Familial Short Stature

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Continuing Education Activity

Familial short stature (FSS) is the condition characterized by the final adult height below the third percentile of the mean for the patient's age, gender, and population and is in line with the parental heights. Such patients are otherwise healthy and have normal growth velocity and bone age. This activity outlines the evaluation and management of FSS and highlights the role of the interprofessional team in managing patients with this condition.


  • Describe the advances in the pathophysiology of familial short stature (FSS).
  • Outline the evaluation of FSS and distinguish it from other causes of short stature.
  • Summarize the management strategies of familial short stature.
  • Explain the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by familial short stature.


Familial short stature (FSS) is a condition in which the final adult height achieved is less than the third percentile for the patient's age, gender, and population. Nevertheless, it is consistent with parental height in the absence of nutritional, hormonal, acquired, genetic, and iatrogenic causes. It is considered one of the most common causes of short stature, along with the constitutional delay in growth and puberty (CDGP), from which it can easily be distinguished.

A child presenting with short stature (SS) two or more standard deviations (SD) below the mean for age, gender, and population where no other causes can be found deemed to have idiopathic short stature (ISS). Having adopted this definition, some authorities have included cases of FSS and CDGP as part of ISS. Hence, a category of familial ISS is distinguished from the non-familial ISS. On the other hand, others have listed it as a separate entity. Regardless of the classification which one follows, it is clear that FSS is a distinct entity whereby patients attain a final adult height consistent with their target height, unlike ISS. Thus, the final height attained is considerably less than the ultimate expected height in ISS.

Although the consensus is that small cumulative effects of multiple genes are responsible for FSS, it is being questioned, especially when the SS condition is extreme. This may be especially true, as more and more monogenic gene defects are discovered in cases diagnosed either as FSS or ISS and other family members. This article addresses the features of FSS and covers distinctions among CDGP, ISS, and other causes of short stature. It also describes the latest advances in the study of various monogenic gene defects discovered in cases of SS, occurring in some families.


FSS also called genetic short stature (GSS) is considered a normal variant of growth (along with CDGP). It is believed to be caused by small contributions of multiple genes (polygenic inheritance) although this has not been firmly established. FSS may also be caused by maternal constraint or short stature of the mother.[1]

When short stature that runs in families is very severe, namely, less than three standard deviations below the mean for age, gender, and study population, then monogenic defects should be strongly considered and investigated.


Among all causes of short stature in children, a fifth is pathological, caused by poor nutrition, chronic diseases, known genetic causes, hormonal disorders, and treatment modalities, such as medications and radiation.

The majority (remaining four-fifths) are considered normal variants of growth and are equally divided between FSS and CDGP. In the Utah Growth Study, among 555 children with SS, around 18 percent of boys and 16 percent of girls had combined FSS and CDGP.[2] In another study, the incidence of FSS in CDGP was reported as 40 percent.[3]

FSS is reported throughout the world in all races, geographical areas and occurs equally in both sexes.


FSS patients have a proportionate short stature (SS). The provider's responsibility does not end with the diagnosis of FSS. An examination should include establishing the exact cause of the SS, especially when the SS is severe and/or subtle evidence of genetic diseases is present.

Genome sequencing techniques and bioinformatics have emerged as novel methods to diagnose monogenic defects of genetic short stature in families.[4]

Conditions transmitted genetically and responsible for SS include growth hormone (GH) receptor gene mutations, GH gene deletions, mutations in the PROP1, POUF1, SHOX genes, and familial pseudo-hypoparathyroidism, and some causes of familial hypothyroidism.

Monogenic causes of SS are often inherited and occur in families.[5] In some cases, defects in the genes encoding the growth plate; the NPR2 variants cause defects in the C-type natriuretic peptide receptor that regulates the growth plate in a paracrine fashion and can be responsible for short stature in families.[6][7]

A case of SS in the proband and her mother due to microdeletion of the X chromosome (Xp22.33 deletion), a cause of Turner syndrome, with preserved ovarian function and capability to transmit the defect vertically to offspring has been reported.[8]

Some cases with SS in families can be traced to syndromic causes that may or may not have all classical features of the syndromes. A family with short stature and Silver-Russell-like phenotype due to a microdeletion in chromosome12q14.3 has been described with varying features in the index case and other relatives.[9]

Some patients and their family members who were initially classified as FSS or ISS were found to have Leri-Weill dyschondrosteosis (LWD) caused by heterogeneous defects in the SHOX gene.[10]

Defects in the growth hormone-insulin-like growth factor (GH-IGF1) axis may be responsible for some familial cases of short stature. The latter includes GH resistance, as well as IGF1 mutations or other gene anomalies. An IGF1 receptor gene anomaly has also been described in families. When a patient and several family members present with a) low birth weight and length, b) normal or high IGF1 levels, c) exaggerated GH response to stimulation tests, and d) poor response to GH therapy compared to the more commonly occurring small for age (SGA) short stature patients, IGF1 receptor mutations or haploinsufficiency of the IGF1 gene must be sought for.[11][12]

Short children with FSS showed normal IGF1 but higher basal and GHRH-Arginine stimulated GH levels when compared to normal control children as well as those with GH deficiency, thus proving a decreased peripheral GH sensitivity in these patients. Higher GH levels are necessary to keep IGF1 in the target range.[13]

A novel heterozygous IGF1 splicing mutation in a large family with FSS has also been described.[14]

Isolated GH defects in some families are inherited in autosomal recessive, dominant, or x-linked fashion.[15][16]

History and Physical

Commonly in FSS cases, a birth history will reveal a normal birth weight and length.

A history of childhood illnesses, chronic conditions involving the respiratory, cardiovascular, gastrointestinal, renal, rheumatologic, and endocrine systems should be obtained and will be absent in cases of FSS.

A family history of short stature (SS) is essential for the diagnosis of FSS. Either one or both parents have a SS. Sometimes there may be factors in either or both parents that may have been acquired in utero or after birth that have contributed to parental SS. This fact will serve to revise the diagnosis.

A child with FSS will grow with a normal growth velocity, albeit in the lowest percentile. Such a child will also progress to puberty at the appropriate age range. In FSS, the final height is in the target height range for the family.

In those children with combined FSS and CDGP, the SS will be more severe, brought to attention when puberty is delayed and will attain a final predicted height at a later age than their peers.

A recent study of children with FSS, CDGP, and idiopathic growth hormone deficiency (IGHD) showed a tendency for IGHD to have a progressive decrease in the height standard deviation scores (Ht SDS) throughout the first five years of life, whereas in FSS and CDGP it was seen mainly in the first two years. When serial heights/lengths are measured, this observation may help detect these conditions earlier.[17][18]

A nutritional evaluation will reveal a good appetite, appropriate weight gain, and correct weight for age, and the absence of significant deficiencies in FSS.

A history of any use of medications like corticosteroids or other treatments that can interfere with growth, like radiation therapy for malignant disorders, should be obtained.

Serial height/length, sitting height, height velocity, weight, and head circumference plotted on a Growth Curve will yield useful clinical information. When the patient transitions from length to the height measurements when the infant reaches two years of age, it is important to remember that a discrepancy of up to 1 cm may be noted (height less than length). Accurate measurements using proper techniques are important.[19] From such baseline measurements, it is possible to calculate the ratios of upper to lower body heights, which may be useful in classifying possible causes of SS.

An arm span to height ratio will reveal a proportionate SS in FSS consistent with expected target adult heights. The child with FSS is otherwise healthy and active except for the SS. An international consensus has recommended the use of a corrected target height (cTH); instead of the traditional Tanner formula because the latter was found to underestimate the child's height when compared with short parents. The cTH is calculated by multiplying the mean of the SD of the child's father's and mother's Ht SD by 0.72. The lower limit of the TH is set at cTH minus 1.6 SD.[20]

A careful physical examination should reveal any dysmorphic features to rule out genetic disorders of bone or cartilage that may produce SS and other syndromic features of known causes of genetic SS, such as Noonan, Turner, or Silver-Russell syndromes.

In some cases of SS, with a diagnosis of FSS, subtle features of monogenic disorders may be present and should be sought diligently and will help serve to revise the diagnosis.


Following a thorough history and relevant physical examination, most cases of familial short stature (FSS) can be properly diagnosed. Some experienced providers do not investigate at all when the diagnosis of FSS is clear. However, in certain instances, when CDGP occurs in combination with FSS, the provider is dealing with a very short child, much shorter than the usual FSS patient, and added to this is the additional delay in the onset of puberty. A family history of delayed puberty, in addition to SS in other family members, may be a good clue to this combination. Such clues may include a male relative with delayed facial hair growth and late age of onset of shaving or a female relative with delayed menarche.

A bone age (BA) estimation using an x-ray of the non-dominant hand along with standard tables of ossification provides vital tools. The BA equals the chronological age (CA) in FSS.

A short child much below the usual percentile of FSS, even when SS is familial, will need investigations consistent with the history and physical examination to exclude pathological causes of short stature.

Patients with partial growth hormone deficiency (GHD) cannot be definitively distinguished from FSS, ISS, or CDGP, given the sensitivity of the GH stimulation tests currently available. Hence, for such cases, clinical judgment must prevail.

A list of investigations that may be useful in excluding other causes of SS are the following:

  1. Bone age (X-ray of the non-dominant hand and wrist); compared with age-specific standards. (Greulich and Pyle charts).
  2. Hemogram, hemoglobin electrophoresis (for suspected thalassemia)
  3. Serum albumin (nutritional status)
  4. Thyroid function tests (hypothyroidism)
  5. IGF1, IGFBP3, and GH stimulation tests (GH deficiency, insensitivity)
  6. Renal function tests (chronic kidney disease)
  7. Liver function tests (liver diseases)
  8. Serum calcium, phosphorus, alkaline phosphatase, intact PTH (hypophosphatemic rickets, pseudo-hypoparathyroidism)
  9. Serum anti-gliadin antibodies and anti-endomysial antibodies (celiac disease)
  10. Karyotyping (Turner syndrome)
  11. Genetic analysis and special tests: GH receptor gene mutations, GH1 gene deletion, post-translational signaling defects of GH, low or undetectable GH binding protein, IGF1 gene deletion and inactivating mutations, or GH inactivating antibodies (selected rare cases of FSS with unexplained IGF1 deficiency; secondary causes of low IGF1, like malnutrition and liver disease, must first be excluded).[21]

Treatment / Management

Once the diagnosis of familial short stature (FSS) is established, its management follows. Support care and reassurance for both the child and family are required and may need a team effort. Family expectations must be addressed, and realistic outcomes should be emphasized.

One study of recombinant growth hormone (rGH) for short normal children (FSS) showed a marginal increase in final height (2.5 cms). In such cases, the authors concluded that it did not justify either the exorbitant costs or the hazards of long-term exposure to rGH.[22]

In only two studies, which divided the GH treated children with SS into FSS and non-FSS subgroups, was the height increment in FSS compared to the non-FSS subgroups and was determined to be much lower.[23][24][25]

The studies conducted thus far on rGH therapy in SS, which have included children with FSS, have had several limitations like insufficient numbers, lack of control groups, different dosages of rGH, and undiagnosed conditions producing pathological SS.

Given the lack of definitive evidence of the benefits of rGH in FSS, especially a lack of benefit in self-esteem and/or quality of life, the FDA has not approved treatment with rGH for this indication. The treatment cost is prohibitive, and the response in both familial and non-familial ISS is very unpredictable. More well-designed studies are needed in this area, and any attempt to use GH for FSS should be considered as "off-label."

Recombinant IGF1 is useful in IGF1 deficiency due to gene deletions or mutations.

Attention must be given to detect psychological problems in children with FSS, which may be the result of teasing, bullying, and discrimination by peers as well as society. Although it is generally believed that such problems are universal in children with SS, there may be a selection bias. This is because the majority of the data are from pediatric clinics, where children with problems are seen. In the Wessex growth study, a large sample of community-dwelling children whose only problem was SS was studied. Results did not show increased cognitive, psychosocial, or maladaptive dysfunction, thus dispelling the myth that SS universally has psychosocial issues.[26]

Differential Diagnosis

The most important and equally common condition that has to be differentiated from familial short stature (FSS) is CDGP. In most cases, the differentiation is simple. Children with CDGP resemble FSS because they have normal birth length and weight; they have a "catch down growth" that crosses percentiles and have a normal growth rate. However, they differ since they are slightly above the growth curve, develop puberty later, and have a bone age that is delayed by at least two years. The final height in CDGP is much greater than that found in FSS:

Height velocity or the rate of linear growth can help to differentiate the causes:

Normal height velocity: familial short stature and CDGP.

Slow height velocity: growth hormone deficiency.

GSS: final height that is below the 3rd percentile.

CDGP: final height in the normal range.

The majority of children born small for gestational age (SGA) will catch up with height and weight during the first two years of life. A few, however, fail to catch up and remain short. This type of individual can be distinguished by obtaining a careful history.

Other causes of proportionate SS are Turner, Noonan, and Russell-Silver syndromes are differentiated by various associated physical findings and investigations.

The children with FSS have an adequate nutritional status and are easily distinguished from states of malnutrition, where weight is affected more than height.

Chronic systemic illnesses have features peculiar to their condition and can be easily distinguished from FSS; since children with FSS are healthy and active.

Hypothyroidism may present with SS; but have a delayed bone age, deceleration of growth velocity, and other characteristic findings. Thyroid function tests will help confirm the diagnosis.

Cushing syndrome is a rare cause of SS. In this case, children are sick, have distinguishing physical findings, delayed bone age, growth deceleration, and typical laboratory test results.

Classical GH deficiency has physical features of the condition, symptoms, signs of deficiencies of other pituitary hormones, delayed bone age, very significant SS, growth deceleration that extends from onset of the disease and continues throughout, a low IGF1, IGFBP3, and poor GH responses to stimulation tests.

It is when GH deficiency is partial or incomplete that distinguishing it from FSS or CDGP becomes difficult. Here, the GH stimulation tests are not sensitive enough to make that determination.[21]

In pre-pubertal boys older than 11 years and girls older than ten years, it is important to prime with sex steroids before GH stimulation studies; otherwise, many children with CDGP (and some with combined FSS and CDGP) may be misdiagnosed as GH deficiency and unnecessarily exposed to rGH therapy. There is a significant difference in the GH response to stimulation when sex-steroid priming is employed. Either 2 mg of 17-beta-estradiol (for both boys and girls) orally two days before the test or testosterone (for boys) 50 mg intramuscularly a day before the procedure is recommended. Obesity blunts GH responses to stimulation testing. Many normal children also show ambiguous responses following a single stimulation procedure. Therefore, it is important to test with two modalities for accurate classification.[21][27]


Children with familial short stature (FSS) will attain their predicted height when the mid-parental height is taken into consideration but will end up as short adults compared to others of the same age, gender, and population.


There are no complications if an expectant approach is adopted in FSS. Psychological problems should be diligently sought and managed early, and efficiently; otherwise, it may affect the child's psyche, school performance, and cause low self-esteem.


Familial short stature is caused by multiple factors, and its effects are not only on the phenotype; rather, they are on the psyche of the patients and their families as well. Consequently, it is imperative to take on board different disciplines to enhance patient outcomes. Following are the mandatory consultations:

  • Primary care (family medicine, pediatrics)
  • Pediatric endocrinology
  • Laboratory medicine
  • Clinical genetics and molecular medicine
  • Clinical psychology

Deterrence and Patient Education

Education of the family coping with classic familial short stature (FSS) is extremely important to avoid unnecessary investigations and treatments. They should be made to understand why short parents have short children. Simple terminology to explain the genetic nature of the condition should be employed.

For children exhibiting combined FSS and CDGP, the SS may be more profound, and families should be counseled to engage in investigations to exclude pathological SS.

At the same time, if evaluation implicates monogenic disorders that warrant more extensive testing, the appropriate approach should be pursued.

The services of a clinical psychologist will sometimes be necessary. Such a professional can play a vital role in helping the child with FSS and the family cope with unforeseen life experiences.

Pearls and Other Issues

Children with GSS will ultimately attain a final height that is below the 3rd percentile. Whereas children with CDGP will achieve a final height in the normal range. However, this differentiation may not be absolute.

The height velocity is normal in children with familial (or genetic) short stature. But it is slowed in children presenting with GH or thyroid deficiencies.

Enhancing Healthcare Team Outcomes

Quite often, in practice, the primary care providers must be familiar with the entity of familial short stature (FSS) as it is frequently encountered. Indeed, they should be prepared to try to convince anxious parents that rGH treatment has not been approved for FSS. This is in contrast to some cases of ISS, where some studies have (not conclusively) demonstrated benefit.[22][23][24] [Level 2]

The laboratory medicine personnel should be provided with a summary of the child's clinical history. Coordination between the laboratory staff and the provider will help conduct tests such as GH stimulation more accurately.

Occasionally, genetic tests may be needed, and extensive counseling on testing, avoidance of unnecessary procedures, and adaptation to the environment will need inter-professional communication with the provider, laboratory, nurses, and clinical psychologists to improve outcomes and enhance team performance.

Article Details

Article Author

Venkatraman Rajkumar

Article Editor:

Muhammad Waseem


8/7/2022 9:16:17 AM

PubMed Link:

Familial Short Stature



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