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Idiopathic Short Stature


Idiopathic short stature (ISS) refers to extreme short stature that does not have a diagnostic explanation (idiopathic designates a condition that is unexplained or not understood) after an ordinary growth evaluation. The term has been in use since at least 1975 without a precise percentile or statistical definition of “extreme”.

Associated Anatomy

After GH is secreted from the pituitary gland (located at the base of the brain) it is carried through the blood stream attached to the blood by ‘binding’ to a ‘ receptor’ on the cell surface. When the IGF’s have been transported to the bone they are released and absorbed by the growth plates to produce bone growth.


There is no known cause for idiopathic short stature.

Differential Diagnosis

The term ISS was originally used to describe a growth problem that occurs when all known causes of growth failure have been ruled out.

In the diagnostic work−up for ISS, dysmorphic syndromes must be excluded, but it is not agreed how far genetic testing should go before the condition can be labeled as idiopathic. For example, there is wide agreement that all girls should be tested for Turner syndrome, but there is no consensus of whether all short children should be tested for a heterozygous deletion or mutation of SHOX, which has been described in about 2.5% of ISS children. Recently a clinical score was developed to predict the likelihood of a SHOX defect and this can be used for improved selection of patients for testing. There is no agreement on either what skeletal dysplasias should be excluded or what cut−off limit with respect to body proportions should be used. To assess body proportion, in Europe the sitting height/height (SH/H) ratio and in the United States the upper/lower segment ratio is used, but both of these ratios are strongly influenced by secular trend and reliable references are not available.


Somatropin (Humatrope, Nutropin, Genotropin, Saizen, Tev-Tropin, Norditropin)

hGH produced via recombinant DNA technology in Escherichia coli; widely available since 1985. Currently, only 1 of the 10 largest reported clinical studies has demonstrated that therapy can increase final adult height in patients with normal variant short stature. This most recent NIH-funded study was randomized, placebo controlled, and took place over 14 y. Investigators demonstrated average gain in height did not exceed 4 cm when rhGH treatment of normal variant short stature began prior to puberty and continued through completion of puberty. They did not identify any clinical feature that, prior to start of therapy, could predict whether an individual patient would respond to rhGH and to what degree. Whether several years of daily injections are worth the potential, but not promised, relatively small increase in final adult height remains a personal and individual decision involving the patient, patient’s family, and physician.

Mecasermin (Increlex)

Recombinant human insulinlike growth factor-1 (rhIGF-1) indicated for long-term treatment of GF in children with severe primary IGFD (primary IGFD defined as basal serum IGF-I level and height SD scores ≤ -3, normal or elevated serum GH level). IGF-I is essential for normal growth of children’s bones, cartilage, and organs by stimulating uptake of glucose, fatty acids, and amino acids into tissues. IGF-I is the principal hormone for linear growth and directly mediates GH actions. Primary IGFD is characterized by absent IGF-I production despite normal or elevated GH release.


By definition, 2.5% of the U.S. population is short. The Utah Growth Study is the largest population-based survey of growth in children published to date. These investigators assessed height and growth velocity in nearly 115,000 American children. Among the 555 children with short stature (defined as height below the third percentile) and poor growth rate (defined as growth velocity < 5 cm annually), only 5% had an endocrine disorder. In addition, 48% of the children with growth hormone deficiency (GHD) or Turner syndrome (TS) in this large cohort had been undiagnosed or untreated.



By definition, children with ISS have normal GH secretion, which is almost always investigated by a pharmacological GH provocation test. Theoretically, they could have reduced spontaneous 24−hr GH secretion. However, the assessment of spontaneous GH secretion is very rarely included in the clinical evaluation of short stature and the entity of GH neurosecretory dysfunction still remains controversial. Some ISS children have been found to have low concentrations of growth hormone binding protein (GHBP), suggesting reduced GH receptor (GHR) function. These patients tend to have lower IGF−I levels yet higher endogenous GH secretion, suggestive of partial GH insensitivity (GHI). An overlap exists between ISS patients and those with partial or atypical GHI. This was appreciated from the study of the European cohort of GHI patients, some of whom did not have the typical appearance of Laron syndrome. In fact, some had milder short stature and normal facial appearance with less biochemical abnormalities. However, it has to be pointed out that the vast majority of ISS children have IGFI in the low normal range and normal GH concentrations.

Possible Complications

Possible complications of short stature in general include:

  • arthritis later in life
  • delayed mobility development
  • dental problems
  • bowed legs
  • hearing problems and otitis media
  • hydrocephalus, or too much fluid in the brain cavities
  • hunching of the back
  • limb problems
  • swaying of the back
  • narrowing of the channel in the lower spine during adulthood and other spine problem
  • sleep apnea
  • weight gain
  • speech and language problems

Individuals with ISS may have poorly developed organs and pregnancy complications, such as respiratory problems

Possible Treatment

By definition, normal short stature does not require treatment for physical health benefits. Therefore, justification for growth enhancement therapy requires demonstration of individual or societal benefits, evidence of efficacy with absolute safety, and cost-benefit. Treatment of ISS with rhGH, as might be expected by the lack of definitive psychosocial problems attendant on short stature per se, has generally not been shown to affect school achievement, psychosocial measures, or quality-of-life when rhGH treated and untreated normal short children are compared.

The use of insulin-like growth factor 1 or aromatase inhibitors have been proposed as an alternative to growth hormone.

Primary Prevention

After completion of puberty, no further growth in height is possible.  An early diagnosis is, therefore, critical to the success of the treatment.

When started at an early enough age, growth hormone can significantly increase the final height of many children with ISS.

Risk factors

In 15% of cases a history of a low birth weight or length for gestational age (SGA) is found. This means that in approximately 80% of the short children presented to a pediatric clinic there is no history of a low birth weight and/or length, and no pathology can be detected. The vast majority of them have normal variants of growth (FSS or CDGP) and will attain an adult height within the target height range.


Active Not Recruiting

Number of studies: 1



Number of studies: 24


Enrolling by Invitation

Number of studies: 0


Not Yet Recruiting

Number of studies: 0



Number of studies: 5


Results Available

Number of studies: 8


Results Not available

Number of studies: 24



Number of studies: 0



Number of studies: 2



Number of studies: 1


Typical Test

If a short child comes to the clinic, the diagnostic process is aimed at detecting the cause of his or her shortness, through a thorough medical history, physical examination, laboratory tests, and radiological examinations. If no clues for any known etiology of short stature are found, the ‘‘diagnosis” (by exclusion) of idiopathic short stature can be made.