Short stature and growth hormone disorders

• Short stature means a child's height is more than 2 standard deviations below the mean for age, sex, and population, roughly the 3rd percentile, though some texts use the 2.3rd percentile.^[1]
• Most short children are healthy: the commonest explanations are familial short stature and constitutional delay of growth and puberty, both benign variants.^[1][2]
• The single most useful question is not "how short is this child?" but "how fast is this child growing?", because a falling growth velocity is the earliest sign of a pathological cause.^[1][7]
• Red flags (disproportion, severe shortness, crossing percentiles, abnormal development, midline defects, systemic symptoms) point to skeletal, genetic, endocrine or chronic-disease causes and should be investigated rather than observed.^[1][8]
• Bone age (a left hand and wrist X-ray) is the test that best separates constitutional delay (delayed bone age) from familial short stature (bone age about equal to chronological age).^[5]
• Treat the cause: thyroid hormone for hypothyroidism, disease control for chronic illness, and recombinant growth hormone for confirmed growth hormone deficiency and for Turner syndrome, given early and monitored to bone age 14 years.^[4][8]

By the end of this page you should be able to:

1. Define short stature and distinguish normal growth variants from pathological causes.
2. Take an accurate auxological history and examination and identify red flags.
3. Choose first-line investigations, including screening labs and bone age.
4. Explain why bone age is interpreted differently in familial short stature, constitutional delay, hypothyroidism and growth hormone deficiency.
5. Outline the treatment of growth hormone deficiency in childhood, including dose, route, monitoring and stopping criteria.
6. Describe the growth hormone (and pubertal induction) plan used in Turner syndrome.
7. Know when to refer a short child to paediatric endocrinology.

Short stature is one of the commonest reasons for referral to a paediatric endocrinology clinic, accounting for up to half of new visits.^[1] It is a presentation, not a diagnosis: the child is small, and the task is to decide whether this is a healthy variant or the first sign of a disorder that can be treated. The aim of evaluation is therefore not to make a child taller by any means, but to find the children who have something that treatment can help, and to avoid over-treating the many who do not.^[1]

Growth is remarkably regular in healthy children, and it is governed by genetics, nutrition, hormones (growth hormone, thyroid hormone, insulin-like growth factor 1 and sex steroids) and by the health of the major organs. A useful way to organise the problem is to follow the standard teaching sequence: what short stature is, what the normal pattern of growth is, which conditions disturb it, how the child presents, what the examination shows, how to investigate, and what to do.

Endocrine causes of short stature include growth hormone deficiency, hypothyroidism, Cushing syndrome, premature or delayed puberty, and pseudohypoparathyroidism. They are only a minority of cases, but they are the most treatable, so they must not be missed.^[1][8]

Short stature is defined as a height more than 2 standard deviations below the mean for age, sex and population, which usually corresponds to about the 2.3rd percentile; many clinicians and many growth charts use the 3rd percentile as a practical cut-off.^[1] A more severe degree, below 3 standard deviations, is more likely to have an identifiable pathological cause.^[1]

Two things matter as much as the height itself.

1. Growth velocity. A single height measurement only says the child is short. A series of measurements says whether the child is slowing down. A normal child follows a percentile; a child whose percentile is falling is the child who needs investigation.^[1][7]
2. Proportion. Are the limbs and spine in normal proportion? Disproportion (short trunk, short limbs, or a raised sitting-height-to-standing-height ratio) points to skeletal dysplasia or rickets; proportionate short stature narrows the differential to endocrine, chronic, or normal-variant causes.

Common classification terms used in practice:

• Familial short stature (genetic short stature). A healthy child with short parents, a normal growth velocity, and bone age roughly equal to chronological age.^[2][5]
• Constitutional delay of growth and puberty. A healthy child with delayed growth and delayed puberty, a delayed bone age (by at least 2 standard deviations), and a family history of late puberty. Ultimate height is usually within the parental range.^[2][5]
• Idiopathic short stature. Short stature not explained by a recognised condition, after adequate evaluation; GH stimulation tests are normal.^[6]
• Pathological short stature. Caused by systemic illness, endocrine disease, skeletal dysplasia, or a genetic syndrome.

Children may have both familial short stature and constitutional delay, so the labels are not mutually exclusive.^[2]

Target height (mid-parental height) is estimated from the parents' heights and is usually quoted as a range, to allow for genetic scatter. Bone age can then be combined with the current height in methods such as Bayley-Pinneau or Tanner-Whitehouse to predict adult height, although these predictions have wide individual variation and should be presented cautiously to families.^[5]

The causes are grouped below by system. Normal variants are the most common, and a careful history and examination will usually point towards them. Where a specific cause is named, it is because a specific treatment exists.

Familial short stature and constitutional delay of growth and puberty are by far the most common benign causes.^[1][2] Familial short stature reflects the child's genetic height potential: growth runs along a low but stable percentile, development is on time, and bone age is close to chronological age.^[2][5] Constitutional delay presents with a child who is short for age, slim, appears younger than their years, and enters puberty late, with a family history of "late bloomers." Bone age is delayed by at least 2 standard deviations, and height age is close to bone age.^[2][5]

These are the causes a generalist must recognise, because each has a treatment.^[1][8]

• Growth hormone deficiency. Inadequate secretion of growth hormone from the pituitary (about 1 in 2,000 to 1 in 10,000 children).^[7] May be congenital (isolated or part of multiple pituitary hormone deficiency, sometimes with midline defects or neonatal hypoglycaemia) or acquired (craniopharyngioma, trauma, infection, irradiation, or idiopathic). Presents with slow growth, often disproportionate to weight (the child looks plump), delayed bone age, and low serum insulin-like growth factor 1.^[1][7]
• Hypothyroidism. Underactive thyroid function slows height growth; the child is short, lethargic, cold intolerant, constipated, with dry skin and hair and sometimes a goitre. Newborn screening catches congenital cases, but acquired cases present later. Thyroid hormone replacement restores growth.^[1][8]
• Cushing syndrome and chronic glucocorticoid exposure. Excess cortisol (endogenous or from inhaled or oral steroids) impairs growth.^[1]
• Precocious puberty. Early sex steroid exposure accelerates growth but advances bone age, so final height is reduced.^[1]
• Pseudohypoparathyroidism. Resistance to parathyroid hormone with short stature among other features.^[1]

Growth is a sensitive indicator of overall health. Almost any chronic illness can slow growth before other symptoms become obvious. Common examples are coeliac disease, inflammatory bowel disease, chronic kidney disease, congenital heart disease, anaemia, chronic infection (including tuberculosis and HIV), and poor nutrition or malabsorption.^[1][8] Children with these conditions often show weight failure before height failure.

These children are usually disproportionate, with a short trunk or short limbs, sometimes with additional physical features or a skeletal radiographic pattern.^[1][5]

• Turner syndrome. A sex-chromosome disorder in phenotypic females with one intact X chromosome and partial or complete absence of the second; prevalence is about 50 per 100,000 females. Short stature is present in most, with growth failure beginning before birth and accelerating in the first years of life.^[3][4]
• Other genetic associations. Down syndrome, Noonan syndrome, Silver-Russell syndrome, Prader-Willi syndrome and SHOX gene deficiency (short stature homeobox-containing gene), among others.^[1][5]
• Achondroplasia and other chondrodysplasias (rhizomelic or mesomelic shortening).
• Bone age is delayed in Turner syndrome, in many genetic syndromes, and in chronic disease.^[5]

Infants born below the 10th percentile for gestational age often catch up in the first two years. A subset does not, and remains short; this group is considered for evaluation and for growth hormone treatment.^[1]

Prolonged high-dose steroids, chemotherapy, and radiation (especially cranial irradiation) can cause growth failure. Psychosocial deprivation can produce a reversible growth failure known as psychosocial short stature.^[1]

Red flags are the features that move a child from "observe and re-measure" to "investigate now".^[1][8]

• Severe short stature (below 3 standard deviations, or far below the family range).
• Falling growth velocity, especially crossing two or more percentile spaces on the growth chart.
• Disproportion of limbs or spine, or abnormal body proportions.
• Dysmorphic features or obvious physical stigmata of a syndrome.
• Midline defects (cleft lip or palate, single central incisor, optic nerve hypoplasia, micropenis, neonatal hypoglycaemia) suggesting hypothalamic-pituitary problems.
• Pubertal delay or disorder (markedly early or late puberty for age).
• Neurological symptoms (headaches, visual disturbance) suggesting an intracranial lesion.
• Systemic symptoms (chronic diarrhoea, abdominal pain, poor weight gain, excessive thirst or polyuria, fatigue, cold intolerance).
• A height clearly below mid-parental target without a family explanation.

Urgent referral is needed for neonatal or infantile hypoglycaemia with growth failure, for rapidly progressive headaches or visual loss, and for any child below 2 standard deviations whose growth has clearly slowed.

A good history already narrows the list before any test is ordered.

• Pregnancy and birth (gestation, birth weight, placental function), because intrauterine growth restriction can set lifelong growth patterns.
• Growth trajectory (previous clinic or school measurements, growth-chart position), which separates a stable small child from a child who is slowing.
• Nutrition (intake, absorption, bowel habit, chronic vomiting or diarrhoea).
• Systemic symptoms suggesting chronic illness (fatigue, infection frequency, respiratory symptoms, polyuria or polydipsia).
• Development and puberty (milestones, pubertal onset, family timing of puberty).
• Family heights and pubertal timing for both parents and siblings; a family of short late bloomers usually explains the picture.
• Medication history including inhaled or oral steroids, and any chemotherapy or radiotherapy.
• Past medical history (renal, cardiac, hepatic, endocrine or genetic disease).
• Education, social context and psychological wellbeing, because deprivation and distress both affect growth and because being short has psychosocial effects.

Examination is both diagnostic and reassuring for families.

• Auxology. Measure height with a wall-mounted stadiometer, weight, and head circumference in young children. Plot all values on an appropriate growth chart and record growth velocity measured on more than one occasion where possible.
• Body proportions. Arm span and sitting height; calculate the sitting-height-to-standing-height ratio. Short limbs suggests skeletal dysplasia; short trunk suggests rickets or vertebral problems.
• Pubertal stage (Tanner staging) and testicular volume in boys, because pubertal status changes interpretation.
• Dysmorphism and stigmata (neck webbing, low-set ears, cubitus valgus, widely spaced nipples, congenital lymphoedema in girls with Turner syndrome; characteristic facies in Noonan or Down syndrome).
• Organ-specific signs (goitre, jaundice, hepatosplenomegaly, cardiac murmur, clubbing).
• Neurological and visual fields if intracranial disease is suspected.
• Midline and genital examination (micropenis, cryptorchidism, single central incisor).

A child with abnormal proportions, dysmorphism, or neurological signs should not be managed with observation alone.

Short stature never occurs in isolation from the rest of development, so growth is always interpreted against the child's stage.

• Toddlers and school-aged children. Growth should be checked against head circumference (which is affected early by undernutrition and thyroid disease), motor milestones and learning. Global developmental delay with short stature points towards a syndromic, metabolic or chronic disease cause rather than a simple growth variant.
• Puberty is the second major growth window. A child who is short but still prepubertal may have constitutional delay or growth hormone deficiency; a child who is losing height percentile after pubertal onset may be losing growth potential because sex steroids advance bone age.
• Delayed puberty with delayed bone age (constitutional delay) usually corrects with time. Delayed puberty with a bone age that is not delayed suggests organic disease (for example inflammatory bowel disease, anorexia or excessive exercise).
• Precocious puberty produces early tallness followed by early epiphyseal closure and a short adult height; small testicular volumes or absent pubertal signs at an inappropriate age redirect the investigation.
• Nutrition and chronic disease affect weight before height. When weight falls first, think intake, absorption, chronic infection or renal disease. When height falls but weight is preserved, think growth hormone deficiency or early puberty-related loss.
• Neurodevelopment in Turner syndrome is typically near normal, but early diagnosis in girls with short stature and pubertal delay allows both growth treatment and planned pubertal induction.

Investigation should be directed by the history and examination, but a basic panel is used widely and is inexpensive.^[8]

First-line screening includes:

• full blood count (anaemia, chronic disease);
• kidney function and urinalysis;
• liver function tests and ESR or CRP;
• coeliac screening (tissue transglutaminase antibody with total IgA);
• thyroid function tests (TSH and free T4);
• fasting glucose if polyuria or polydipsia is present.

Growth hormone markers may be useful but are not diagnostic alone: a low serum IGF-1 for age and sex (often with low IGFBP-3) supports growth hormone deficiency, while a normal IGF-1 does not exclude it, and IGF-1 is also low in malnutrition and chronic disease.^[1][7]

Bone age. A left hand and wrist X-ray, usually compared with the Greulich-Pyle or Tanner-Whitehouse atlas (automated methods such as BoneXpert are increasingly used), is the single most informative test in the assessment of short stature.^[5] Its interpretation follows the diagnosis:

• Familial short stature. Bone age is close to chronological age.^[5]
• Constitutional delay. Bone age is delayed by at least 2 standard deviations (often 1 to 2 years or more), with height age close to bone age.^[5]
• Growth hormone deficiency. Bone age is delayed, often markedly.^[5]
• Hypothyroidism. Severe or congenital hypothyroidism causes growth arrest with delayed bone age, irregular ossification centres and a sclerotic metaphyseal band; acquired hypothyroidism delays fusion of secondary ossification centres.^[5]
• Precocious puberty and hyperthyroidism advance bone age.^[5]
• Turner syndrome. Bone age is delayed.^[5]

Therefore, "bone age" is not a number to be memorised; it is a biological clock. A hand X-ray tells you how much growth time the child still has.

Specific tests for the suspected cause.

• Growth hormone stimulation testing. Growth hormone is secreted in pulses, so random levels are unhelpful. Provocative tests (for example clonidine, arginine or glucagon; insulin tolerance in selected cases) are used when auxology and IGF-1 suggest deficiency. Two separate stimulation tests are standard in most systems.^[6][7] Reported cut-offs cluster around 10 ng per mL, but the thresholds vary (commonly 5 to 10 ng per mL) and should be adjusted to the assay used; newer monoclonal assays report lower values than older polyclonal ones, and equivocal results need cautious interpretation.^[6]
• Magnetic resonance imaging of the hypothalamic-pituitary region when growth hormone deficiency is proven, especially with red flags, multiple hormone deficiency, or congenital forms.^[6]
• Karyotype in all girls with unexplained short stature or with features of Turner syndrome. The Endocrine Society advises chromosome assessment in girls with short stature; a minimum of 30 metaphases is advised and a 45,X line or mosaicism confirms Turner syndrome.^[4][8]
• Cortisol and sex steroid studies as indicated (for example in Cushing syndrome or suspected multiple pituitary hormone deficiency).
• Other imaging or endoscopy directed by symptoms (coeliac biopsy, renal ultrasound, cardiac echocardiography).

In newborns, random growth hormone concentrations and very low (or absent) IGF-1 may support severe congenital growth hormone deficiency, but these are specialist assessments.^[6][7]

Management is directed at the cause. The principles apply across settings.

Normal variants. Reassurance, clear explanation to the family, and confirmation with growth monitoring on more than one visit. For constitutional delay with severe distress in adolescence, a short course of low-dose sex steroid (testosterone in boys, oestrogen in girls) can be used to induce puberty and a growth spurt; this is specialist-directed and is not given if bone age is too young. In clinical surveys, puberty induction for hypogonadotropic hypogonadism is begun at 13 to 14 years (bone age 12 to 13 years) in boys and 12 to 13 years (bone age 11 to 12 years) in girls in some centres, but timing is always individualised.^[6] For familial short stature, growth hormone is not offered routinely, because gain is modest; it is considered only when short stature is extreme, and even then families should understand the modest benefit and the years of injections.^[2][6]

Hypothyroidism. Levothyroxine replacement, dosed and monitored by TSH and free T4, restores growth velocity. Treat early, because prolonged hypothyroidism erodes final height.^[8]

Chronic disease. Treat the underlying condition (for example gluten-free diet for coeliac disease, disease-modifying treatment for inflammatory bowel disease, transplant or dialysis planning in chronic kidney disease, nutritional rehabilitation). Growth often improves once the disease is controlled.^[1][8]

Growth hormone deficiency in childhood. Recombinant human growth hormone is given by daily subcutaneous injection in the evening.^[6] Many consensus surveys report starting doses of 0.025 to 0.035 mg per kg per day in prepubertal children, with somewhat higher doses in puberty, adjusted to growth velocity and IGF-1.^[6] Daily subcutaneous evening injection is universal practice.^[6] In specialist practice the dose is titrated to weight or body surface area and to keep IGF-1 in the normal range for age and pubertal stage.^[6] Monitoring includes height and growth velocity every 3 to 6 months, bone age (about yearly), IGF-1, fasting glucose, and thyroid function, with fundoscopic review before starting and when indicated.^[6] Therapy is stopped when growth velocity falls below about 2 cm per year and bone age is above 16 years in boys or 14 years in girls, or when target height is reached.^[6] Congenital deficiency needs formal re-evaluation in the transition period, because some children diagnosed in childhood do not remain deficient as adults.^[7]

For adult growth hormone deficiency (childhood-onset or newly acquired in adults), evaluation and replacement are specialist matters; adult doses start low and are titrated to normal IGF-1, with attention to glucose tolerance, lipids and quality of life.^[7]

Turner syndrome. Growth hormone is an approved and effective treatment for short stature in Turner syndrome, and should be offered early because growth failure begins before birth and is rapid in the first years of life.^[4] The 2024 international Turner Syndrome consensus recommends:

• offer growth hormone from as young as 2 years if there is evidence of growth failure, short stature, or likelihood of short stature, and later whenever epiphyses remain open; ^[4]
• starting dose 45 to 50 micrograms per kg per day (1.3 to 1.5 mg per square metre per day), increasing up to a maximum of 68 micrograms per kg per day (2.0 mg per square metre per day) if the response is suboptimal; ^[4]
• continue treatment until little growth potential remains (bone age at least 14 years and/or height velocity below 2 cm per year); ^[4]
• monitor height at least every 6 months and IGF-1 at least annually, keeping IGF-1 in the normal range for age and pubertal stage; ^[4]
• screen for hypothyroidism (TSH every 1 to 2 years from age 2 years, and with new symptoms) and manage with thyroid hormone when needed.^[4]

Puberty induction in Turner syndrome follows bone age and FSH levels: low-dose oestrogen is started at 11 to 12 years if FSH is raised in two tests, and increased slowly over 2 to 4 years, with cyclic progesterone 200 mg for 10 to 12 days a month once breakthrough bleeding occurs.^[4] Patients need lifelong multidisciplinary follow-up, particularly of the cardiovascular system and of autoimmune thyroid disease.^[4]

Idiopathic short stature (height below minus 2.25 standard deviations, no definable cause, normal GH testing) remains the only licensed non-replacement indication for growth hormone in some health systems; benefit is modest and individual, and decisions should be taken with families on the evidence, including the uncertain psychosocial benefit of being slightly taller.^[6]

Psychosocial support. Treat counselling, particularly for children whose distress about height is severe, as part of management rather than as an extra.^[1][8]

Refer (or discuss) with paediatric endocrinology when:

• height is below minus 2 standard deviations, or severe shortness relative to the family;
• growth velocity is clearly below normal or falling;
• there are red flags (disproportion, dysmorphism, neurological or systemic symptoms);
• growth hormone deficiency, Turner syndrome or other endocrine, genetic or skeletal cause is suspected;
• hypothyroidism is central (pituitary) rather than primary, or is not controlled on standard doses;
• the child is a newborn or infant with growth failure or hypoglycaemia;
• growth hormone treatment is being considered, since prescribing, monitoring and transition to adult care are specialist functions.

• Adolescents and transition. Childhood-onset growth hormone deficiency must be re-tested (usually with an insulin tolerance test with an adult cut-off) before committing to lifelong adult replacement; many children, especially after cranial irradiation, will have outgrown their childhood diagnosis. Administer puberty at the appropriate time so that final height is not sacrificed to normal pubertal timing.^[6][7]
• Pregnancy in Turner syndrome requires a planned, multidisciplinary assessment, because pregnancy carries cardiovascular and obstetric risk and should be avoided with severe aortic dilatation.^[4]
• Low-resource settings. Accurate measurement (a stadiometer, a tape on the wall, the same observer) and a growth chart are free and are the most important intervention. Identify red flags; treat coeliac disease, chronic infection, kidney disease, and hypothyroidism with locally available therapy; do chromosome testing for short girls; growth hormone is expensive and often unavailable, so ensure the (often larger) benefit of treating the underlying cause is not missed.^[8]
• Adults with lifelong short stature. Care focuses on the underlying cause, metabolic health, joint and spine protection, self-esteem and social inclusion, rather than on height gain.

• Short stature is a height more than 2 standard deviations below the mean (about the 3rd percentile).^[1]
• Most short children are healthy; familial short stature and constitutional delay of growth and puberty are the commonest explanations.^[1][2]
• Growth velocity is a better clue than a single height: a falling percentile suggests pathology.^[1][7]
• Red flags are severe shortness, disproportion, dysmorphism, crossing percentiles, systemic or neurological symptoms, and midline defects.^[1]
• Bone age is delayed in constitutional delay, growth hormone deficiency, hypothyroidism and Turner syndrome, but about equal to age in familial short stature.^[5]
• First-line screening (full blood count, kidney and liver function, coeliac screen, TSH and free T4, IGF-1) is cheap and directs further testing.^[8]
• Karyotype all unexplained short girls for Turner syndrome (prevalence about 50 per 100,000 females).^[3][4]
• Growth hormone deficiency is treated with daily subcutaneous recombinant growth hormone, starting at 0.025 to 0.035 mg per kg per day, monitored every 3 to 6 months, and stopped when growth velocity is below 2 cm per year and bone age above 16 years in boys or 14 years in girls.^[6]
• Growth hormone for Turner syndrome should be started as early as possible, at 45 to 50 micrograms per kg per day up to 68 micrograms per kg per day, continuing to bone age 14 years or height velocity below 2 cm per year.^[4]
• Hypothyroidism responds to thyroid hormone replacement, restoring growth velocity.^[8]
• Treatment of the underlying chronic disease often restores growth more than hormone therapy would.^[1][8]

Delayed puberty; hypothyroidism in children; hypopituitarism and multiple pituitary hormone deficiency; Turner syndrome; sickle cell disease is not relevant; chronic kidney disease; coeliac disease; infantile hypotonia; developmental and growth monitoring; childhood bone tumours.

DONE