How to define short stature

A child with height two standard deviations below the mean (−2SD or 3rd percentile) as compared to children of the same age, gender, and race is considered to have short stature.

Physiology

Human growth is influenced by environmental, genetic and hormonal factors. Epidemiological studies have shown that non-pathological factors such as nutrition, psychological influences, physical activity and climate play important roles on growth. 

Human linear growth starts from fertilisation and progresses through prenatal, infantile, childhood and adolescent phases to be completed by fusion of the epiphyseal growth plates. 

The determinants of fetal growth include maternal nutritional status, placental sufficiency, placental insulin-like growth factor 1(IGF1) and fetal insulin. In addition, various growth factors like epidermal growth factor, fibroblast growth factor, nerve growth factor, and parathyroid hormone-related peptide (PTHrP) also play an important role in fetal growth. GH has minimum effect on intrauterine growth.

Postnatal growth is determined by nutritional factors, hormones, and the genetic potential of an individual. During infancy, growth is predominantly influenced by the nutritional status of the child. During the prepubertal period, hormones like GH–IGF1, thyroxine, and insulin play an important role, while pubertal growth spurt is caused by a progressive increase in gonadal steroids and the consequent GH–IGF1 surge. However, the final height of an individual is determined by his/her genetic potential. This is possibly attributed to predetermined chondrocyte potential for skeletal growth, IGF1 sensitivity, rate of ossification maturation, and ethnicity of an individual.

The secretion and action of growth hormone can be disrupted by mutations in genes affecting the synthesis of growth hormone itself, its binding proteins and receptors or the production of pituitary transcription factors. Other hormones, eg, thyroid hormone, adrenal androgens, sex steroids, glucocorticoids, ghrelin, leptin and insulin also interact with the growth hormone-insulin-like growth factor-1 axis. 

Normal growth pattern during childhood

Age	Height velocity (per year)
Birth	50cm
0–1 year	25 cm
1–2 years	12.5 cm
2–3yearsr	8 cm
3 years – puberty	5 cm
Puberty           Boys           Girls	9.5cm 8.5 cm

Classification of short stature

Primary: Intrinsic to the growth plate 

Syndromes 

• Turner syndrome
• Cornelia de Lange syndrome
• DiGeorge syndrome (velocardiofacial syndrome)
• Down syndrome
• Noonan syndrome
• Prader-Willi-Labhart syndrome
• Von Recklinghausen’s disease (neurofibromatosis type 1)
• Silver-Russell syndrome

Skeletal dysplasia

• Achondroplasia
• Hypochondroplasia
• Dyschondrosteosis (Leri-Weill and other defects in the

SHOX gene)

• Osteogenesis imperfecta I—VI
• Mucopolysaccharidosis (type IH, IS, Il—VII)

SGA / IUGR

Secondary: Extrinsic to the growth plate 

Nutritional insufficiency 

Chronic illness

Endocrine disorders

• Growth hormone deficiency
• Hypothyroidism
• Cushing syndrome
• Pseudohypoparathyroidism
• Short adult stature caused by accelerated bone maturation, e.g. precocious puberty, hyperthyroidism, congenital adrenal hyperplasia, exogenous estrogens or androgens

• Other disorders of the growth hormone-IGF axis (primary IGF-I deficiency and resistance)

• Bio inactive growth hormone
• Abnormalities of the growth hormone receptor (growth hormone insensitivity syndrome, Laron syndrome), Abnormalities of GH signal transduction, e.g. STAT5B defect
• ALS (acid-labile subunit) deficiency
• IGF-I deficiency
• IGF resistance (IGFIR defects, post-receptor defects)

Metabolic disorders

Disorders of calcium and phosphorus metabolism

Disorders of carbohydrate metabolism

Disorders of lipid metabolism

Disorders of protein metabolism

Psychosocial

Emotional deprivation

Anorexia nervosa

Depression

Iatrogenic

Systemic glucocorticoid therapy

Local glucocorticoid therapy (inhalation, intestinal, other) Other medication

Treatment of childhood malignancy

Total body irradiation

Chemotherapy

Familial

Familial (idiopathic) short stature

Constitutional delay of growth and puberty

Idiopathic short stature

     Non-familial (idiopathic) short stature

Clinical assessment

Early assessment of short stature is important to establish a diagnosis. The assessment involves history, examination (careful phenotyping), pubertal staging and accurate auxology. Parents’ heights should be recorded.

History 

Birth History

• Birth length, weight, head circumference, gestational age
• Special features regarding pregnancy (intrauterine growth retardation, drug intoxications, infections) and birth (breech delivery, asphyxia)
• Neonatal hypoglycemia and jaundice
• Consanguinity 

Feeding problems in the first year 

Nutrition (if nutrition is poor, weight is usually affected more than height)

Hypotonia

Previous growth data

Developmental milestones / intellectual retardation

Systems enquiry 

Chronic illness

Previous diseases and operations, medication

(e.g. corticosteroids)

Recurrent infections 

Age at start of pubertal signs (girls: breast development, boys’ testicular enlargement)

Parental height (preferably measured, rather than reported)

Family history of short stature / other disorders

Maternal lifestyle / Ethnic background

puberty of the mother and father

Social environment and psychosocial functioning

Examination

Height 

Weight 

Head circumference 

Disproportion (sitting height) 

Asymmetry 

Examination of all the systems to look for evidence of chronic disease (eg Blood pressure, clubbing, etc)

Dysmorphic features 

Frontal bossing, mid-facial hypoplasia

Thyroid size

Muscular hypertrophy

Hepatomegaly, splenomegaly

Pubertal staging 

Micropenis / Cryptorchidism

Signs of neglect or abuse

Investigations

Primary

Full blood count (FBC) with Hb

Renal function (creatinine and electrolytes)

Liver function test

ESR 

Calcium, Phosphate, (Ca / PO4) Alkaline Phosphatase 

Bone age 

Free thyroxine (fT4), thyroid-stimulating hormone (TSH) 

Tissue transglutaminase (TTG), Immunoglobulin A (IgA) 

Karyotype should be done in all girls with unexplained short stature and/or delayed puberty

Secondary

Primary investigations are followed by secondary investigations, which will be decided by a Paediatric endocrinologist based on age, history and physical examination. 

Insulin-Like Growth Factor- 1 (IGF-I)

8 am cortisol

GH Stimulation test: Since GHD is a rare cause of short stature, evaluation of GH–IGF1 axis is recommended only after careful exclusion of common causes of growth failure, including chronic systemic diseases, hypothyroidism, rickets, Turner’s syndrome, pseudohypoparathyroidism, and skeletal dysplasias.

IGF-BP3

IGF-1 generation test

LH, FSH

Testosterone / estradiol

Prolactin

USS abdomen if suspect, Turner syndrome

Skeletal X-rays (if disproportion is present) for Skeletal dysplasia

MRI brain/pituitary: All patients with documented GHD should be subjected to MR imaging of the Sellar region to exclude the possibility of Sellar–suprasellar mass lesions, structural defects of the pituitary gland and stalk or midline defects.

Genetic testing

Management

Depending on the condition, various treatments are available. For chronic illnesses treatment of the underlying disorder alone may often result in the improvement in growth.

Treatment with GH should always be initiated and monitored by a paediatric endocrinologist. All children and adolescents fulfilling the licensed indications will be offered treatment with rhGH according to the recent NICE guidelines. Growth hormone dose, duration, and follow-up investigations should be decided by a paediatric endocrinologist according to the clinical condition and response to treatment.

Referral to Paediatric Endocrinologist in children with short stature 

Children with height below the 3^rd centile or Height >3SD below the mean for age and gender 

Projected height more than 2.0 SDS below the mid-parental height centile.

Growth velocity < 4 cm per year or growth curve crosses downward by ≥1 centile curve in the growth chart over a period of 12 months

Children with IUGR who do not catch up to the growth curve by 4 years of age.

Bone age is more than two standard deviations below chronological age.

Girls with no signs of puberty (>Tanner stage 2 breast development) by age 13 and boys with no signs of puberty (>Genitalia Tanner stage 2 or testicular volumes >4 ml) by age 14

Diagnosis of conditions approved for recombinant growth hormone therapy.

Children with a suspected genetic origin of short stature

Diagnostic workup of a short child

References

1. https://www.bsped.org. uk/media/oolhsxet/clinical-standards-for-growth-assessment-and referral-criteria-for-children-with-a-suspected-growth-disorder.pdf

2. Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 1. Short stature. Horm Res 2007;68(supp 2):1-5

3. Oostdijk w, Grote FK, de Muinck Keizer-Schrama SM, Wit JM. Diagnostic approach in children with short stature. Horm Res. 2009;72(4):206-17.

4. Collett-Solberg PF, Jorge AA, Boguszewski MC, Miller BS, Choong CS, Cohen P, et al. Growth hormone therapy in children: research and practice – A review. Growth Horm IGF Res. 2019 Feb;44:20–32.

5. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. The Journal of clinical endocrinology and metabolism. 2008,93(11):4210-7.

Dr. U.A.M. Dimarsha De Silva, Consultant Paediatric Endocrinologist, National Hospital, Galle.

Reviewed by Dr Navoda Atapattu