Idiopathic short stature — A practical definition of idiopathic short stature (ISS) is a height below 2 standard deviations (SD) of the mean for age, in the absence of any endocrine, metabolic, or other diagnosis. These children have normal (often at the lower limit) height velocity and no biochemical or other evidence for a specific growth retarding condition, which implies normal results for endocrine screening tests, including those for growth hormone deficiency. Genome-wide studies indicate that the majority of the variation in adult height is explained by several hundred genetic variations, each with a small effect [8]. However, in a small proportion of the population, short stature is caused by specific genetic variations with large effect. As an example, emerging evidence suggests that mutations in the Short Stature HOmeoboX (SHOX) gene are responsible for 1 to 4 percent of individuals who would otherwise have been classified as having "idiopathic" short stature (see 'SHOX mutations' below). In addition to these genetic contributors to ISS, it appears that epigenetic changes may play a role in some cases of ISS. In one study, ISS was associated with increased methylation of two promoter regions for the insulin-like growth factor 1 (IGF-1) gene; these epigenetic changes are predicted to reduce the individual's sensitivity to growth hormone [9]. (See "Growth hormone insensitivity syndromes", section on 'Impaired IGF1 promoter function'.)
Growth hormone therapy is approved in the United States for children with ISS, which is defined for this purpose by a more stringent threshold for height (below -2.25 SD of the mean, and a predicted adult height is <63 inches [160 cm] for males and <59 inches [150 cm] for girls). However, the use of growth hormone for this group of patients remains controversial. Studies have shown that consumer preferences (family concern) and physician attitudes are important drivers of treatment decisions, independent of patient characteristics [10]. Treatment indications and efficacy are discussed in detail separately. (See "Growth hormone treatment for idiopathic short stature".)
ISS is a diagnosis of exclusion. The child's height percentile is below the range predicted by the mid-parental height and the bone age is not delayed, but there is no evidence of underlying genetic, systemic, or endocrine disease [11]. Although this may be a variant of normal growth, patients with this growth pattern warrant monitoring for the possibility of unrecognized underlying disease.
There is ongoing controversy about the nomenclature of ISS. Here, we use the term to refer to non-familial cases (ie, those without patterns of familial short stature). Others consider familial short stature and CDGP to be subcategories of ISS [11,12].
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, sufficient to be within the normal range (length above -2 SD, ie, >2.3rd percentile). Catch-up growth may be delayed in infants who are born preterm in addition to SGA, but often continues into childhood to approach the range predicted by the family's height. SGA can be caused by maternal, placental, or fetal factors. In many cases these factors (such as intrauterine constraint from a small uterus) are transient and are followed by vigorous catch-up growth during infancy. (See "Infants with fetal (intrauterine) growth restriction".)
About 10 percent of SGA infants, particularly those born with more severe SGA, do not experience catch-up growth to reach the normal range by two years of age. This group of SGA infants can be considered to have a pathologic pattern of growth, so they are discussed later in this topic review. (See 'Other causes of short stature that may be pathologic' below.)
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