Short Stature
Synonyms and keywords:

# Overview
Short stature is characterized as a condition in which the height of the person in the 3rd percentile is the average height of the age , sex, and population group. According to Ranke (1996), Short stature is defined as a condition in which the height of an individual is two standard deviations (SD) below the corresponding mean height of a given age, sex and population group.  

# Historical Perspective
- In 1967 by Pierre Maroteaux was the first man to ever mention dwarfism.
- He is largely credited for establishing the link between the genetic condition and prenatal micromelic for the patients with dwarfism.
- In 1994, Dr. John Wasmoth and his team discovered the cause of achondroplasia while researching the topic of dwarfism.

# Classification
There are two types of short stature,

### Proportionate short stature (PSS)
Proportionate short stature (PSS) is when the person is small, but limbs and trunk height are in proportions. 

### Disproportionate short stature (DSS)
Whereas in disproportionate short stature (DSS), the normal proportion of limbs and trunk height  is absent, and the individual shows a great difference in their sitting and standing height. 

# Pathophysiology
- Short stature may be normal; therefore a detailed family history of growth patterns and direct measurement of the parents is an important part of evaluating if the short stature is due to the genetic causes and potentials of the child.
- If the Short stature results from growth failure or premature closure of the epiphysial growth plates, it secondary to a pathologic condition or due to an inherited disorder. Therefore, pathophysiology depends on the underlying cause.

# Causes

## Physiological causes of short stature

### Familial short stature
- In familial short stature, individuals have low-normal height velocity throughout their life.
- They have normal height velocity which distinguishes them from the pathologic causes of short stature.
- Also, they can be distinguished from the individuals with constitutional growth delay, as their bone age is in accordance to their chronologic age. 

### Constitutional delay of growth and puberty
- Constitutional delay of growth and puberty (CDGP) is also called constitutional short stature for pre-pubertal children, results in childhood short stature but leads to relatively normal height in adulthood.
- Children are of normal size at birth. However, a severe and prolonged decrease in growth rate is observed starting at three to six months of age.
- By three or four years of age, children with CDGP usually are growing at a low-normal rate. The growth curve that remains below the third percentile for height.
- In addition children also have delayed pubertal maturation. This leads to a marked height discrepancy during the early teenage years compared with their peers but is followed by catch-up growth when they do enter puberty. The hallmark of CDGP is delayed skeletal age.

### Idiopathic short stature
- Idiopathic short stature (ISS) is a height below 2 standard deviation (SD) of the mean for age, in the absence of any endocrine, metabolic, or other causes.
- These children are at the lower limit of the normal height velocity, with normal lab findings. 

### Small for gestational age infants with catch-up growth
- Most infants born small for gestational age (SGA) experience catch-up growth by two years of age. In this way, they are able to reach the normal range of their height.
- However, in preterm neonates, the catch-up growth may be delayed. 
- About 10 percent of SGA infants, particularly those born with more severe SGA, do not experience catch-up growth. This group of SGAinfants can be considered to have a pathologic pattern of growth. 

## Pathologic causes of short stature

### Systemic disorders with secondary effects on growth
- Malnutrition can lead to short stature with a delayed pattern of growth. The hallmark is low weight-for-height.
- Malnutrition can be due to inadequate food supply, or it may be due to an underlying condition which affects food intake or absorption or increases energy requirement of the body.  
- Glucocorticoids are used for the treatment of a variety of diseases in children, such as asthma, leading to growth failure in children. 
- Glucocorticoids can interfere with endogenous growth hormone secretion and action, bone formation, nitrogen retention, and collagen formation. 
- The growth effects of glucocorticoids are related to the type, dose, and duration of the exposure. If glucocorticoids are discontinued, children usually experience some catch-up growth. Growth impairment is more pronounced if it is given for a longer duration of action and when it is used daily as compared with an alternate-day regimen.
- Some chronic gastrointestinal diseases such as Inflammatory bowel disease and celiac disease results in short stature. Children tend to have a greater decrease in weight than the height (ie, they are underweight-for-height).
- The growth failure is caused by the inflammatory disease process, as well as decreased food intake, malabsorption, or glucocorticoids.
- Childhood rheumatologic diseases, especially systemic juvenile idiopathic arthritis, are frequently associated with growth retardation.
- This can be partly due to the inflammatory process driven by the proinflammatory cytokines and also caused by the high-dose glucocorticoids often used for management.
- Growth failure is seen in at least one-third of children with chronic kidney disease. 
- The primary causes of growth failure in children with chronic kidney disease are disturbances of growth hormone metabolism and its main mediator, insulin-like growth factor 1 (IGF-1). 
- Other factors may include metabolic acidosis, uremia, poor nutrition secondary to dietary restrictions, anorexia of chronic illness, anemia, calcium and phosphorus imbalance, renal osteodystrophy, or use of high-dose glucocorticoids. Affected patients are candidates for growth hormone therapy until renal transplantation, and some of these patients may also benefit from growth hormone therapy after transplantation.  
- Children with cancer have poor growth rate due to poor food intake, nausea, vomiting, and increased caloric utilization. 
- Also, anorexia, nausea, and vomiting induced by chemotherapy and radiotherapy also can contribute to impaired growth. 
- In pulmonary diseases, such as cystic fibrosis, growth failure is caused by multiple mechanisms, including poor food intake, maldigestion or malabsorption, chronic and recurrent infection, and increased energy requirements.
- In asthma, growth failure is usually due to the use of glucocorticoids for the treatment. 
- In severe congenital heart diseases, growth failure is common. Sometimes, it is the presenting feature of the heart disease.
- The major causes include, anorexia and increased basal energy requirements. 
- Growth failure is associated with immunologic deficiencies such as common variable immunodeficiency or severe combined immunodeficiency syndrome, and infections such as HIV.
Metabolic disorders can lead to growth failure in children and adolescents.
- The most common metabolic disorder in children is type 1 diabetes mellitus. It causes short stature and attenuated growth because of the caloric deficit resulting from severe glucosuria. Also,  type 1 diabetes causes a decrease in IGF-1 production or action, which has a negative correlation with adult height. Diabetes with very poor glycemic control leads to Mauriac syndrome, characterized by attenuated linear growth, and delayed puberty, hepatomegaly, and Cushingoid features.
- Vitamin D deficiency can lead to rickets in children characterized by abnormal epiphyseal development, bowing of the extremities, and diminished growth.

### Genetic Causes
Several genetic disorders have prominent effects on growth.
- Turner's Syndrome 
- SHOX gene variant 
- Prader-Willi Syndrome 
- Noonan syndrome 
- Silver-Russell syndrome 
- Skeletal dysplasia/growth plate abnormalities 

### Endocrine Causes
- Cushing syndrome: Cushing syndrome results in increased glucocorticoids and is characterized by the combination of weight gain and growth retardation, resulting in excessive weight-for-height. Glucocorticoids directly inhibits the development of epiphyseal cartilage in growing long bones resulting in growth retardation.
- Hypothyroidism: Growth failure is an important feature of hypothyroidism. Due to hypothyroidism, the bone age is delayed. However, it is a treatable and reversible cause of short stature as once it is identified and treated, children achieve the normal growth potential.
- Growth hormone deficiency: If growth hormone deficiency is congenital, then postnatal growth failure along with delayed bone age is seen. The patient has very low serum concentrations of growth hormone, IGF-1, and IGF-binding protein-3 (IGFBP-3. Additional findings are hypoglycemia, prolonged jaundice, and micropenis in boys, especially if gonadotropins are deficient as well. In children, whose height may still be within the normal range for age, has less severe growth failure. Acquired or secondary growth hormone deficiency occurs in case of intracranial tumor (eg, craniopharyngioma), cranial irradiation, and head trauma.

## Psychosocial short stature
It is a growth disorder that is observed between the ages of 2 and 15, caused by extreme emotional deprivation or stress which causes decrease in growth hormone (GH) and somatomedin secretion, resulting in very short stature. Patient's weight is inappropriate for the height with immature skeletal age. 

# Differential Diagnosis
- Endocrine disorders: Growth hormone deficiency (GHD), insulin-like growth factor-1 (IGF-1), growth failure, constitutional growth delay, growth failure, stunted growth, structural brain abnormalities, or pituitary lesions, pituitary microadenomas, congenital hypothyroidism, idiopathic short stature, intrauterine growth deficiency, etc.
- Genetic disorders: Down syndrome, Turner syndrome, 3M syndrome, Noonan syndrome, Prader-Willi syndrome, Aarskog syndrome, Silver-Russell syndrome, etc.
- Bone diseases: Dwarfism, Achondroplasia (short-limbed dwarfism), diastrophic dysplasia (short-limbed dwarfism), spondylo-epiphyseal dysplasia (short-trunk dwarfism), rickets, etc
- Chronic disorders: Cystic fibrosis, Crohn disease, juvenile idiopathic arthritis (JIA), anemia, chronic renal insufficiency, inflammatory bowel disorder, chronic malnutrition, etc
- Psychological distress 

# Epidemiology and Demographics
In the United States, 2.5% of the population is short.  A study conducted on the school children age 4-16 years in the  South Indian Population shows the overall prevalence of short stature was 2.86%.

## Gender
- Short stature is equally prevalent among both males and females, but studies show that boys were admitted more than the girls. This could be due to the reason that males are more likely to be brought to medical attention because of the prevalence of social expectations and pressures as compared to the females.
- On the other hand, in Rosario, Argentina, the higher prevalence was found in females (16.4%) than males (8.4%) (p<0.001). The short stature in females was related to age, weight, and abdominal obesity.

## Age
- Different ethnic groups have different average statures, which are essential to take into consideration while comparing mean parameters.
- Any individual who has not attained the union of epiphyseal plates, can get affected.

## Race
- Short stature is more prevalent among Hispanic children as compared to the other populations.

# Risk Factors
- Common risk factors in the development of short stature are diet, environment, and genetics.

# Diagnosis

## Diagnostic Criteria
- The diagnostic criteria of short stature is when the height is 2 or more standard deviations below the mean for age and gender within a population (below the 2.5th percentile).

## Symptoms
- Symptoms of the short stature depend on the underlying cause.

## Physical Examination
- Short stature can be diagnosed by Anthropometric measurements including height vertex, body weight, trunk height, and limb length of an individual. These are assessed in relation to age, sex, and population.
- In achondroplasia, enlarged head with frontal bossing, depressed nasal bridge, mid-face hypoplasia and skull.

## Laboratory Findings
The laboratory studies used to assess the major causes of short stature include,
- Measurement of serum levels of insulin-like growth factor-I (IGF-I), formerly named somatomedin C, and IGF binding protein-3 (IGFBP-3). Measurement of serum levels of growth hormone.
- Karyotype for the genetic causes of the short stature.
- Other tests include,
CBC for hematologic diseases.
Serum total thyroxine (total T4) and thyrotropin (TSH) levels to test for hypothyroidism.
Antiendomysial immunoglobulin A (IgA) and immunoglobulin G (IgG), transglutaminase IgG, and antigliadin IgG titers for gluten enteropathy. Erythrocyte sedimentation rate for inflammatory bowel disease.
Serum transferrin and pre-albumin concentrations for malnutrition.
Sweat chloride test for cystic fibrosis.  
- CBC for hematologic diseases.
- Serum total thyroxine (total T4) and thyrotropin (TSH) levels to test for hypothyroidism.
- Antiendomysial immunoglobulin A (IgA) and immunoglobulin G (IgG), transglutaminase IgG, and antigliadin IgG titers for gluten enteropathy. Erythrocyte sedimentation rate for inflammatory bowel disease.
- Serum transferrin and pre-albumin concentrations for malnutrition.
- Sweat chloride test for cystic fibrosis.  

## Electrocardiogram
- In Noonan syndrome, which is one of the genetic cause of short stature, electrocardiogram (ECG) shows left axis deviation, abnormal R/S ratio over the left precordium, and an abnormal Q wave. 
- In Turner's Syndrome, ECG findings include ectopic supraventricular and ventricular activity. 

## X-ray
- Xray anteroposterior view of left hand and wrist is done to assess the bone age in children with short stature.
- Xray findings of longstanding untreated hypothyroidism include epiphyseal dysgenesis. The spine shows platyspondyly and thoraco-lumbar kyphosis.

## Ultrasound
- Ultrasound helps in evaluation of thyroid pathologies, such as thyroid dysgenesis, ectopic thyroid gland, goiter or thyroid mass. 

## CT scan
There are no CT scan findings associated with .
OR
 CT scan may be helpful in the diagnosis of . Findings on CT scan suggestive of/diagnostic of  include , , and .
OR
There are no CT scan findings associated with . However, a CT scan may be helpful in the diagnosis of complications of , which include , , and .

## MRI
- MRI is the modality of choice for the evaluation of pituitary-hypothalamic axis (PHA) in order to identify Congenital hypopituitarism or brain tumor, which can cause isolated growth hormone deficiency (IGHD) or multiple pituitary hormone deficiencies (MPHDs) leading to growth retardation.
- In achondroplasia, MRI brain reveals small base of the skull, narrowed foramen magnum, syringomyelia, myelomalacia, hydrocephalus, and lumbar spinal stenosis.

## Other Diagnostic Studies
-  may also be diagnosed using .
- Findings on  include , , and .

# Treatment

## Medical Therapy
- The primary management of short stature should be to treat the underlying cause.
- If the short stature is caused due to a hormonal deficiency it should be managed with hormonal treatment.
- These include treating growth hormone deficiencies and constitutional growth delays with gonadotropin-releasing hormone analogues (GnRHa), aromatase inhibitors, recombinant human insulin-like growth factor- 1 (RhIGF-1), low-dose androgen therapy, recombinant human growth hormone (rhGH) etc. 
- In addition to treating  the underlying cause, patients should be provided with psychosocial counselling and support in order to help them cope with psychosocial distress as a result of their short stature.

## Surgery
- Bone lengthening surgery is being performed not only for the treatment of dwarfism and/or skeletal deformities caused by congenital abnormalities, tumors and infections. 
- The surgery is performed using Ilizarov method with circular external fixation. This is called cosmetic leg lengthening or symmetrical extended limb lengthening.  

## Prevention
- There are no primary preventive measures available for short stature.
- Once diagnosed it could be managed, with either medical or surgical options.