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INTRODUCTION — Short stature is a term applied to a child whose height is 2 standard deviations (SD) or more below the mean for children of that sex and chronologic age (and ideally of the same racial-ethnic group). This corresponds to a height that is below the 2.3rd percentile. Short stature may be either a variant of normal growth or caused by a disease.
The most common causes of short stature beyond the first year or two of life are familial (genetic) short stature and delayed (constitutional) growth, which are normal non-pathologic variants of growth. The goal of the evaluation of a child with short stature is to identify the subset of children with pathologic causes (such as Turner syndrome, inflammatory bowel disease or other underlying systemic disease, or growth hormone deficiency). The evaluation also assesses the severity of the short stature and likely growth trajectory, to facilitate decisions about intervention, if appropriate.
This topic will review the main causes of short stature. The diagnostic approach to children with short stature is discussed separately. (See "Diagnostic approach to children and adolescents with short stature".)
BIOLOGY OF LINEAR GROWTH — Emerging evidence reveals that normal and pathologic variations in linear growth depend on the balance between proliferation and senescence of chondrocytes at the growth plate. This process is regulated by many systems, including:
●Endocrine mechanisms – Growth hormone (GH), insulin-like growth factor I (IGF-I), androgens, and thyroid hormone all stimulate chondrogenesis, while glucocorticoids inhibit chondrogenesis. Estrogens promote linear growth by stimulating GH and IGF-I secretion, but also accelerate chondrocyte senescence, leading to fusion of the growth plates and cessation of linear growth .
●Proinflammatory cytokines – Some cytokines negatively regulate growth plate function. These are elevated in chronic inflammatory diseases, in which they slow linear growth and also growth plate senescence, which permits catch-up growth after the cytokine effect resolves [2,3].
●Paracrine mechanisms – Including fibroblast growth factors, bone morphogenetic proteins, parathyroid hormone-related protein, and others.
●Cartilage extracellular matrix – Includes collagens, proteoglycans, and other proteins.
●Intracellular pathways – Chondrocyte transcription factors including SHOX, several SOX genes, and the MAPK signaling pathway. (See 'SHOX mutations' below.)
Together, these effects on the growth plate explain the variations in linear growth observed clinically in health and disease, including normal growth and the pubertal growth spurt, normal variation in height, and "idiopathic" short stature due to polymorphisms in these or other genes (see 'Normal variants of growth' below), and growth delay due to malnutrition, inflammatory disease, or glucocorticoid exposure (see 'Pathologic causes of growth failure' below), as well as severe growth failure seen in a variety of skeletal dysplasias (see "Skeletal dysplasias: Specific disorders"). In some cases, loss-of-function mutations in a gene are associated with short stature, while gain-of-function variants in the same gene are associated with tall stature [4-6].
In the clinical setting, these observations explain why GH has variable effects on growth in children with short stature. GH is highly effective in individuals with GH deficiency, but may also have nonspecific stimulatory effects on the growth plate that can partially compensate for growth problems due to some other molecular defects.
NORMAL VARIANTS OF GROWTH
Familial short stature — Familial or genetic short stature is most often a normal variant, termed familial or genetic short stature (figure 1). These individuals usually have low-normal height velocity throughout life. The otherwise normal height velocity generally distinguishes these children from those with pathologic causes of short stature. Their bone age is consistent with their chronological age, which helps distinguish them from children with constitutional delay of growth (table 1). (See 'Constitutional delay of growth and puberty' below.)
Constitutional delay of growth and puberty — Constitutional delay of growth and puberty (CDGP, sometimes called constitutional short stature for prepubertal children) results in childhood short stature but relatively normal adult height. Children with CDGP are usually of normal size at birth. However, a downward shift in growth rate begins at three to six months of age that is parallel to that seen in most normally growing children in this age group, but tends to be more severe and prolonged. By three or four years of age, children with CDGP usually are growing at a low-normal rate (eg, about 4 to 5 cm/year in preadolescent girls, and 3.5 to 4.5 cm/year in preadolescent boys). The result is a growth curve that remains below, but parallel to, the third percentile for height. In addition to a low preadolescent growth rate, they tend to have delayed pubertal development. 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 (figure 2).
The hallmark of CDGP is delayed skeletal age; it is more closely related to the height age (age at which one's height would be average) than the chronologic age (table 1). For these patients, height data should be interpreted according to bone age rather than chronological age to accurately reflect height potential. Because the bone age is delayed, growth typically continues longer than normal, often resulting in adult stature within the normal range. In many cases, there is a family history of delayed growth and puberty in one or both parents (sometimes described as being a "late bloomer").
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 . 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 I (IGF-I) gene; these epigenetic changes are predicted to reduce the individual's sensitivity to growth hormone . (See "Growth hormone insensitivity syndromes", section on 'Impaired IGF-I 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 for males and <59 inches 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 . 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 . 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 [10,11].
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.)
PATHOLOGIC CAUSES OF GROWTH FAILURE
Systemic disorders with secondary effects on growth — Almost any serious disease can cause growth failure (table 2). The abnormalities of growth and development that occur in children with acute or chronic illnesses may result from the primary disease process because of increased energy needs or nutritional deprivation (eg, decreased intake or malabsorption). Growth also may be affected by treatments, such as radiation therapy (a permanent effect), glucocorticoids, stimulants used for attention deficit disorder (ADD), or chemotherapy (mostly transient effects, but may have a small permanent effect if treatment is prolonged [12-15]). Some diseases may cause secondary derangements of the hormones that affect growth.
Diseases or processes that are particularly important causes of growth failure are outlined below. Other disorders that can cause growth failure with weight loss are outlined in a separate topic review. (See "Evaluation of weight loss in infants over six months of age, children, and adolescents", section on 'Differential diagnosis'.)
Undernutrition — Insufficient nutrition tends to lead to short stature with a delayed pattern of growth. Under-nutrition can be isolated (eg, caused by inadequate food supply or self-imposed restriction, such as fear of obesity ), or it may be a component of an underlying systemic disease that interferes with food intake or absorption, or increases energy needs. The hallmark of under-nutrition is low weight-for-height.
Glucocorticoid therapy — Since glucocorticoids are used for treatment of a variety of diseases, they are a common cause of growth failure in children. The growth failure can develop with or without other symptoms of glucocorticoid excess, known as Cushing syndrome (see 'Cushing syndrome' below). They suppress growth through several different mechanisms, including interference 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.
The relative effects of different glucocorticoids on growth are similar, but not identical, to the relative potencies for hypothalamic-pituitary-adrenal axis suppression . Growth impairment is more pronounced with agents with a longer duration of action (eg, dexamethasone > prednisone > hydrocortisone). It is most pronounced when glucocorticoids are administered daily as compared with an alternate-day regimen . Some inhibition of linear growth occurs even at the doses that are used for physiological replacement (ie, prednisone doses of 3 to 5 mg/m2 per day; approximately 0.075 to 0.125 mg/kg per day), and progressive growth impairment is seen with increasing doses . As an example, in a large series of children with growth failure due to chronic treatment with glucocorticoids for a systemic disease, the mean prednisone-equivalent dose was 0.5 ± 0.6 mg/kg per day . Growth impairment can even occur with prolonged administration of inhaled glucocorticoids during childhood, although the overall effect of these agents on adult height appears to be small [20,21]. (See "Pharmacologic use of glucocorticoids", section on 'Dose' and "Major side effects of inhaled glucocorticoids", section on 'Growth deceleration'.)
Prolonged treatment with systemic glucocorticoids may have persistent effects on growth after therapy is discontinued. In a study of 224 children with cystic fibrosis who previously had been treated for up to four years with either alternate-day prednisone or placebo, mean height after age 18 years (on average six to seven years after cessation of therapy) was significantly lower in boys who had received either high- or low-dose prednisone (170.5 and 170.7 versus 174.6 cm with placebo; p = 0.03) . This effect was most pronounced in boys who had started taking prednisone at six to eight years of age. In contrast, there was no persistent growth impairment in girls treated similarly.
Gastrointestinal disease — Children with growth failure resulting from gastrointestinal disease tend to have a greater deficit in weight than height (ie, they are underweight-for-height) in contrast to those with endocrine disorders, who are often overweight-for-height (see below).
Up to 50 percent of children with Crohn disease have a decrease in height velocity before the onset of gastrointestinal symptoms , and about 10 percent of children with Crohn disease have short stature when the Crohn disease is diagnosed . The growth failure is closely related to the inflammatory disease process (mediated by proinflammatory cytokines), as well as decreased food intake, malabsorption, and/or high-dose glucocorticoids if used for treatment (see "Growth failure and poor weight gain in children with inflammatory bowel disease"). Similarly, celiac disease can present with growth failure, especially in younger children . Both of these disorders are important considerations in the evaluation of a child whose linear growth has slowed, particularly if there are gastrointestinal symptoms and/or slow weight gain. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children".)
Rheumatologic disease — Childhood rheumatologic diseases, especially systemic juvenile idiopathic arthritis (JIA), are frequently associated with growth retardation. This may be a consequence of the proinflammatory cytokines associated with disease activity and is also caused by the high-dose glucocorticoids that are often used for treatment [25,26]. Common presenting symptoms in JIA are fever, arthralgias, rash, and lymphadenopathy, in addition to growth failure. (See "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Growth retardation'.)
Chronic kidney disease — 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-I (IGF-I). 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 if used for treatment. 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. (See "Pathogenesis, evaluation and diagnosis of growth impairment in children with chronic kidney disease" and "Growth hormone treatment in children with chronic kidney disease and postrenal transplantation".)
Metabolic acidosis alone can also impair growth, as occurs in children with renal tubular acidosis . Alkali therapy may lead to attainment and maintenance of normal stature . (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children".)
Cancer — Children with cancer may grow poorly before diagnosis because of poor food intake, nausea, vomiting, and increased caloric utilization. After diagnosis, anorexia, nausea, and vomiting induced by chemotherapy and radiotherapy also can contribute to impaired growth. These effects often subside within one to two years of initiating treatment, and some children then have catch-up growth [28,29].
Late growth failure is common in children who received cranial radiotherapy because it can damage the hypothalamus and cause insufficiency of one or more hormones from the pituitary, including growth hormone, gonadotropins, and thyroid stimulating hormone (TSH) [30-34]. In younger children, especially girls, cranial radiotherapy can cause precocious puberty and adult short stature. Primary hypothyroidism also can occur if the thyroid gland was in the radiation field. Spinal irradiation may result in slow growth of the spine with relative preservation of normal limb growth. (See "Bone problems in childhood cancer patients", section on 'Altered epiphyseal growth'.)
Pulmonary disease — Cystic fibrosis is both a pulmonary and gastrointestinal disease. Growth failure in this disorder may be caused by multiple mechanisms, including poor food intake, maldigestion or malabsorption, chronic infection, and increased energy requirements (work of breathing) . (See "Cystic fibrosis: Clinical manifestations and diagnosis" and "Cystic fibrosis: Nutritional issues".)
Immune deficiencies also may present with pulmonary symptoms and/or growth failure. (See "Causes of bronchiectasis in children".)
Asthma has been associated with a deceleration of height velocity, which is most pronounced with severe disease. Growth failure in children with asthma is more often due to treatment with glucocorticoids. (See 'Glucocorticoid therapy' above.)
Cardiac disease — Growth failure is common in children with severe heart disease of any cause. The major pathogenetic factors are thought to be anorexia and increased basal energy requirements . Occasionally, growth failure is the presenting feature of the heart disease. (See "Suspected heart disease in infants and children: Criteria for referral".)
Immunologic disease — Human immunodeficiency virus (HIV) infection is associated with growth failure. Mechanisms include anorexia, malabsorption, diarrhea, severe infections, and failure of one or more organ systems . (See "Pediatric HIV infection: Classification, clinical manifestations, and outcome", section on 'Wasting syndrome'.)
Growth failure also can occur with other immunological deficiencies such as common variable immunodeficiency or severe combined immunodeficiency syndrome. As with HIV infection, multiple factors are probably involved. (See "Common variable immunodeficiency in children" and "Severe combined immunodeficiency (SCID): An overview".)
Metabolic diseases — Growth failure is common in children and adolescents with many of the inborn disorders of metabolism. Among acquired metabolic diseases, the most common is type 1 diabetes mellitus. In the past, type 1 diabetes mellitus was an important cause of short stature and attenuated growth because of caloric deficit resulting from severe glucosuria . However, it is now rare because of improvements in therapy. Children with type 1 diabetes have some decrease in IGF-1 production or action, and there is a negative correlation between hemoglobin A1C (as an index of metabolic control) and adult height [39,40]. Nonetheless, in children with fair to good metabolic control, growth and adult height are usually within normal ranges. Occasionally, children with diabetes and very poor glycemic control develop Mauriac syndrome, characterized by attenuated linear growth, delayed puberty, hepatomegaly, and Cushingoid features. (See "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Growth'.)
Any disorder associated with vitamin D deficiency or decreased vitamin D action can cause hypophosphatemia and rickets; rickets is characterized by abnormal epiphyseal development, bowing of the extremities, and diminished growth. Vitamin D deficiency in the absence of rickets does not seem to affect linear growth. (See "Overview of rickets in children" and "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia".)
Endocrine causes of growth failure — Primary endocrine disorders with effects on growth are uncommon but are important to identify because they can be treated (table 2). In general, these disorders are characterized by excessive weight for height. They should be considered in any child with markedly reduced height velocity, and especially in those with other pituitary disorders, brain tumors, septo-optic dysplasia (also known as optic nerve hypoplasia), midline brain and facial defects, neonatal hypoglycemia, history of cranial irradiation, or a familial pattern of growth hormone deficiency . Any patient with an abnormality of one pituitary hormone (central hypothyroidism, Cushing disease, or growth hormone deficiency) should be evaluated for other pituitary hormone deficiencies.
Cushing syndrome — Cushing syndrome is caused by excessive glucocorticoids and is characterized by the combination of weight gain and growth retardation, resulting in excessive weight-for-height (figure 3) [42-44].
Endogenous Cushing syndrome (caused by excessive endogenous production of cortisol) is rare in children. The most common cause is a corticotropin (ACTH)-secreting pituitary adenoma (Cushing disease) [42,44,45]. The syndrome also may be caused by an adrenal adenoma, especially in younger children. In one series of children with endogenous Cushing syndrome, growth retardation was common (83 percent), but most patients had bone age within normal limits at diagnosis . Other key clinical features are central obesity, suprascapular fat pad ("buffalo hump"), abdominal striae, hirsutism, acne, and neuropsychological symptoms . The best tests to establish the diagnosis are a 24-hour urine collection for free cortisol (and creatinine), or a dexamethasone suppression test. Measurements of serum cortisol are not reliable screening tests, unless performed late at night. (See "Epidemiology and clinical manifestations of Cushing's syndrome" and "Establishing the diagnosis of Cushing's syndrome".)
Exogenous sources of glucocorticoids (eg, due to glucocorticoid therapy for asthma or inflammatory bowel disease) are a much more common cause of Cushing syndrome. (See 'Glucocorticoid therapy' above.)
Hypothyroidism — Growth failure is a well-recognized consequence of hypothyroidism during childhood and may be the presenting feature. The bone age is usually delayed; as a result, many children with hypothyroidism have a reasonably normal growth potential once the disorder is identified and treated. The evaluation should include measurements of both TSH and free thyroxine to allow detection of both primary and central hypothyroidism. Measurement of serum TSH alone will not detect central hypothyroidism as it can be low, normal, or even slightly elevated. (See "Acquired hypothyroidism in childhood and adolescence".)
Growth hormone deficiency — Growth hormone deficiency usually results from deficiency of growth hormone-releasing hormone (GHRH). It can also be caused by sellar and parasellar tumors (eg, craniopharyngioma ) that destroy the pituitary gland itself, in which case there may be deficiencies of multiple hormones produced by the anterior pituitary (see "Clinical manifestations of hypopituitarism"). Children with growth hormone deficiency can have striking catch-up growth during growth hormone replacement therapy . Children with a sellar or parasellar tumor that causes growth hormone deficiency occasionally experience rapid catch-up growth after surgical resection of the tumor without growth hormone treatment; this phenomenon is known as "growth without growth hormone" and is not fully understood [48,49]. A rare cause of growth hormone deficiency is an inactivating mutation of the GHRH receptor that is inherited in an autosomally recessive manner .
If growth hormone deficiency is congenital and complete, the diagnosis is relatively easy to confirm. Affected children present with severe postnatal growth failure, delayed bone age, and very low serum concentrations of growth hormone, IGF-I, and IGF-binding protein-3 (IGFBP-3, the major circulating binding protein for IGF-I) . Additional findings are hypoglycemia, prolonged jaundice, and micropenis, especially if gonadotropins are deficient as well.
In children with less severe growth failure, whose height may still be within the normal range for age, the decision to undertake detailed testing should be based on strict auxological criteria. It is therefore mandatory to obtain accurate serial measurements of height. Any evidence of central nervous system disease or other anterior pituitary hormone deficiencies should lead to measurement of IGF-I and provocative testing of growth hormone (growth hormone stimulation tests). These provocative tests are not definitive but can be a valuable diagnostic tool when combined with auxological and bone age data and measurements of IGF-I and IGFBP-3. (See "Diagnosis of growth hormone deficiency in children".)
Congenital growth hormone insensitivity is a very rare disorder characterized by high serum growth hormone concentrations with low serum IGF-I and IGF binding-protein-3 concentrations . In its complete form, this condition is called Laron-type dwarfism (complete growth hormone insensitivity) . (See "Growth hormone insensitivity syndromes".)
Sexual precocity — Several conditions are associated with increased secretion of gonadal steroids (estradiol in girls and testosterone in boys), which have two consequences. One is sexual precocity. The other is accelerated epiphyseal development, which causes rapid childhood growth but more rapid advancement of bone age. As a result, height age is advanced compared with chronologic age, but it lags behind the markedly accelerated bone age. If their growth is not halted, these tall children will be short adults because early epiphyseal closure stops linear growth prematurely.
There are two types of sexual precocity:
●Gonadotropin-dependent precocious puberty (GDPP), also known as central (or true) precocious puberty, refers to the early occurrence of normal puberty. Precocious puberty historically had been defined as sexual development in girls before the age of eight years and in boys before the age of nine years; however, data for girls, particularly black girls, indicate that the age of onset of normal puberty is younger [52-54]. The hallmarks of precocious puberty are accelerated growth and advanced bone age, plus breast development in girls and penile enlargement and sexual hair growth in boys . The pattern of secretion of pituitary gonadotropins and gonadal sex steroids is normal but early. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of central precocious puberty (CPP)'.)
●Gonadotropin-independent precocious puberty (GIPP), also known as peripheral precocious puberty, refers to sexual precocity due to adrenal or gonadal disorders (or rarely tumor production of human chorionic gonadotropin in boys). This pattern also may be seen in the setting of McCune-Albright syndrome or exposure to exogenous sex steroids. The clinical manifestations are similar to those of GDPP, except that the sexual development may be that of the opposite sex, eg, androgen effects in girls with congenital adrenal hyperplasia. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of peripheral precocity'.)
Children with untreated chronic hyperthyroidism may rarely have a similar pattern with rapid growth accompanied by early epiphysial maturation [56,57]. Pubertal timing is generally normal. (See "Clinical manifestations and diagnosis of hyperthyroidism in children and adolescents", section on 'Growth'.)
Genetic diseases with primary effects on growth — Several genetic disorders have prominent effects on growth. These disorders occasionally present with short stature as the initial clinical manifestation. Many other genetic disorders, such as Down syndrome, include short stature but are not listed here because stature is not a primary identifying characteristic.
Turner syndrome — Turner syndrome is an important consideration in girls with short stature and especially growth failure, because shortness may be the presenting feature of the syndrome; other physical abnormalities are variably expressed (table 3). Virtually all girls with Turner syndrome have short stature, with an average adult height about 20 cm shorter than predicted by the mid-parental height. In addition, affected patients usually have absent or very delayed pubertal development and may have a square "shield" chest, webbed neck, cubitus valgus (increased carrying angle of the arm), genu valgum (inward tilting knees), shortened fourth metacarpals, and Madelung deformity of the forearm (picture 1 and image 1). A Madelung deformity is a growth disturbance in the distal radial epiphysis that results in volar and ulnar tilted distal radial articular surface, volar translation of the hand and wrist, and a dorsally prominent distal ulna and wrist pain; this condition is sometimes termed "bayonet wrist". Prompt diagnosis of Turner Syndrome is important because of associated cardiovascular, renal, and endocrine abnormalities, which may require treatment, including growth hormone therapy. (See "Clinical manifestations and diagnosis of Turner syndrome".)
SHOX mutations — Mutations in the Short Stature HOmeoboX (SHOX)-containing gene on the X chromosome cause a syndrome in which the primary manifestation is short stature, which tends to be more severe in girls (MIM #300582). In addition to short stature, individuals with this mutation tend to have shorter forearms and lower legs (with reductions in arm span and leg length compared with trunk), Madelung deformity of the forearm (focal dysplasia of the distal radial physis) (picture 1 and image 1), cubitus valgus (increased carrying angle of the arm), high arched palate, and muscular hypertrophy (reflected as a short, stocky appearance), as compared with those with idiopathic short stature but no SHOX mutation . These skeletal abnormalities are similar to those seen in many patients with Turner syndrome. (See "Sex chromosome abnormalities", section on 'Xp22 SHOX deletions'.)
SHOX mutations are present in approximately 1 to 4 percent of patients who would otherwise have been classified as having "idiopathic" short stature [58-60]. The SHOX gene is found in the pseudoautosomal region of the X and Y chromosomes, and also is responsible for the short stature and skeletal deformities associated with Turner syndrome, Leri-Weill dyschondrosteosis, and Langer mesomelic dysplasia [59,61-64] (see "Skeletal dysplasias: Specific disorders", section on 'Leri-Weill dyschondrosteosis'). Growth hormone treatment is effective in increasing linear growth in patients with isolated SHOX deficiency [65-67]. (See "Growth hormone treatment for idiopathic short stature".)
Prader-Willi syndrome — Prader-Willi syndrome (PWS) is the most common syndromic form of obesity. Obesity and hyperphagia typically develop during early childhood and can be severe. Other common clinical characteristics are hypotonia and feeding problems during infancy, developmental delay, and hypogonadism. Short stature is common but may not develop until late childhood when the child fails to undergo a pubertal growth spurt. Treatment with growth hormone improves linear growth and body composition. (See "Clinical features, diagnosis, and treatment of Prader-Willi syndrome".)
Noonan syndrome — Noonan syndrome (MIM #163950) is a relatively common autosomal dominant disorder with an estimated incidence of one in 1000 to 2500 live births. Approximately 50 percent of children with Noonan syndrome have a mutation in the PTPN11 gene, mapped to chromosome 12q24.1, which encodes the non-receptor protein tyrosine phosphatase SHP2 [68-70]. Children with mutations in PTPN11 have mild growth hormone resistance . Less common mutations have been described in KRAS, SOS1, and NRAS (which, like PTPN11 mutations, result in upregulation of the RAS-MAP kinase pathway [72-77]), as well as mutations in RAF1, RIT1, MAP2K1, and BRAF [71,78,79]. Mutations in one these genes are found in approximately 70 percent of individuals with Noonan syndrome. Noonan syndrome and neurofibromatosis type 1 may occur together in patients with certain NF1 mutations [80-82] (see "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis"). Some patients with PTPN11 mutations also have a syndrome that includes giant cell lesions of bone or soft tissues. (See "Giant cell tumor of bone".)
Noonan syndrome is characterized by minor facial dysmorphism (hypertelorism, downward eye slant, and low-set ears), proportionate short stature, and heart disease, most often pulmonic stenosis and hypertrophic cardiomyopathy [68,83,84]. Other common findings include a short webbed neck, chest deformity (pectus excavatum), cryptorchidism, intellectual disability (mental retardation), bleeding diathesis, and lymphedema [68,84,85]. There appears to be a modest association between Noonan syndrome and several types of cancer, including neuroblastoma, acute leukemia, low grade glioma, and embryonic rhabdomyosarcoma [86,87].
The cardiac manifestations were assessed in an echocardiographic study of 118 patients with Noonan syndrome . A dysplastic pulmonary valve was present in eight patients (7 percent), six of whom had significant stenosis. Among the 110 patients without valve dysplasia, significant pulmonic stenosis was present in 22 (20 percent). Other abnormalities included secundum atrial septal defects, localized anterior septal hypertrophy, and diffuse hypertrophy.
Short stature associated with Noonan syndrome can be treated effectively with growth hormone and is an approved indication by the US Food and Drug Administration (FDA). (See "Treatment of growth hormone deficiency in children".)
Russell-Silver syndrome — Russell-Silver syndrome (MIM #180860, also known as Silver-Russell syndrome and Russell-Silver dwarfism) is characterized by severe intrauterine growth restriction and postnatal growth retardation with a prominent forehead, triangular face, downturned corners of the mouth, and body asymmetry (hemihypertrophy) [88,89]. The facial features tend to become less obvious with age. The majority of infants have feeding difficulties, and mild developmental delay is seen in about one-third of subjects . In about 60 percent of subjects, the syndrome is associated with epigenetic alterations involving either hypomethylation of an imprinting control region that regulates expression of the insulin-like growth factor-2 (IGF-2) gene and others on chromosome 11p15.5. IGF-2 is known to have important effects on growth, especially during fetal development. About 10 percent of cases are caused by maternal uniparental disomy of chromosome 7 . Accordingly, one study describes severe pre- and post-natal growth restriction in four members of the same family with clinical features of Russell-Silver syndrome, due to a paternally-inherited mutation in the IGF-2 gene .
A few reports describe growth hormone treatment of individuals with Russell-Silver syndrome (which was given based on the indication of growth hormone therapy for individuals born small for gestational age) [92-95]. These individuals had a modest growth response to growth hormone. When growth hormone was started at a young age, the mean adult height in treated subjects was -1.3 SD, compared with an adult height of -3.6 to -2.9 SD in untreated subjects with this disorder . Of note, individuals with the hypomethylation defect tend to have inappropriately high levels of IGF-I and IGFBP-3, suggesting a reduced sensitivity to IGF-I [90,96].
Skeletal dysplasias — Skeletal dysplasias associated with short stature are caused by inherited defects in cartilage/bone development and are often associated with disproportionate short stature (with limbs disproportionately short for the trunk, or vice versa). Some present prenatally and are detected on prenatal ultrasound, whereas others present during childhood with short stature. These disorders should be suspected in a child presenting with short stature and bone deformities, recurrent fractures, or abnormal findings on radiographs (eg, enchondromas, bowing or shortening of the long bones, vertebral defects, or rib abnormalities). There are a variety of types, with very variable phenotypes, including achondroplasia, hypochondroplasia, spondyloepiphysial dysplasia, and osteogenesis imperfecta. In one study, subtle skeletal dysplasias were found in 18.5 percent of patients previously labeled as either idiopathic short stature (ISS) or having been born small for gestational age (SGA) . The most common forms were dyschondrosteosis (due to SHOX mutations in 61.5 percent of those undergoing genetic testing) and hypochondroplasia (due to FGFR mutations in 25 percent of those subjects undergoing genetic testing). These disorders were especially prevalent among those with parents who are also very short. (See "Skeletal dysplasias: Specific disorders" and "Skeletal dysplasias: Approach to evaluation" and "Achondroplasia".)
Other causes of short stature that may be pathologic — Some individuals with apparent ISS may have underlying disorders that are pathologic but not diagnosed during a standard evaluation. If the short stature is severe, these patients warrant a detailed evaluation and ongoing monitoring for the possibility of subclinical underlying systemic disease. These patients also are candidates for growth hormone therapy. (See 'Idiopathic short stature' above and "Diagnostic approach to children and adolescents with short stature" and "Growth hormone treatment for idiopathic short stature".)
About 10 percent of infants born SGA fail to experience catch-up growth sufficient to be within the normal range by two years of age. This growth pattern is more likely in those with severe SGA and can be considered pathologic, although the underlying mechanisms are unclear and likely vary. Depending on the extent of their catch-up growth during childhood and adolescence, these children may also benefit from growth hormone therapy. (See "Growth hormone treatment for children born small for gestational age".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Turner syndrome".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: My child is short (The Basics)")
●Short stature is defined as height that is 2 standard deviations (SD) or more below the mean height for children of that sex and chronological age in a given population. This translates to a height that is below the 2.3rd percentile. (See 'Introduction' above.)
●The two most common causes of short stature are familial (genetic) short stature and constitutional delay of growth and puberty (CDGP), which are normal variants of growth. These growth patterns often can be distinguished from one another, but some children have features of both (table 1). (See 'Normal variants of growth' above.)
●Almost any serious systemic disease can cause growth failure (table 2). Systemic disorders or processes that may present with growth failure and/or delayed puberty include undernutrition, glucocorticoid therapy, gastrointestinal disease (especially Crohn disease and celiac disease), and renal disease. (See 'Systemic disorders with secondary effects on growth' above.)
●A variety of genetic syndromes and congenital malformations are associated with short stature. Turner syndrome is particularly important because shortness and/or absent pubertal development may be the presenting feature, with or without other characteristic clinical features (see 'Turner syndrome' above). Most of these syndromes can be recognized by characteristic clinical features. These include Noonan, Russell-Silver, and Down syndromes. (See 'Genetic diseases with primary effects on growth' above.)
- Nilsson O, Weise M, Landman EB, et al. Evidence that estrogen hastens epiphyseal fusion and cessation of longitudinal bone growth by irreversibly depleting the number of resting zone progenitor cells in female rabbits. Endocrinology 2014; 155:2892.
- Emons JA, Boersma B, Baron J, Wit JM. Catch-up growth: testing the hypothesis of delayed growth plate senescence in humans. J Pediatr 2005; 147:843.
- Sederquist B, Fernandez-Vojvodich P, Zaman F, Sävendahl L. Recent research on the growth plate: Impact of inflammatory cytokines on longitudinal bone growth. J Mol Endocrinol 2014; 53:T35.
- Olney RC, Bükülmez H, Bartels CF, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. J Clin Endocrinol Metab 2006; 91:1229.
- Bartels CF, Bükülmez H, Padayatti P, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 2004; 75:27.
- Hannema SE, van Duyvenvoorde HA, Premsler T, et al. An activating mutation in the kinase homology domain of the natriuretic peptide receptor-2 causes extremely tall stature without skeletal deformities. J Clin Endocrinol Metab 2013; 98:E1988.
- Wood AR, Esko T, Yang J, et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet 2014; 46:1173.
- Ouni M, Castell AL, Rothenbuhler A, et al. Higher methylation of the IGF1 P2 promoter is associated with idiopathic short stature. Clin Endocrinol (Oxf) 2015.
- Cuttler L, Marinova D, Mercer MB, et al. Patient, physician, and consumer drivers: referrals for short stature and access to specialty drugs. Med Care 2009; 47:858.
- Wit JM, Clayton PE, Rogol AD, et al. Idiopathic short stature: definition, epidemiology, and diagnostic evaluation. Growth Horm IGF Res 2008; 18:89.
- Cohen P, Rogol AD, Deal CL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 2008; 93:4210.
- Swanson JM, Elliott GR, Greenhill LL, et al. Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry 2007; 46:1015.
- Biederman J, Spencer TJ, Monuteaux MC, Faraone SV. A naturalistic 10-year prospective study of height and weight in children with attention-deficit hyperactivity disorder grown up: sex and treatment effects. J Pediatr 2010; 157:635.
- Poulton AS, Melzer E, Tait PR, et al. Growth and pubertal development of adolescent boys on stimulant medication for attention deficit hyperactivity disorder. Med J Aust 2013; 198:29.
- Faraone SV, Biederman J, Morley CP, Spencer TJ. Effect of stimulants on height and weight: a review of the literature. J Am Acad Child Adolesc Psychiatry 2008; 47:994.
- Lifshitz F, Moses N. Nutritional dwarfing: growth, dieting, and fear of obesity. J Am Coll Nutr 1988; 7:367.
- Allen DB. Growth suppression by glucocorticoid therapy. Endocrinol Metab Clin North Am 1996; 25:699.
- Punthakee Z, Legault L, Polychronakos C. Prednisolone in the treatment of adrenal insufficiency: a re-evaluation of relative potency. J Pediatr 2003; 143:402.
- Allen DB, Julius JR, Breen TJ, Attie KM. Treatment of glucocorticoid-induced growth suppression with growth hormone. National Cooperative Growth Study. J Clin Endocrinol Metab 1998; 83:2824.
- Wolthers OD, Pedersen S. Growth of asthmatic children during treatment with budesonide: a double blind trial. BMJ 1991; 303:163.
- Doull IJ, Freezer NJ, Holgate ST. Growth of prepubertal children with mild asthma treated with inhaled beclomethasone dipropionate. Am J Respir Crit Care Med 1995; 151:1715.
- Lai HC, FitzSimmons SC, Allen DB, et al. Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis. N Engl J Med 2000; 342:851.
- Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn's disease. Gastroenterology 1988; 95:1523.
- Hernández M, Argente J, Navarro A, et al. Growth in malnutrition related to gastrointestinal diseases: coeliac disease. Horm Res 1992; 38 Suppl 1:79.
- Bechtold S, Roth J. Natural history of growth and body composition in juvenile idiopathic arthritis. Horm Res 2009; 72 Suppl 1:13.
- Polito C, Strano CG, Olivieri AN, et al. Growth retardation in non-steroid treated juvenile rheumatoid arthritis. Scand J Rheumatol 1997; 26:99.
- McSherry E, Morris RC Jr. Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis. J Clin Invest 1978; 61:509.
- Nandagopal R, Laverdière C, Mulrooney D, et al. Endocrine late effects of childhood cancer therapy: a report from the Children's Oncology Group. Horm Res 2008; 69:65.
- Clayton PE, Shalet SM, Morris-Jones PH, Price DA. Growth in children treated for acute lymphoblastic leukaemia. Lancet 1988; 1:460.
- Ogilvy-Stuart AL, Shalet SM. Growth and puberty after growth hormone treatment after irradiation for brain tumours. Arch Dis Child 1995; 73:141.
- Ogilvy-Stuart AL, Stirling HF, Kelnar CJ, et al. Treatment of radiation-induced growth hormone deficiency with growth hormone-releasing hormone. Clin Endocrinol (Oxf) 1997; 46:571.
- Constine LS, Woolf PD, Cann D, et al. Hypothalamic-pituitary dysfunction after radiation for brain tumors. N Engl J Med 1993; 328:87.
- Clarson CL, Del Maestro RF. Growth failure after treatment of pediatric brain tumors. Pediatrics 1999; 103:E37.
- Collet-Solberg PF, Sernyak H, Satin-Smith M, et al. Endocrine outcome in long-term survivors of low-grade hypothalamic/chiasmatic glioma. Clin Endocrinol (Oxf) 1997; 47:79.
- Karlberg J, Kjellmer I, Kristiansson B. Linear growth in children with cystic fibrosis. I. Birth to 8 years of age. Acta Paediatr Scand 1991; 80:508.
- Thommessen M, Heiberg A, Kase BF. Feeding problems in children with congenital heart disease: the impact on energy intake and growth outcome. Eur J Clin Nutr 1992; 46:457.
- McKinney RE Jr, Robertson JW. Effect of human immunodeficiency virus infection on the growth of young children. Duke Pediatric AIDS Clinical Trials Unit. J Pediatr 1993; 123:579.
- Mauras N, Merimee T, Rogol AD. Function of the growth hormone-insulin-like growth factor I axis in the profoundly growth-retarded diabetic child: evidence for defective target organ responsiveness in the Mauriac syndrome. Metabolism 1991; 40:1106.
- Clarke WL, Vance ML, Rogol AD. Growth and the child with diabetes mellitus. Diabetes Care 1993; 16 Suppl 3:101.
- Bonfig W, Kapellen T, Dost A, et al. Growth in children and adolescents with type 1 diabetes. J Pediatr 2012; 160:900.
- Rosenfeld RG, Albertsson-Wikland K, Cassorla F, et al. Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab 1995; 80:1532.
- Magiakou MA, Mastorakos G, Oldfield EH, et al. Cushing's syndrome in children and adolescents. Presentation, diagnosis, and therapy. N Engl J Med 1994; 331:629.
- Joshi SM, Hewitt RJ, Storr HL, et al. Cushing's disease in children and adolescents: 20 years of experience in a single neurosurgical center. Neurosurgery 2005; 57:281.
- Kanter AS, Diallo AO, Jane JA Jr, et al. Single-center experience with pediatric Cushing's disease. J Neurosurg 2005; 103:413.
- Storr HL, Chan LF, Grossman AB, Savage MO. Paediatric Cushing's syndrome: epidemiology, investigation and therapeutic advances. Trends Endocrinol Metab 2007; 18:167.
- Gottschling S, Graf N, Meyer S, et al. Intracranial germinoma: a rare but important differential diagnosis in children with growth retardation. Acta Paediatr 2006; 95:302.
- Zantleifer D, Awadalla S, Brauner R. Growth response to growth hormone during the first year as a diagnosis criterion of growth hormone deficiency. Horm Res 1993; 40:123.
- Iwayama H, Kamijo T, Ueda N. Hyperinsulinemia may promote growth without GH in children after resection of suprasellar brain tumors. Endocrine 2011; 40:130.
- Phillip M, Moran O, Lazar L. Growth without growth hormone. J Pediatr Endocrinol Metab 2002; 15 Suppl 5:1267.
- Maheshwari HG, Silverman BL, Dupuis J, Baumann G. Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: Dwarfism of Sindh. J Clin Endocrinol Metab 1998; 83:4065.
- Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev 1994; 15:369.
- Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 1997; 99:505.
- Biro FM, McMahon RP, Striegel-Moore R, et al. Impact of timing of pubertal maturation on growth in black and white female adolescents: The National Heart, Lung, and Blood Institute Growth and Health Study. J Pediatr 2001; 138:636.
- Rogol AD. Early menarche and adult height: reprise of the hare and the tortoise? J Pediatr 2001; 138:617.
- Kaplan SL, Grumbach MM. Clinical review 14: Pathophysiology and treatment of sexual precocity. J Clin Endocrinol Metab 1990; 71:785.
- Takamatsu J, Kobe N, Ito M, Ohsawa N. Body height and weight of patients with childhood onset and adult onset thyrotoxicosis. Endocr J 1999; 46 Suppl:S101.
- Conwell LS. Graves' disease--acceleration of linear growth. J Pediatr Endocrinol Metab 2009; 22:289.
- Rappold G, Blum WF, Shavrikova EP, et al. Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency. J Med Genet 2007; 44:306.
- Binder G, Renz A, Martinez A, et al. SHOX haploinsufficiency and Leri-Weill dyschondrosteosis: prevalence and growth failure in relation to mutation, sex, and degree of wrist deformity. J Clin Endocrinol Metab 2004; 89:4403.
- Franklin SL, Geffner ME. Growth hormone: the expansion of available products and indications. Endocrinol Metab Clin North Am 2009; 38:587.
- Cormier-Daire V, Belin V, Cusin V, et al. SHOX gene mutations and deletions in dyschondrosteosis or Leri-Weill syndrome. Acta Paediatr Suppl 1999; 88:55.
- Ellison JW, Wardak Z, Young MF, et al. PHOG, a candidate gene for involvement in the short stature of Turner syndrome. Hum Mol Genet 1997; 6:1341.
- Munns CF, Berry M, Vickers D, et al. Effect of 24 months of recombinant growth hormone on height and body proportions in SHOX haploinsufficiency. J Pediatr Endocrinol Metab 2003; 16:997.
- Munns CF, Glass IA, Flanagan S, et al. Familial growth and skeletal features associated with SHOX haploinsufficiency. J Pediatr Endocrinol Metab 2003; 16:987.
- Binder G, Schwarze CP, Ranke MB. Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hormone. J Clin Endocrinol Metab 2000; 85:245.
- Blum WF, Crowe BJ, Quigley CA, et al. Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: Two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metab 2007; 92:219.
- Food and drug administration. FDA approves humatrope for short stature. Fed Regist 2003; 68:24003.
- Tartaglia M, Mehler EL, Goldberg R, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001; 29:465.
- Tartaglia M, Kalidas K, Shaw A, et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002; 70:1555.
- Nakamura T, Gulick J, Pratt R, Robbins J. Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations. Proc Natl Acad Sci U S A 2009; 106:15436.
- Razzaque MA, Nishizawa T, Komoike Y, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 2007; 39:1013.
- Roberts AE, Araki T, Swanson KD, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 2007; 39:70.
- Tartaglia M, Pennacchio LA, Zhao C, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 2007; 39:75.
- Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet 2006; 38:331.
- Noordam K. Expanding the genetic spectrum of Noonan syndrome. Horm Res 2007; 68 Suppl 5:24.
- Cirstea IC, Kutsche K, Dvorsky R, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet 2010; 42:27.
- Tartaglia M, Zampino G, Gelb BD. Noonan syndrome: clinical aspects and molecular pathogenesis. Mol Syndromol 2010; 1:2.
- Pandit B, Sarkozy A, Pennacchio LA, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 2007; 39:1007.
- Allanson JE, Roberts AE. Noonan Syndrome. 2001 Nov 15 [Updated 2016 Feb 25]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1124/ (Accessed on August 16, 2016).
- Hüffmeier U, Zenker M, Hoyer J, et al. A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. Am J Med Genet A 2006; 140:2749.
- Nyström AM, Ekvall S, Allanson J, et al. Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1. Clin Genet 2009; 76:524.
- Ekvall S, Sjörs K, Jonzon A, et al. Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome. Am J Med Genet A 2014; 164A:579.
- Burch M, Sharland M, Shinebourne E, et al. Cardiologic abnormalities in Noonan syndrome: phenotypic diagnosis and echocardiographic assessment of 118 patients. J Am Coll Cardiol 1993; 22:1189.
- Allanson JE. Noonan syndrome. J Med Genet 1987; 24:9.
- Witt DR, Hoyme HE, Zonana J, et al. Lymphedema in Noonan syndrome: clues to pathogenesis and prenatal diagnosis and review of the literature. Am J Med Genet 1987; 27:841.
- Hasle H. Malignant diseases in Noonan syndrome and related disorders. Horm Res 2009; 72 Suppl 2:8.
- Kratz CP, Rapisuwon S, Reed H, et al. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet 2011; 157C:83.
- Eggermann T, Gonzalez D, Spengler S, et al. Broad clinical spectrum in Silver-Russell syndrome and consequences for genetic testing in growth retardation. Pediatrics 2009; 123:e929.
- Price SM, Stanhope R, Garrett C, et al. The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria. J Med Genet 1999; 36:837.
- Wakeling EL. Silver-Russell syndrome. Arch Dis Child 2011; 96:1156.
- Butler MG. Genomic imprinting disorders in humans: a mini-review. J Assist Reprod Genet 2009; 26:477.
- Begemann M, Zirn B, Santen G, et al. Paternally Inherited IGF2 Mutation and Growth Restriction. N Engl J Med 2015; 373:349.
- Toumba M, Albanese A, Azcona C, Stanhope R. Effect of long-term growth hormone treatment on final height of children with Russell-Silver syndrome. Horm Res Paediatr 2010; 74:212.
- Ranke MB, Lindberg A, KIGS International Board. Height at start, first-year growth response and cause of shortness at birth are major determinants of adult height outcomes of short children born small for gestational age and Silver-Russell syndrome treated with growth hormone: analysis of data from KIGS. Horm Res Paediatr 2010; 74:259.
- Smeets CC, Renes JS, van der Steen M, Hokken-Koelega AC. Metabolic Health and Long-Term Safety of Growth Hormone Treatment in Silver-Russell Syndrome. J Clin Endocrinol Metab 2017; 102:983.
- Binder G, Seidel AK, Martin DD, et al. The endocrine phenotype in silver-russell syndrome is defined by the underlying epigenetic alteration. J Clin Endocrinol Metab 2008; 93:1402.
- Flechtner I, Lambot-Juhan K, Teissier R, et al. Unexpected high frequency of skeletal dysplasia in idiopathic short stature and small for gestational age patients. Eur J Endocrinol 2014; 170:677.