on their percentile growth chart (so drop down percentiles) and then remain on a lower percentile.
• Over further time, they match their genetic programming and then grow normally along this lower percentile according to their genetic potential. Thus they have normal physical, psychological and behavioural development.
• · Catch down growth starts at 3–6 months of age and is completed by 9–20 months old matching genetic programming.
• Examples include an infant of diabetic mother or an overfed infant.
• However a fall of more than 2 major percentiles warrants investigations as there may be an underlying pathology to blame.

Question 16

Describe growth during puberty

Answer 16

• Puberty is the transition from childhood to the achievement of adult stature through the development of secondary sexual characteristics.
• It is influenced by: genetics, nutrition, hormonal environment and socioeconomic factors.
• Hormone changes begins with the activation of the hypothalamic-pituitary-gonadal axis. There is an increase in sex hormone (oestrogen and androgens) and a huge increase in growth hormone.
• Growth pattern: A phase of acceleration, followed by a phase of deceleration, and the eventual cessation of growth with the closure of epiphyses.

Question 17

What is ‘mini puberty’?

Answer 17

High HPG axis at birth and switches off by 3 months. It turns back on during puberty.

Question 18

Describe physiology of HPG axis during foetal growth

Answer 18

GnRH neurones arise from the olfactory placode where they are developed and they migrate to the hypothalamus along the olfactory tract. This is why individuals with problems with gonadtrophin hormones may have changes in olfaction.
The migration of these GnRH neurones to the hypothalamus is under the control of the genes KAL and FGF8.

Question 19

Describe physiology of HPG axis during infancy and childhood

Answer 19

• Hypothalamic-pituitary-gonadal axis (HPG) “active” at birth.
• 3-6 month & rest of childhood.
• Quiescent from 3-6 months and very low gonadotrophin levels .

Question 20

Describe physiology of HPG axis during puberty

Answer 20

• Puberty - reactivation of HPG axis.
• Neurotransmitters [e.g. Kisspeptin (+), neurokinin B(+), MKRN3(-)] signalling on its receptors in hypothalamus. Under kisspeptin there is pulsatile release of GnRH from GnRH neurones in the hypothalamus into the median eminenence of the pituitary circulation. The GnRH binds to its receptor on gonadotrophs in the anterior pituitary that then release LH/FSH in response.
• Increase in amplitude of GnRH pulses (initially nocturnal, later day time as well). Pulses stronger and more frequent.
• Activate gonadotropic axis for FSH, LH synthesis.
• Feedback to hypothalamus to amplify GnRH release.

Question 21

Start, peak growth spurt and peak height velocity gender specific differnces

Answer 21

Females:
- Starts average 11y with breast development.
- Peak growth spurt: beginning to mid puberty.
- End point: menarche (growth slows down and stop within 12-18 months).
Male:
- Starts average 12-13 years with testicular enlargement >4ml.
- Growth spurt starts: mid/late puberty with 6-10 ml testes.
- Peak height velocity: 10-12 mls testes (average 14 years).
- Male average 12.5-14 cm taller than female due to additional 2 years pre-pubertal growth, greater growth spurt .

Question 22

Overview of skeletal growth

Answer 22

• Osteogenesis starts week 6-7 of life.
• 2 osteogenic pathways: intramembranous ossification (flat bones) and endochondral ossification (long bones).
• Bones grow in length at the epiphyseal plate under the influence of growth hormone with the addition of sex hormones at puberty.

Question 23

Describe skeletal growth and factors affecting it

Answer 23

• Skeletal growth is influenced by both environmental and genetic factors. Bone growth is also more complex than simply just increasing in length, there are different types of bone growth including subperiosteal apposition, endosteal resorption and remodelling.
• The periosteum is the outer membranous cover of long bones.
• Subperiosteal apposition is the process by which long bones add width on the outside by adding layers onto existing layers. In other words it is the process by which bones make themselves thicker.
• Endosteal resorption is the process by which bone is removed in central portion of the bone referred to as spongy bone. There is also remodelling of bone, this mostly occurs in spongy bone.
• Levels of growth hormone can affect skeletal growth (e.g. excess = acromegaly). Growth hormone increases the rate of mitosis of chondrocytes and osteoblasts and also increases the rate of protein synthesis (proteins such as collagen, cartilage matrix and enzymes required for cartilage and bone formation).
• The extent of calcium retention in the body and mineralisation of the bone will also determine skeletal growth. Parathyroid hormone increases the resorption of bone and thereby increases plasma levels of calcium. It also increases absorption of calcium by the small intestine and kidneys. Calcitonin (from C-cells of thyroid) decreases resorption of bone and therefore will decrease plasma calcium.
• Oestrogen/Testosterone promote closure of the epiphysis of long bones, thereby stopping growth. They also help retain calcium in bones and thus maintain a strong bone matrix.

Question 24

Describe Intramembranous Ossification (development of bone)

Answer 24

• Mesenchymal cells group into clusters, and ossification centers form.
• Secreted osteoid traps osteoblasts, which then become osteocytes.
• Trabecular matrix and periosteum form.
• Compact bone develops superficial to the trabecular bone, and crowded blood vessels condense into red marrow.

Question 25

Describe Endochondral Ossification (development of bone)

Answer 25

• Mesenchymal cells differentiate into chondrocytes.
• The cartilage model of the future bony skeleton and the perichondrium form.
• Capillaries penetrate cartilage. Perichondrium transforms into periosteum. Periosteal collar develops. Primary ossification center develops.
• Cartilage and chondrocytes continue to grow at ends of the bone.
• Secondary ossification centers develop.
• Cartilage remains at epiphyseal (growth) plate and at joint surface as articular cartilage.

Question 26

How do bones grow in length ?

Answer 26

Epiphyseal plate = area of growth, layer of hyaline cartilage where ossification occurs. The epiphyseal plate is composed of four zones of cells and activity.

• Long bones grow primarily by elongation of the diaphysis with an epiphysis at each end of the growing bone.
• The epiphyseal plate is the area of growth in a long bone. It is a layer of hyaline cartilage where ossification occurs in immature bones.
• On the epiphyseal side of the epiphyseal plate, cartilage is formed.
• On the diaphyseal side, cartilage is ossified and the diaphysis grows in length.
• At the cessation of growth, the epiphyses fuse to the diaphysis, thus obliterating the epiphyseal plate.

Question 27

Describe body composition during puberty (muscle + fat, gender differences)

Answer 27

Apart from skeletal growth, muscles and fat grows during puberty. Muscle mass is similar in boys and girls during puberty.

• Fat increases in females during puberty higher than males. Women have increased amounts of brown adipose tissue (BAT) and enlarged peripheral fat depots. With men, intra-abdominal fat depots preferentially increased. Therefore, women are pear shaped and men apple shaped .
• Sex differences in the metabolic and endocrine function of these depots are associated with diminished disease risk in women as people who lay down fat in abdomen at risk of CVS disease.

Question 28

Describe social influence on growth

Answer 28

• Growth patterns respond to environmental pressures: E.g. excessive training, anorexia, emotional deprivation (all these delay puberty). E.g. Too much nutrition (increase onset of puberty).
• The growth patterns of individuals respond to environmental pressures. If the environment supports the genetic template that regulates development the interaction will be a positive one and development will thrive. On the other hand environmental forces can prevent individuals from reaching their genetic template potential.
• Thus social/environmental influence is a systemic force that interferes/interacts with the achievement of human growth genetic potential.

Question 29

Describe the ‘developmental origins of adult disease’ hypothesis (‘barker hypothesis’)

Answer 29

Implications of Insults to Crucial Growth Periods to Adult Health. Patients who are small, if they have major catch-up growth increases risk of type II diabetes, CVD, hypertension.