Endocrine growth disorders, growth charts and pubertal staging

Overview

Growth is a sensitive marker of a child's health. Poor growth may be the first sign of hypothyroidism, GH deficiency, Turner syndrome, coeliac disease or emotional deprivation, while abnormal timing of puberty can point to tumours or genetic disorders. PGET questions focus on reading growth charts, calculating mid-parental height, using growth velocity and bone age, and knowing Tanner stages and the age limits for early and late puberty.

Normal growth

• Growth stops when sex steroids (mainly oestrogen, in both sexes) fuse the epiphyses.
• Thyroid hormone is essential for both growth and bone maturation; untreated hypothyroidism gives very delayed bone age.

Measuring and charting growth

• Length lying down under 2 years; standing height over 2 years, with a stadiometer, ideally by the same person at the same time of day.
• Plot on the correct chart for age and sex (WHO charts for under 5 years; national or WHO reference charts for older children). Also plot weight and head circumference, and note pubertal stage.
• Centile lines show how a child compares with others of the same age and sex. Most healthy children grow along a centile line.

Mid-parental (target) height

• Take the average of the two parents' heights, then add 7 cm for a son or take away 7 cm for a daughter.
• The expected adult range is about ±9 cm (two centile spaces) around this value.

Growth (height) velocity

• Height velocity (cm/year) from two measurements at least 4–6 months apart (ideally 12) is more useful than a single height.
• A short child growing at a normal rate is unlikely to have endocrine disease. A child crossing centiles downwards is.

When to investigate

• Height below the 0.4th centile (or well below the 2nd centile).
• Child's centile lies over three centile spaces under the centile predicted from the parents.
• Fall of more than two centile spaces, once measurement error is excluded.
• Low growth velocity (below about 4–5 cm/year before puberty) or signs of underlying disease.

Bone age

• X-ray of the left (non-dominant) hand and wrist, compared with standard atlases.
• Delayed bone age = more growth potential left: constitutional delay, GH deficiency, hypothyroidism (very delayed), chronic illness, malnutrition, Cushing syndrome.
• Bone age equal to chronological age: familial short stature, Turner syndrome (until puberty), skeletal dysplasia.
• Advanced bone age: precocious puberty, CAH, obesity, hyperthyroidism → tall now but may end up short.

Short stature

Usually defined as height below the 2nd (or 3rd) centile, or more than about 2 SD under the average for the child's age and sex.

Two normal variants (most short children)

Pathological causes

• Endocrine: GH deficiency, hypothyroidism, Cushing syndrome (including steroid treatment), poorly controlled diabetes, rickets, pseudohypoparathyroidism.
• Chromosomal and genetic: Turner syndrome (check karyotype in every short girl), Down, Noonan, Prader–Willi, Russell–Silver, SHOX deficiency.
• Chronic disease: coeliac disease, Crohn disease, chronic kidney disease and renal tubular acidosis, cyanotic heart disease, cystic fibrosis, severe asthma, thalassaemia.
• Nutritional: malnutrition (the commonest cause worldwide).
• Psychosocial deprivation: functional GH deficiency that reverses with a better environment.
• Small for gestational age without catch-up growth by about 2–4 years.
• Skeletal dysplasias (e.g. achondroplasia): disproportionate short stature (short limbs).

Growth hormone deficiency

• Congenital (pituitary gene defects, septo-optic dysplasia, midline defects) or acquired (craniopharyngioma, other tumours, cranial irradiation, head injury, infection).
• Neonate: hypoglycaemia, prolonged jaundice, micropenis (if gonadotrophins also low). Birth size is normal because fetal growth depends on insulin and IGF-2, not GH.
• Child: slow growth velocity (below about 5 cm/year), chubby (plump) build, immature "doll-like" face, high-pitched voice, delayed bone age, delayed puberty.
• Investigations: IGF-1 and IGFBP-3 (low; useful screen), GH stimulation tests (insulin tolerance, glucagon, arginine, clonidine; usually two failed tests are needed because false-positives are common; random GH is useless as it is pulsatile), other pituitary hormones, MRI of pituitary and brain.
• Treatment: recombinant human GH (somatropin) by nightly subcutaneous injection, adjusted to growth and IGF-1. A rise in velocity from below 5 to about 7–8 cm/year confirms true deficiency. Side effects: benign intracranial hypertension, slipped upper femoral epiphysis, scoliosis progression, glucose intolerance.

Other indications for growth hormone

• Turner syndrome and SHOX haploinsufficiency
• Chronic kidney disease (GH resistance)
• Prader–Willi syndrome
• Small for gestational age without catch-up growth
• Adults with severe GH deficiency and poor quality of life

Investigations for a short child (first line)

• FBC, ESR/CRP, urea, creatinine and electrolytes, liver tests, calcium, phosphate, ALP (rickets)
• TSH and FT4
• Coeliac serology (anti-tTG with total IgA)
• Karyotype in girls (Turner)
• Bone age
• IGF-1; GH stimulation tests and MRI only if velocity is low and no other cause is found
• Urinalysis (renal disease)

Tall stature

• Familial (tall parents): commonest.
• Constitutional advance, obesity.
• Early puberty / CAH (tall as a child, short as an adult because epiphyses fuse early).
• Hyperthyroidism.
• Genetic: Klinefelter (long legs), Marfan, homocystinuria, Sotos, Beckwith–Wiedemann.
• GH excess (pituitary gigantism): rare; IGF-1 high and GH not suppressed by glucose.

Normal puberty

• Kisspeptin triggers pulsatile GnRH; FSH rises first (initially in night-time pulses), then LH, then sex steroids. Adrenal androgens (adrenarche) rise separately and drive pubic and axillary hair.
• Girls: first sign breast budding (thelarche, Tanner B2), usually between 8 and 13 years; then pubic hair; growth spurt early (around B2–B3); menarche about 2–2.5 years after thelarche, around Tanner stage 4, after the peak growth spurt.
• Boys: first sign testicular enlargement to 4 mL (measured with a Prader orchidometer), usually between 9 and 14 years; then penile growth and pubic hair; growth spurt late (around G4); spermarche around stage 4; adult testes about 15–25 mL; voice breaks.

Tanner stages

Precocious puberty

Definition: signs of puberty before 8 years in girls and before 9 years in boys.

• Boys with central precocious puberty: always image the brain (MRI), because an underlying lesion is common. In girls it is usually idiopathic, though young girls are also imaged.
• Investigations: LH, FSH (basal and after GnRH), oestradiol or testosterone, 17-hydroxyprogesterone, DHEAS, hCG, TFTs, bone age (advanced), pelvic or testicular ultrasound, MRI.
• Treatment: central → long-acting GnRH analogue (continuous stimulation down-regulates the pituitary) to preserve adult height and delay menarche; peripheral → treat the cause (e.g. glucocorticoids for CAH, remove tumours), with aromatase inhibitors or antiandrogens where needed.

Benign variants (not true precocity)

• Premature thelarche: isolated breast development, usually at 1–4 years, no growth spurt, normal bone age; often regresses. Follow up.
• Premature adrenarche: early pubic or axillary hair and body odour (DHEAS mildly raised) after about 5 years, no breast or testicular change; commoner in obese children and girls; exclude non-classic CAH (17-hydroxyprogesterone).

Delayed puberty

Definition: no breast development by 13 years in girls, or testicular volume below 4 mL at 14 years in boys (or failure to progress / no menarche by about 15–16).

• Investigations: LH, FSH, testosterone or oestradiol, TFTs, prolactin, FBC, renal and liver tests, coeliac serology, karyotype (if gonadotrophins are high or the girl is short), bone age, smell test, MRI if gonadotrophins are low and constitutional delay is not clear. In primary amenorrhoea, check the uterus by ultrasound.
• Constitutional delay and permanent hypogonadotropic hypogonadism can be hard to separate early; time (or failure to progress) often decides.
• Treatment: constitutional delay → reassurance or short low-dose testosterone (boys) or oestrogen (girls); hypogonadism → gradual pubertal induction (testosterone in boys; low-dose oestrogen increased slowly in girls, adding a progestogen after breakthrough bleeding or about 2 years); treat the underlying disease.

Quick revision

• Mid-parental height = (father + mother) ÷ 2, ±7 cm (boy +, girl −); range about ±9 cm.
• Velocity matters most; prepubertal below about 4–5 cm/year is abnormal.
• Familial: short parents, normal bone age, normal puberty. Constitutional: late bloomer, delayed bone age, normal final height.
• Short + plump → endocrine (hypothyroid, GHD, Cushing); short + thin → nutrition or chronic disease; disproportionate → skeletal dysplasia.
• Karyotype every short girl (Turner).
• GHD: low IGF-1, two failed stimulation tests, MRI; nightly somatropin.
• Puberty: girls breast bud first (8–13); boys testes 4 mL first (9–14); girls spurt early, boys late; menarche at Tanner 4.
• Precocious: <8 girls, <9 boys; central (high LH/FSH, GnRH analogue, MRI in boys) vs peripheral (low LH/FSH; CAH, McCune–Albright).
• Delayed: none by 13 girls, 14 boys; high LH/FSH = Turner or Klinefelter.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pervez Akbar Khan's Basis of Paediatrics).

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