Aetiology
Causes of short stature include those that are due to normal variation, responsible for the majority of cases, and those due to disease pathology. Short stature may sometimes also be multifactorial (e.g., a patient with poor nutritional status may also have a modest target height, in addition to elements of constitutional delay in growth and development; patients with growth hormone [GH] deficiency have an increased risk of having coeliac disease and inflammatory bowel disease).
Normal variant
Familial short stature (genetic short stature):
Patients are born adequate size for gestational age.
Decrease in growth velocity between 6 and 18 months, followed by steady growth below the 5th percentile until reaching a final height that is appropriate for their target height.
Puberty and bone age are not delayed, and patients are proportionate.
Constitutional delay of growth and development (CDGD):[12]
Also known as constitutional delay of growth and adolescence (CDGA).
Growth deceleration during the first 2 years followed by a normal growth velocity, with acceleration late in adolescence, leading to a final height that is close to the target height.
More frequent in boys; pubertal development in either parent may have been later than average.
Patients have a delayed bone age and delayed pubertal development.
A diagnosis of exclusion; other conditions such as GH deficiency, chronic illness, and hypogonadism need to be ruled out. Growth pattern, physical examination, delayed bone age, and normal baseline laboratory evaluation can help in the differential diagnosis.
Idiopathic condition
Idiopathic short stature (ISS):
Defined as short stature with no organic cause
Applied to healthy children with a height more than two standard deviations below the mean for age and sex (includes some patients with familial short stature and CDGD)
In the US, treatment with GH for selected groups of patients without a documented GH deficiency may be recommended.
Small for gestational age without catch-up:
Endocrine cause
GH is a polypeptide hormone secreted by the anterior pituitary in a pulsatile action. The pulses occur during sleep, exercise, and physiological stress. Its release is regulated by hypothalamic peptides (GH-releasing hormone and somatostatin).
The pituitary gland develops as a result of sequential gene expression and transcription factor interaction. Several of the genes involved in this process have been identified and their function defined. About 12% of patients with congenital hypopituitarism have an identifiable gene defect.
Congenital GH deficiency may be associated with midline abnormalities such as a cleft lip and palate, midfacial hypoplasia, single central incisor. Growth deceleration typically occurs after the age of 2 years.
Acquired GH deficiency may occur after central nervous system (CNS) tumours (e.g., craniopharyngioma), infiltrative disorders, or radiation that involves the hypothalamo-pituitary region.
GH deficiency may be accompanied by other pituitary hormone deficiencies.
Hypothyroidism:
Most thyroid disorders occur more frequently in girls.
May be congenital or acquired.
Cushing syndrome:
Could be a result of a pituitary or adrenal cause of excess corticosteroids, or may be iatrogenic because of exogenous corticosteroids (e.g., children on high-dose corticosteroid treatment for asthma or inflammatory disorders).
GH insensitivity (Laron syndrome):
GH exerts most of its growth-promoting effects by binding to the GH receptor and stimulating the secretion of insulin-like growth factor 1 (IGF-1) from the liver. IGF-1 circulates in the blood bound to IGF-binding proteins (most importantly IGFBP-3), whose secretion from the liver is also under GH control. IGF-1 has both endocrine and paracrine effects.
Insensitivity or resistance to GH results in IGF-1 deficiency and short stature. Levels of IGF-1 and IGFBP-3 normally fluctuate during childhood, peaking around the time of the adolescent growth spurt.[8]
Craniopharyngioma:
Rare, suprasellar, cystic tumour that develops from the nests of epithelium derived from Rathke's pouch, an embryonic precursor of the anterior pituitary.
Presents with headaches, diplopia, raised intracranial pressure, and pituitary dysfunction.
Endocrine dysfunction is variable but typically includes multiple pituitary hormone deficiencies and may present pre- or postoperatively. Treatment includes surgery with or without radiotherapy.
Genetic syndrome
Turner syndrome:
Chromosomal abnormality 45 XO, 46/45 XX/XO, partial X chromosome deletion or circular X chromosome
Dysmorphic features include ovarian dysgenesis, hearing loss, aortic valve, and/or renal abnormalities, and delayed or arrested puberty.
Noonan syndrome:
Short stature with dysmorphic features, congenital heart defects (e.g., pulmonary valve stenosis), learning problems.
Russell-Silver syndrome:
Children born small for gestational age with dysmorphism (triangular face, clinodactyly, asymmetry)
Feeding problems, hypoglycaemia.
Trisomy 21:
Chromosomal abnormality
Dysmorphic features include hypotonia, congenital cardiac and/or gastrointestinal defects, and delayed development.
Prader-Willi syndrome:
Chromosome 15 abnormality; example of genetic imprinting
Characterised by marked hyperphagia, obesity, and learning difficulties.
DiGeorge syndrome:
Chromosome 22 abnormality, also called velocardiofacial syndrome
Associated with cardiac defects, cleft palate, immune deficiency, hypocalcaemia, and learning difficulties.
Chronic illness
Any chronic medical condition can lead to short stature, with or without poor weight gain and faltering growth. The relatively common conditions include:[9][16]
Chronic heart disease (congenital or acquired)
Asthma (moderate or severe)
Cystic fibrosis
Coeliac disease
Inflammatory bowel disease (Crohn's disease and ulcerative colitis)
Juvenile idiopathic arthritis
Chronic kidney failure
Renal tubular acidosis
Any chronic malignancy
Poorly controlled diabetes mellitus.
Musculoskeletal cause
Skeletal dysplasias:[17][18]
Include achondroplasia, hypochondroplasia, and osteogenesis imperfecta
Disproportionate short stature; dysmorphic features may be present.
Rickets:[19]
Severe rickets results in short stature that may be disproportionate.
Spinal disorders:[20][21][22]
Irradiation to the spine
Spinal surgery
Congenital spinal deformities (e.g., hemivertebrae).
Psychosocial cause
Psychosocial deprivation:
Includes child abuse, neglect, starvation, and institutionalisation
Short stature can be a result of psychological and nutritional factors
May lead to faltering growth and short stature even with adequate nutritional intake. A minority develop a clinical picture similar to GH deficiency. Typically resume normal growth once removed from an adverse home environment.
Eating disorders:
Anorexia nervosa
Bulimia nervosa.
Fetal alcohol syndrome:[23]
Fetal abnormalities in children of women with history of excessive consumption of alcohol during pregnancy
Results in a birth size that is small for gestational age, CNS and craniofacial abnormalities, and learning difficulties.
Iatrogenic
Patients with ADHD may have a slowing of growth and/or weight gain after beginning treatment with stimulants. Controversial; effect sizes are small with likely minimal clinical impact.[24][25][26]
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