Short stature

# Overview
Short stature is defined as a height more than 2 standard deviations below the mean for chronological age and sex. It corresponds to a linear height of less than the 3rd percentile. The most common causes of short stature are normal variants of growth like familial short stature and constitutional delay of growth and puberty.

# Historical Perspective
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# Classification
There is no established system for the classification of short stature.
Based on the etiology, short stature may be classified into normal variants of growth or systemic pathological causes. 
Normal variants of growth include- 
- Familial short stature
- Constitutional delay of growth and puberty
- Small for gestational age with catch-up growth
- Idiopathic short stature
For more information about the pathological etiology, refer to causes below.

# Pathophysiology
The exact pathogenesis of short stature is an interplay of many factors. Linear growth is determined by the factors affecting the growth plate cartilage of bones. 
- Genetic factors- GH gene (17q22), SHOX gene variants, Pit-gene mutations, Turner syndrome, Achondroplasia (FGF)
- Hormones that promote growth-
Growth hormone (GH)
Thyroid hormone
Insulin-like growth factor (IGF-1)
Testosterone
- Growth hormone (GH)
- Thyroid hormone
- Insulin-like growth factor (IGF-1)
- Testosterone
- Hormones that inhibit growth plate cartilage-
Glucocorticoids
Estrogen 
- Glucocorticoids
- Estrogen 
- Paracrine factors- Fibroblast growth factor, parathyroid hormone-related protein
- Extracellular matrix proteins- Collagen, proteoglycans

# Causes
The most common causes of short stature are the normal variants of growth- familial short stature and constitutional delay of growth and puberty.
Normal variants of growth include-
- Familial short stature
- Constitutional delay of growth and puberty
- Idiopathic short stature
- Small for gestational age infants with catch-up growth
Pathological causes of short stature include- 
- Malnutrition
- Treatment with Glucocorticoids
- Endocrine causes-
Growth hormone deficiency
Hypothyroidism
Cushing's syndrome
Rickets (vitamin D deficiency)
Type I diabetes mellitus
- Growth hormone deficiency
- Hypothyroidism
- Cushing's syndrome
- Rickets (vitamin D deficiency)
- Type I diabetes mellitus
- Genetic syndromes
Turner syndrome
Noonan syndrome
Prader-Willi syndrome
Russell- Silver syndrome
Achondroplasia
- Turner syndrome
- Noonan syndrome
- Prader-Willi syndrome
- Russell- Silver syndrome
- Achondroplasia
- Systemic diseases-
Gastrointestinal causes- Celiac disease, Inflammatory bowel disease (Crohn's disease), Malabsorption syndromes
Pulmonary causes- Cystic fibrosis, obstructive diseases like bronchial asthma
Cardiology causes- Untreated congenital heart diseases 
Chronic Kidney Disease
Malignancy
Rheumatological causes- Idiopathic juvenile arthritis
Hematological causes- Sickle cell anemia
Immunodeficiency- Immune deficiencies, HIV infection
Infectious diseases- Parasitic infestations like Ascariasis, Enterobius.
Environmental pollutants- Lead exposure 
- Gastrointestinal causes- Celiac disease, Inflammatory bowel disease (Crohn's disease), Malabsorption syndromes
- Pulmonary causes- Cystic fibrosis, obstructive diseases like bronchial asthma
- Cardiology causes- Untreated congenital heart diseases 
- Chronic Kidney Disease
- Malignancy
- Rheumatological causes- Idiopathic juvenile arthritis
- Hematological causes- Sickle cell anemia
- Immunodeficiency- Immune deficiencies, HIV infection
- Infectious diseases- Parasitic infestations like Ascariasis, Enterobius.
- Environmental pollutants- Lead exposure 

# Differentiating familial short stature from constitutional delay

# Epidemiology and Demographics
The incidence of short stature according to its definition is approximately 2.5% i.e more than 2 standard deviations below the mean for chronological age and sex.
The prevalence varies according to different environmental and genetic factors.
According to a study by Lindsay et al, the prevalence of growth hormone deficiency in the United States is 1: 1348. 
A study by Velayutham et al showed that the prevalence of short stature in school-going population in South India is 2.86%. 
According to a study by Mouzan et al, the prevalence of short stature ranged from 1.8% to 11.3% in males and 1.2% to 10.5% in females. 
There is no racial predilection to short stature.
Males are more commonly affected by short stature due to growth hormone deficiency.

# Risk Factors
Common risk factors in the development of short stature include- 
- Genetic factors
- Environmental factors
- Diet- undernutrition during pregnancy, malnutrition of infants
- Low birth weight
- Low gestational age at birth

# Screening
Linear height is measured serially and charted at every well-child visit. The growth pattern should be charted and height velocity must be noted.
The infancy-childhood-puberty mathematical model may be used to detect abnormalities.
- Infancy- Nutrition dependent; rapid linear growth of about 30-35cm
- Childhood- Growth hormone-dependent; linear growth with constant height velocity
- Puberty- Sex steroids and growth hormone; pubertal growth spurt at around age 10 for girls and age 12 for boys. 

# Natural History, Complications, and Prognosis
If left untreated, short stature results in lower than normal adult height.

# Diagnosis

## Diagnostic Study of Choice
The diagnosis of short stature is based on the definition of a height more than 2 standard deviations(SD) below the mean for chronological age and sex. This corresponds to a height of less than 2.3rd percentile.  Serial measurements of height and height velocity must be done at every well-child visit and a growth chart must be monitored. For infants less than 2 years of age, the length is measured lying down. For children more than 2 years of age, standing height is measured.

## History and Symptoms
The majority of patients with short stature are diagnosed by serial measurements of height.
When short stature is associated with underlying pathology, history of the following may be seen-
- Premature birth, small for gestational age
- Malnutrition- Weight loss, loss of appetite
- Crohn's disease- Diarrhea, weight loss, rectal bleeding
- Immunodeficiency syndromes or cystic fibrosis- recurrent infections
- Hypothyroidism- Cold intolerance, weight gain, dry skin, constipation
- Cushing's syndrome- thin skin, striae, central obesity
- Asthma- chronic cough
- Arthralgia
- Chronic systemic illness
- Use of glucocorticoids
- Learning disability in developmental disorders

## Physical Examination
Patients with short stature usually appear normal. If associated with underlying conditions, other features related to the underlying disease may be seen.
The following features must be noted on physical examination- 
- Length or height plotted on a growth chart corresponding to age and sex
- Weight and weight-for-age
- Height velocity- measured in cm/year by calculating the difference in height with a time difference of at least 6 months
- Midparental height- Represents the potential or genetic target height 
Boys- (father's height + mother's height + 13 cm)/2
Girls- (father's height + mother's height  13 cm)/2
- Boys- (father's height + mother's height + 13 cm)/2
- Girls- (father's height + mother's height  13 cm)/2
- Bone age
Delayed- Constitutional delay in growth and puberty, underlying systemic illness
Normal- Familial short stature
Advanced- Precocious puberty
- Delayed- Constitutional delay in growth and puberty, underlying systemic illness
- Normal- Familial short stature
- Advanced- Precocious puberty
- Adult height prediction
Other features suspicious of pathological causes of short stature may be associated with-
- Turner syndrome- webbed neck, low-set ears
- Malnutrition
- Celiac disease- oral ulcers, anal tags
- Cystic fibrosis- weight loss

## Laboratory Findings
There are no specific diagnostic laboratory findings associated with short stature. Associated findings due to an underlying pathological illness may be seen.   
- Growth hormone deficiency- Low growth hormone; growth hormone provocative/stimualtion tests
- Low insulin-like growth factor 1 (IGF-1)
- Low thyroid hormone, high TSH- Hypothyroidism
- Karyotyping
- Immunoglobulin measurement- immunodeficiencies
- Positive IgA anti-tissue transglutaminase- Celiac disease

## Electrocardiogram
An ECG may be helpful in the diagnosis of congenital heart disease as a cause of short stature.

## X-ray
An x-ray is used to determine the bone age in the diagnosis of the cause of short stature.

## Echocardiography or Ultrasound
Echocardiography/ultrasound  may be helpful in the diagnosis of short stature when associated with congenital heart disease.

## CT scan
There are no CT scan findings associated with short stature.

## MRI
There are no MRI findings associated with short stature. An MRI may be useful when short stature is associated with growth hormone deficiency. Suggestive findings include absence of the anterior pituitary gland (empty sella), an ectopic posterior pituitary gland, and hypoplasia of the pituitary gland.  

## Other Imaging Findings
There are no other imaging findings associated with short stature.

## Other Diagnostic Studies
There are no other diagnostic studies associated with short stature.

# Treatment

## Medical Therapy
The mainstay of treatment for short stature due to growth hormone deficiency is growth hormone replacement therapy.  
- Recombinant human Growth hormone (rhGH)- Initial dosing and adjustments are based on weight, body surface area, growth response, and increase in height velocity.
- Dose- Starting recommended dose is 25 g/kg/day up to 43 g/kg/day
- Regular assessment with growth velocity and IGF-1 levels must be done every 6-12 months.
Low levels of IGF-1 indicate poor adherence, inadequate storage, or the presence of another condition 
High IGF-1 levels indicate IGF-1 insensitivity
- Low levels of IGF-1 indicate poor adherence, inadequate storage, or the presence of another condition 
- High IGF-1 levels indicate IGF-1 insensitivity
- Inadequate response 
Height velocity <2 cm/year
Change in height velocity with a standard deviation of less than <0.3/year during the first 612 months of therapy
- Height velocity <2 cm/year
- Change in height velocity with a standard deviation of less than <0.3/year during the first 612 months of therapy
Other pharmacologic medical therapies for other causes of short stature include- 
- Recombinant IGF-1
- Testosterone
- Aromatase inhibitors- Anastrazole, letrozole
- Estrogen
- GnRH analogs
Patients with an underlying disorder resulting in short stature should be treated for the disorder.

## Surgery
Surgical intervention is not recommended for the management of short stature.

## Primary Prevention
There are no established measures for the primary prevention of short stature.
Adequate maternal nutrition during pregnancy is an important factor.

## Secondary Prevention
There are no established measures for the secondary prevention of short stature.