Idiopathic and syndromic short stature: news

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Growth is the result of the interaction of genetic, nutritional, hormonal and environmental factors. Physiological growth is defined by height on the 50th percentile or otherwise in line with the genetic target, with a regular growth rate and with skeletal maturation corresponding to chronological age. Ultimate stature is affected by the age of onset of pubertal development and parental stature

It is possible to speak of “short stature” in the case of a height that is at least two standard deviations (SD) below the average height for subjects of the same sex de chronological age in the reference population .

In the care of children, periodic measurement of their growth is important: in fact, a normal growth rate is an indication of good health, while a slowdown in growth rate may be caused by the presence of diseases, especially chronic ones, including endocrinological causes.

During childhood, children grow at a relatively constant rate, slowing down from school age; thereafter, puberty is the time of greatest statural growth. The rate of physiological statural growth (i.e., between the 10th and 90th percentiles) is as follows:

  • 2 to 4 years old: 5.5-9 cm/year;
  • 4 to 6 years old: 5-8.5 cm/year;
  • from age 6 to puberty: 4-6 cm/year for males; 4.5-6.5 cm/year for females;
  • during puberty there is the so-called pubertal spurt, a growth of 8-14 cm/year due to the effect of sex hormones and growth hormone (growth hormone, GH), following which the final height is reached. Puberty occurs earlier in females, between 8 and 10 years of age, while in males it begins about two years later, between 10 and 12 years .

The family pediatrician monitors the child’s growth during scheduled visits at filter ages, also called “health budgets.” The health budget is the ideal time to conduct a comprehensive visit and assess the child’s growth. These filter visits are conducted with standard timings.

In the event that growth below the third percentile or parental target is detected during a checkup, or a slowing of growth or, in the most worrisome cases, stunting of growth, more in-depth investigations should be undertaken. If necessary following the initial evaluations, the pediatrician may deem it appropriate to refer the patient to a center specializing in auxology to perform further investigations through pediatric endocrinologists.

After a thorough history and objective examination, the first parameters to be evaluated in addition to height and weight are:

  • the rate of growth: as illustrated above, it is essential to have regular measurements over time to reconstruct the child’s growth history;
  • target height: height is largely determined by genetics, so an estimate of the child’s ultimate height can be made from the average of the parents’ heights, from which 8.5 cm should be added or subtracted depending on whether the child is a boy or a girl. During a thorough assessment, if possible the parents’ height should preferably be measured rather than reported verbally;
  • projected height: this is determined through growth curves in children over the age of two, for whom there are then enough measurements to determine the curve along which the child’s growth is continuing. By following the curve until maturity-that is, around the age of 20 years-the definitive stature can be estimated: if this is within 8.5 cm (2 SD) of the target height, the height is in the expected range for the family. In the case of absolute short stature, but with projected height in the family range, this is called familial short stature, a variant of normal growth.


In the case of finding pathological data, further investigations are carried out, including:

  • Hematochemical examinations: evaluating not only endocrinological aspects, but also aspects of general function and nutritional status.
  • Bone age study: is performed through an X-ray of the left hand. By studying the degree of bone maturation in this region, an estimate of the stage of bone growth can be made. In addition, this examination can provide essential information to frame some specific causes of short stature.
  • Hormone stimulation test: to assess GH secretion and rule out its possible deficiency.
  • MRI of the brain: to rule out organic pathological causes.
  • Possible genetic tests.


The aim of these evaluations is to identify, among children of short stature, those with underlying pathological causes. In addition, the severity of short stature and the likely growth trajectory are also assessed to facilitate decisions on intervention, if appropriate.

Idiopathic short stature (ISS) is defined as a height less than 2 standard deviations from the mean for age and sex-a definition of short stature seen above-in the absence of any endocrine, metabolic, or other diagnosis. Idiopathic short stature is therefore a diagnosis of exclusion following the assessments listed above. Therefore, at the current state of knowledge ISS is considered as a variant of normal growth, since all possible pathological causes have been excluded. Notably, children diagnosed with ISS do not have GH deficiency: in fact, hormone stimulation tests are in the normal range .

Children with ISS may have a family history of short stature and have a stature below normal but within the parental target range (familial ISS) or below the familial target range (non-familial ISS). Delayed skeletal maturation and delayed onset of pubertal development may also be present .

Height is a polygenic trait influenced by several genes. In the past decade, improved diagnostic techniques have led to the discovery of causative mutations in genes involved in GH/IGF-1 axis function and growth plate physiology. However, many cases of ISS still remain “idiopathic.” In the future, more frequent identification of underlying causes will allow better stratification and facilitate tailored management .

Therapy with rhGH has been proposed and approved in some countries for the treatment of children with ISS, but the extreme heterogeneity of the ISS population inevitably affects the response to rhGH treatment .

In Italy, regional commissions have been established to approve rhGH therapy in children with ISS. Selection criteria are based on auxologic data, pubertal development, and exclusion of other causes of short stature, and patients are reevaluated over time to verify the effectiveness of therapy.

The main recognized genetic causes of syndromic short stature include:

  • SHOX gene variants: responsible for 1-4% of individuals who would otherwise be classified as “idiopathic short stature.” Variants of the SHOX (short stature homeobox) gene, located on the X chromosome, cause a syndrome whose primary manifestation is short stature, which tends to be more severe in girls. These patients typically have skeletal abnormalities whereby they differ from children with idiopathic short stature. It is known that rhGH treatment in children with SHOX gene deficiency increases height velocity and adult height. However, it is difficult to assess a prediction of response to therapy .
  • Turner syndrome (TS): one of the most common chromosomal abnormalities. Turner syndrome is a sex chromosome disorder caused by partial or complete loss of an X chromosome. This syndrome is important to consider in girls with short stature, and particularly with growth difficulties, because short stature may be the presenting feature of the syndrome; other physical abnormalities are variably expressed. If left untreated, the ultimate height in Turner syndrome is about 20 cm shorter than in the general female population. Therapy with rhGH optimizes growth .
  • Noonan syndrome (NS): is a relatively common predominantly autosomal dominant syndrome associated with short stature, congenital heart disease, and increased cancer risk. Possible mechanisms of short stature in NS include: growth hormone deficiency, neurosecretory dysfunction, and GH resistance. Consequently, rhGH therapy has been approved for patients with NS in recent years, and numerous studies have reported accelerated growth velocity and improved ultimate stature. Concerns remain about the possible development of neoplasms, which requires continuous monitoring of NS patients receiving GH therapy .
  • Prader-Willi syndrome (PWS): is the most common syndromic form of obesity. Short stature is common in this syndrome, but may not develop until late childhood, when pubertal growth spurt does not occur in the child. Both quantitative and qualitative defects in the GH/IGF-1 axis revealing GH deficiency have been demonstrated in most children with PWS. Growth hormone treatment in these patients increases linear growth and improves body composition .

In Italy, the prescription of recombinant growth hormone (somatotropin – rhGH) charged to the National Health Service (SSN) is regulated by AIFA Note 39. This note approves treatment with rhGH in the genetic syndromes discussed above, specifically:

  • Statural deficits in subjects with genetically demonstrated altered SHOX gene function;
  • Statural deficits in patients with cytogenetically demonstrated Turner syndrome;
  • Genetically proven Noonan syndrome subjects with stature ≤-2.5 SD;
  • Subjects with Prader Willi syndrome, genetically demonstrated, with normal respiratory function and not affected by: severe obesity (defined by BMI >95th centile), uncontrolled diabetes mellitus, obstructive sleep apnea syndrome excluded by polygraphy or polysomnography, active cancer, active psychosis

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