The child with tall stature and/or abnormally rapid growth

INTRODUCTION — Statural growth, a fundamental characteristic of childhood, is a complex process that is determined by the interaction of genetics, nutrition, and socioeconomic factors [1]. Regular assessment of growth is an essential part of pediatric practice and includes comparison of a child's growth pattern to established norms. When determining the normality of a child's growth pattern, serial measurements of height and calculation of height velocity (HV) is more useful than a single height-for-age percentile [2]. In interpreting a child's HV, allowance must be made for age, pubertal maturation, and other factors.

The causes, diagnosis, and treatment of children with abnormally rapid growth and tall stature will be reviewed here. The evaluation of children with short stature is discussed elsewhere. (See "Causes of short stature" and "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 1 (IGF-1), androgens, and thyroid hormone all stimulate chondrogenesis, while glucocorticoids inhibit chondrogenesis. Estrogens promote linear growth by stimulating GH and IGF-1 secretion, but also accelerate chondrocyte senescence, leading to fusion of the growth plates and cessation of linear growth [3]. As a result, estrogen deficiency or insensitivity (eg, caused by pathogenic variants in the estrogen receptor and aromatase genes), inhibits closure of the epiphyses, thus causing continued linear growth and tall stature. (See 'Uncommon endocrine causes' below.)

●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 [4,5].

●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 "Causes of short stature", section on 'SHOX gene variants'.)

Although many genetic alterations at the growth plate diminish growth (see "Causes of short stature"), several other genetic conditions promote linear growth. These include gain-of-function pathogenic variants in NPR2 [6,7] and loss-of-function variants in FGFR3 that cause a syndrome characterized by camptodactyly (ie, bent finger that cannot be straightened), tall stature, and hearing loss (CATSHL) [8,9]. In addition, pathogenic variants that lead to alterations in epigenetic regulation are noted as the causes of Sotos syndrome, Weaver syndrome, and DNMT3A overgrowth syndrome [10-13]. Marfan syndrome is caused by certain pathogenic variants in FBN1, whereas other variants in FBN1 cause Weill-Marchesani syndrome, which includes short stature [14]. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on '5q35 deletion syndrome (Sotos syndrome)' and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

EVALUATION OF CHILDREN AND ADOLESCENTS WITH TALL STATURE — Although tall stature is as common as short stature, few children or their families seek medical attention for tall stature, presumably because it is socially acceptable and may be advantageous. Referrals for tall boys who are otherwise healthy are very rare. Referral for tall girls was common in the past but is now infrequent because of the increased social acceptance of tall girls and tall women in many societies.

Most children who grow excessively are part of a continuum of a normal distribution curve, and only a minority will have a defined abnormality of growth [15-17]. Nevertheless, it is important to identify children in whom tall stature or an accelerated growth rate is a symptom of an underlying disorder (table 1).

Evaluation of a child suspected of having tall stature is guided by answering the following questions:

●Is the child's height abnormal for the population?

●Is the child's growth abnormally rapid?

●Is the child's growth within the range for the biologic family?

●Is there evidence of accelerated growth?

The answers to these questions guide a focused history and physical examination, and, in some cases, laboratory evaluation, to determine the cause and appropriate management [15].

Is the child's height abnormal for the population? — Normal growth is defined by the variance of growth within the reference population. The normal range usually is defined as length or height within 2 standard deviations from the population mean (Z-score between -2 and +2). This threshold is equivalent to a height between the 2.3^rd percentile and 97.7^th percentile.

Tall stature is typically defined as length or height ≥97.7^th percentile (Z-score ≥2) compared with the reference population. Less stringent definitions use length or height ≥95^th percentile (Z-score ≥1.66). Height percentiles and Z-scores can be determined by plotting on a height-for-age chart or by using a calculator (calculator 1 and calculator 2). (See "Measurement of growth in children", section on 'Length or height'.)

For children with early puberty for their age, use of standard height-for-age references may exaggerate their degree of tall stature. For these children, growth potential may be more accurately assessed by using special Tanner stage-adjusted (TSA) growth standards, which are captured in this online calculator or by plotting the child's growth on a TSA-adjusted growth curve, selected for their stage of pubertal maturation (sexual maturity rating) [18].

Is the child's growth abnormally rapid? — The second step in evaluating tall stature is determination of the child's growth rate or height velocity (HV). This requires serial measurements of height. Growth can be considered unusually rapid if:

●The height-for-age curve has deviated upward across two major height percentile curves (eg, from below the 75^th percentile to above the 90^th percentile) in children between two years of age and the onset of puberty (figure 1A-B). This pattern of growth reflects rapid height velocity, even if the patient has not developed tall stature. During the peripubertal period, height percentiles often increase for children who begin their pubertal growth spurt early then return to previous channels before their peers do the same.

●Or, if the child is growing more rapidly than the following rates (which represent the 90^th percentile for HV):

•Age two to four years – HV more than 9 cm/year (>3.5 inches/year)

•Age four to six years – HV more than 8.5 cm/year (>3.3 inches/year)

•Age six years to puberty:

-HV more than 6 cm/year for boys (>2.4 inches/year)

-HV more than 6.5 cm/year for girls (>2.6 inches/year)

●For a more precise assessment of linear growth, the child's HV can be plotted on an HV chart (figure 2A-B) to determine the HV percentile for the child's age and sex.

Is the child's growth within the range for the family? — The heights of the biologic parents reflect the genetic component for the child's growth. A general estimate of a child's genetic height potential can be obtained by calculation of the midparental height, which is based upon the heights of both parents and adjusted for the sex of the child. Whenever possible, the parents' heights should be directly measured rather than self-reported. The calculation can be performed using a calculator (calculator 3). This yields prediction of the child's adult height, sometimes called "target height". For both boys and girls, 8.5 cm (3.3 inches) on either side of this calculated value represents the 3^rd to 97^th percentiles for predicted adult height. (See "Normal growth patterns in infants and prepubertal children", section on 'Predicted height'.)

This method is substantially less accurate than the bone-age based method described below because it does not reflect disease processes or environmental contributions to growth, which may affect skeletal maturation. (See 'Bone age' below.)

Is there evidence of accelerated growth? — For children with abnormally rapid HV, and especially those whose anticipated adult height is tall for the biologic family, we suggest determination of bone age.

Bone age — Bone age is a measure of skeletal maturity, obtained by assessing the appearance and shape of the growth plates and bones of the left hand and wrist from a radiograph; this requires expert interpretation by a radiologist or endocrinologist with experience in the technique. The results can be used to inform estimates of the child's growth potential and likely adult height.

The bone age also helps to determine the differential diagnosis for the child's rapid growth. Most endocrine causes of tall stature are associated with advanced bone age, except for sex hormone deficiency or insensitivities, which are associated with delayed bone age. By contrast, familial tall stature usually is associated with normal bone age. (See 'Statural overgrowth in infancy' below and 'Statural overgrowth in childhood and adolescence' below.)

History and physical examination — The child's pattern of growth, medical history (including detailed family history), and physical examination are the mainstays of assessment of tall and/or rapidly growing children. When dysmorphic features are found, special effort should be made to rule out the disorders and syndromes that are associated with excessive growth, including referral to an appropriate subspecialist, if available. Features that suggest a specific cause of overgrowth are outlined in the table and detailed below (table 1).

STATURAL OVERGROWTH IN INFANCY — Accelerated growth occurring during fetal life and infancy has several causes.

Maternal diabetes mellitus — Maternal diabetes mellitus is the most common cause of large-for-gestational age infants. As an example, a population-based study of infants born to mothers with type 1 diabetes showed that 47 percent were large for gestational age, defined as weight greater than 90^th percentile [19]. Maternal hyperglycemia leads to fetal hyperglycemia, which in turn causes fetal hyperinsulinemia. The hyperinsulinemia results in increased fetal growth, an increase in subcutaneous tissue, and enlargement of most organs, including the liver. Affected infants usually are large, more so in weight than in length [20]. Because of hyperinsulinemia, infants of diabetic mothers should be monitored for hypoglycemia during the first hours and days of life [21]. The hyperinsulinemia is transient, so this condition does not in itself cause overgrowth in infancy or childhood. However, there is an association between macrosomia at birth caused by maternal diabetes and later development of obesity. (See "Infants of mothers with diabetes (IMD)".)

Cerebral gigantism — Infants with cerebral gigantism (Sotos syndrome, MIM #117550) tend to be large at birth and continue to grow rapidly during the early years of childhood. Puberty usually occurs early in these children, resulting in premature epiphyseal fusion and, hence, adult height is normal in many of these children [22,23]. Thus, intervention usually is not needed. Distinctive dysmorphic features include macrocephaly, high forehead, frontal bossing, hypertelorism, prominent jaw, high arched palate, intellectual disability, and poor coordination. Most affected children have advanced bone age. Growth hormone secretion and serum insulin-like growth factor 1 (IGF-1) concentrations are normal. Most patients have intellectual disability; in a study of 52 patients with Sotos syndrome, the mean intelligence quotient score was 61, with a standard deviation of 17 [24].

The syndrome is sporadic in most cases, although some familial cases segregating in an autosomal dominant pattern have been described. Pathogenic variants of the NSD1 gene have been identified in the majority of individuals with Sotos syndrome [25]. (See "Microdeletion syndromes (chromosomes 1 to 11)", section on '5q35 deletion syndrome (Sotos syndrome)'.)

Beckwith-Wiedemann syndrome — Infants with the Beckwith-Wiedemann syndrome (MIM #130650) have a growth pattern similar to that of children with cerebral gigantism [26]. Affected children are tall and have advanced bone age and rapid growth during early childhood, which then slows; adult height is above the range predicted for the family [27]. Cardinal features present in most patients are macroglossia, abdominal wall defects (eg, omphalocele), macrosomia, ear creases/pits, organomegaly, neonatal hyperinsulinemic hypoglycemia, lateralized overgrowth, and risk for embryonal tumors including hepatoblastoma, neuroblastoma, and Wilms tumor [28,29]. Overexpression of insulin-like growth factor 2 (IGF-2) is probably an important determinant of the phenotype, although there are other growth-regulatory genes in the region that may also participate [30]. (See "Beckwith-Wiedemann syndrome" and "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)

Other overgrowth syndromes — In addition to cerebral gigantism described above, other syndromes that are associated with generalized overgrowth include Perlman syndrome (MIM #267000), Simpson-Golabi-Behmel syndrome (MIM #312870), Weaver syndrome (MIM #277590), Marshall-Smith syndrome (MIM #602535), Malan syndrome (MIM #614753) [31], and Gorlin syndrome (MIM #109400) [32].

In addition to Beckwith-Wiedemann syndrome described above, syndromes that are associated with segmental (patchy) overgrowth include isolated hemihyperplasia (MIM %235000), CLOVE syndrome (MIM #612918), and Klippel-Trenaunay syndrome (MIM %149000) (see "Capillary malformations (port wine birthmarks) and associated syndromes", section on 'Associated syndromes'); as well as segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus (SOLAMEN) syndrome and Proteus syndrome (MIM #176920). (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Proteus-like syndrome'.)

STATURAL OVERGROWTH IN CHILDHOOD AND ADOLESCENCE — Accelerated growth occurring in childhood or adolescence can result from familial factors as well as both endocrine and nonendocrine disorders. Endocrine causes can involve hormone excess, deficiency, or resistance.

Normal variant of growth

Familial tall stature — Familial tall stature, also known as constitutional tall stature, is a variant of the normal pattern of childhood growth and development. It is defined as a condition in which the height of an individual is 2 standard deviations above the corresponding mean height for same age and sex in the population, in the absence of pathologic causes of tall stature [17].

Diagnosis — The diagnosis of familial tall stature is established by a family history of tall stature and lack of dysmorphic features, which permits distinction from the syndromes of excessive growth. These children usually have a height velocity in the high-normal range (around 6 cm/year between six years and puberty). The bone age is normal and may be used to predict adult stature. (See 'Bone age' above.)

Treatment — Medical treatment of children and adolescents with familial tall stature was common in the past, particularly for girls, but is now strongly discouraged except in extreme cases [33,34]. This is because of increased cultural acceptance of tall stature and recognition of side effects of treatment, which include reduced fertility [35] and increased prevalence of depression not related to adult height [36]. The data presented below come from studies of children with familial tall stature, but they may be applicable to other causes of rapid growth in which the underlying disorder cannot be corrected.

Psychosocial problems in tall adolescent girls and boys have been recognized by pediatricians and endocrinologists, and in the past these were often used as a rationale for treatment [37-39]. However, dissatisfaction with treatment is common among girls who were treated for tall stature. In one study, more than 40 percent of treated women were dissatisfied with their (or their parent's) decision to assess and treat [40]. Dissatisfaction was related to the patient not having an active role in the decision-making, negative experiences with the assessment or treatment procedures, side effects of therapy, or late complications that women believed were associated with the therapy.

Sex steroids have been used in the treatment of tall boys and girls since the late 1950s. The goal is to promote premature epiphyseal fusion [41,42]. Estrogen causes epiphyseal fusion in both girls and boys [43,44]. The effects of steroid hormones on bone maturation are caused by an indirect action mediated by the growth hormone-IGF-1 axis, combined with a direct effect on the epiphyses [45].

●Estrogens – For treatment of tall girls, estrogen in the form of estradiol or ethinyl estradiol, was used relatively frequently starting in the 1950s and peaking in the 1990s [46]. Treatment was usually started when the patient's bone age was between 10 and 12 years, and always before a bone age of 14 to 15 years [47]. The earlier the intervention, the more likely that adult height would be decreased [47]. Treatment was continued until the epiphyses fused because post-treatment growth may be substantial if cessation is premature.

The following considerations should guide treatment decisions:

•The mean adjusted height reduction after estrogen treatment varies from 1.1 to 2.4 cm, and ranges vary from -2.6 cm to 6.2 cm [48,49], significantly less than previously claimed [46].

•Estrogen side effects include nausea, weight gain, edema, and hypertension; other potential problems, such as thromboembolism and endometrial hyperplasia, have not been definitely related to estrogen therapy in children but also should be discussed.

•Estrogen treatment during adolescence may have a negative impact on later fertility [50,51]. This was illustrated in a study of 1243 adult women with hereditary tall stature, 310 of whom had been treated with estrogen as adolescents [35]. After adjustment for age, those who had received estrogen had an increased risk of infertility (inability to conceive after 12 months of trying; relative risk [RR] 1.8, 95% CI 1.4-2.3) and had lower fecundity (40 percent less likely to conceive in any given menstrual cycle of unprotected intercourse) when compared with those who had not received estrogen therapy. There were no differences in the distribution of infertility diagnoses between the estrogen-treated and untreated groups, and the mechanism for the increase in risk is unknown. (See "Overview of infertility".)

●Androgens – Androgens also accelerate epiphyseal fusion, presumably via aromatization to estrogens [17]. Although testosterone can be given as treatment of constitutional tall stature in boys, its use for this purpose is extremely uncommon and not without risk. Usually, it is given in the form of a long-acting intramuscular testosterone ester, mean dose 500 mg/m² per month. In clinical practice, 500 mg every two weeks, or 250 mg every one or two weeks are used [17,52]. It is more effective if started when the bone age is less than 14 to 15 years of age and can increase growth if started at older bone ages [47].

●Epiphysiodesis – Percutaneous epiphysiodesis is a surgical damage of the growth plates of the tibia and femur under general anesthesia with a small surgical drill, with the purpose of restriction of excessive growth in very tall boys and girls. In a study of 77 Dutch adolescents, treatment with this procedure resulted in a 7.0 cm (± 6.3 cm) reduction in adult height compared with predicted height in boys and a 5.9 cm (± 3.7 cm) reduction in adult height in girls [53]. Short-term complications were reported in 5.1 percent and long-term complications in 2.6 percent of treated patients. This treatment option should be considered only in very tall patients, if a surgeon with appropriate experience with this procedure is available and if the patient and their family understand that data are limited and that it is not possible to predict a positive outcome in an individual patient.

Endocrine disorders

Precocious puberty — Sexual precocity is much more common in girls than boys. It can be central (also known as gonadotropin-dependent precocious puberty) or peripheral (also known as gonadotropin-independent precocious puberty) [54]. In both cases, linear growth is accelerated during childhood, often with markedly advanced bone maturation. This results in the paradox of the tall child who, because of very early epiphyseal closure, will be short as an adult. (See "Definition, etiology, and evaluation of precocious puberty".)

Central precocious puberty is either idiopathic or secondary to a central nervous system abnormality. Peripheral precocious puberty may be caused by congenital adrenal hyperplasia, virilizing adrenal, testicular and ovarian tumors, ovarian cysts, testotoxicosis (familial male-limited precocious puberty), McCune-Albright syndrome, human chorionic gonadotropin-secreting tumors (in males) and, rarely, longstanding severe primary hypothyroidism (Van Wyk-Grumbach syndrome). (See "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of central precocious puberty' and "Definition, etiology, and evaluation of precocious puberty", section on 'Causes of peripheral precocity'.)

Hyperthyroidism — Hyperthyroidism caused by endogenous overproduction of thyroid hormones or overtreatment with exogenous thyroxine may lead to increased growth and advanced bone age; if endogenous or exogenous hyperthyroidism occurs during infancy, it may lead to craniosynostosis [55]. Treatment restores euthyroidism and normalizes the growth rate, leading to "catch-down" growth. As a result, the tall stature and transient increase in linear growth that occurs while the child is hyperthyroid usually do not require separate intervention. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents" and "Evaluation and management of neonatal Graves disease".)

Uncommon endocrine causes

●Sex hormone deficiency or insensitivity – Permanent hypogonadism, that is, permanent deficiency of testosterone in males or of estrogen in females, results in delayed skeletal maturation, a prolonged period of growth, and tall stature with eunuchoid proportions (long legs, diminished upper-lower segment ratio, and low sitting height compared with height). As an example, case reports describe several male patients with estrogen deficiency resulting from aromatase deficiency or estrogen resistance caused by a pathogenic variant of the estrogen receptor gene. These individuals had incomplete epiphyseal closure and extreme tall stature, as well as osteopenia [43,44]. (See "Evaluation and management of primary amenorrhea" and "Causes of primary hypogonadism in males".)

●Growth hormone excess – Excessive growth hormone secretion causes gigantism in growing children and acromegaly after fusion of the epiphyses, usually in adults. Although rare in children, the possibility of gigantism should be considered when the height exceeds +3 to +4 standard deviations (>99.9^th percentile) [56]. Bone age is normal or may be delayed if the adenoma interferes with pituitary secretion of gonadotropins. (See "Pituitary gigantism".)

●Familial glucocorticoid deficiency – Familial glucocorticoid deficiency is a grouping of rare autosomal recessive disorders characterized by hypoglycemia, seizures, and increased skin pigmentation. The type 1 form (MIM #202200) is also associated with tall stature or advanced bone age and clinical manifestations of adrenal insufficiency and is caused by pathogenic variants of MC2R [57-60]. The type 2 form is caused by pathogenic variants in the MRAP gene and is not associated with tall stature [61]. Biochemical findings in both forms include extremely high plasma adrenocorticotropic hormone (ACTH) concentrations, together with low or undetectable serum cortisol concentrations that do not increase in response to exogenous ACTH stimulation. (See "Causes of primary adrenal insufficiency in children", section on 'Familial glucocorticoid deficiency'.)

Excessive production of adrenal androgens probably is responsible for the tall stature. Another suggestion is that the high plasma ACTH concentrations may activate melanocyte-stimulating hormone receptors in cartilaginous growth plates and that the increase in height is caused by the unopposed anabolic action of growth hormone [57].

●Familial glucocorticoid resistance – Familial glucocorticoid resistance (MIM #615962, also known as generalized glucocorticoid resistance) is caused by variants in the NR3C1 gene. It is a rare cause of hypercortisolism but may lead to excessive growth because the resistance leads to increased ACTH levels, which may then stimulate adrenal androgen production and generalized hyperpigmentation. The disorder presents in females with hirsutism, male pattern baldness, menstrual abnormalities, and infertility, and presents in males with isosexual precocious puberty, abnormal spermatogenesis, and infertility. Because this is a form of peripheral precocity, the testes are relatively small compared with the degree of growth and virilization. The bone age is advanced and many individuals who are quite tall during childhood and adolescence do not become unusually tall adults [62]. (See "Premature adrenarche", section on 'Other hyperandrogenic causes of premature pubarche' and "Causes of differences of sex development", section on 'Glucocorticoid resistance'.)

●Congenital total lipodystrophy – Congenital total lipodystrophy (MIM #608594 and others) is a rare autosomal recessive disorder. The diagnosis can be based on clinical criteria, but genetic testing is the gold standard [63]. The main clinical features, in addition to overgrowth and acromegaloid changes, are generalized absence of subcutaneous fat, muscular hypertrophy, hyperpigmentation, enlargement of the penis or clitoris, advanced bone age, insulin resistance, hyperinsulinemia, hyperlipidemia, and nonketotic hyperglycemia [64,65]. Large doses of insulin are given to avoid decompensation, but normoglycemia may not be attainable. Adult height in these patients tends to be normal or tall [66]. (See "Lipodystrophic syndromes", section on 'Congenital generalized lipodystrophy'.)

Nonendocrine disorders

Obesity — Common obesity (ie, not syndromic or monogenic) may be accompanied by modest overgrowth and early onset of puberty, especially in girls [67]. These children usually have diminished overall growth hormone production but normal serum concentrations of insulin-like growth factor 1 (IGF-1) and IGF binding proteins, typically in conjunction with tall stature for age prior to puberty. However, bone age may be advanced and puberty may start early, causing premature epiphyseal fusion so that adult height is not increased. These adolescents often attain normal adult height unless puberty starts unusually early, in which case they may not reach their midparental target height [68]. (See "Clinical evaluation of the child or adolescent with obesity".)

Melanocortin 4 receptor pathogenic variant — Children with obesity due to pathogenic variants in the melanocortin 4 receptor (MIM #618406), which is the most common monogenic cause of obesity in humans, also tend to have increased liner growth [69,70]. This results in height that is taller than predicted from their obesity alone. Possible mechanisms include an increase in growth hormone pulsatility, which contrasts to the decreased level seen in exogenous obesity, and an increase in insulin secretion. (See "Obesity: Genetic contribution and pathophysiology", section on 'Heritable factors'.)

Klinefelter syndrome — Klinefelter syndrome is caused by an abnormality in chromosome number in which two or more X chromosomes are present in phenotype males [71]. The most common abnormal karyotype is 47,XXY. Prepubertal boys often are tall for their age with relatively long legs compared with the trunk, and they may have learning disabilities, mainly in expressive language. Small testes and gynecomastia are the most common features on physical examination during adolescence. Other genital abnormalities may be present, such as small phallus, hypospadias, and cryptorchidism. Almost all boys enter puberty but there is marked heterogeneity in the degree of virilization. Bone age may be normal or delayed, depending on the level of testosterone secretion. (See "Causes of primary hypogonadism in males", section on 'Klinefelter syndrome' and "Hypospadias: Pathogenesis, diagnosis, and evaluation" and "Specific learning disorders in children: Clinical features", section on 'Risk factors'.)

Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations are typically normal in prepubertal children with Klinefelter syndrome, but are often high in adolescents and adults. Usually, serum testosterone concentrations are in the low normal adult range. Testosterone treatment can be initiated during the pubertal years to facilitate development of secondary sexual characteristics and minimize the psychologic complications of hypogonadism [72].

47,XYY (Jacobs) syndrome — Boys with a 47,XYY karyotype tend to have tall stature and mild problems in motor and language development [73]. Adults with this syndrome are tall, have large teeth, radioulnar synostosis, clinodactyly, tremor, incoordination, and sometimes neurodevelopmental problems including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders [74]. No treatment for the tall stature is required, unless desired by the patient. (See "Sex chromosome abnormalities", section on '47,XYY syndrome'.)

Marfan syndrome — Marfan syndrome (MIM #154700) is an autosomal dominant abnormality of connective tissue characterized by tall stature, long, thin fingers (arachnodactyly), disproportionately long arms compared with the trunk (dolichostenomelia), hyperextension of joints, and lens subluxation, usually in the upward and outward direction. Pectus excavatum, scoliosis, aortic or mitral regurgitation, and aortic root dilatation may be present. Bone age usually is normal. Female and male patients with this syndrome may attain excessively tall height, and treatment with estrogen in women and testosterone in men may be indicated, especially if any orthopedic problem is present. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

The basic defect in Marfan syndrome has been traced to an altered fibrillin gene (FBN1) on chromosome 15q21.1 [75,76]. Fibrillin is a connective tissue protein found in microfibrils, a constituent of elastic tissue; these microfibrils are abundant in affected tissues [76].

Homocystinuria — Classic homocystinuria (MIM #236200) is an inherited inborn error of methionine metabolism caused by a deficiency of the enzyme cystathionine synthetase [77,78]. Some of the clinical features are similar to those of Marfan syndrome, with subluxation of the lens being the most consistent finding, although the direction of subluxation is usually downward and inward. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders" and "Ectopia lentis (dislocated lens) in children", section on 'Genetic causes'.)

Fifty percent of patients with homocystinuria have intellectual disability. Life-threatening thromboembolic phenomena may occur at any age, and early onset of osteoporosis is seen [79]. A subset of patients respond to treatment with pyridoxine (vitamin B6); a methionine-restricted diet also may be helpful [80]. No treatment for the tall stature is recommended.

Neurofibromatosis type 1 — Neurofibromatosis type 1 (MIM #162200) is an autosomal dominant disorder that comprises at least 85 percent of all cases of neurofibromatosis [81]. It is caused by an abnormality of neural crest differentiation and migration during the early stages of embryogenesis. This disorder is linked to the NF1 gene that encodes neurofibromin, a protein that normally restricts cell proliferation. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

Short stature is common (as a result of precocious puberty), but rare patients are excessively tall who have otherwise unexplained dysregulated growth hormone secretion [82,83]. Thus, neurofibromatosis should be considered in patients with overgrowth.

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: Growth hormone deficiency and other growth disorders".)

SUMMARY AND RECOMMENDATIONS

●Definitions – Tall stature is defined as length or height ≥97.7^th percentile (Z-score ≥2) for the population. Less stringent definitions use length or height ≥95^th percentile (Z-score ≥1.66). Height percentiles and Z-scores can be determined by plotting on a height-for-age chart (figure 1A-B) or calculated using a calculator for standing height for boys (calculator 1) or for girls (calculator 2). Abnormally rapid growth is suggested if a child's height has deviated upward across two major height percentile curves between two years of age and the onset of puberty. (See 'Is the child's height abnormal for the population?' above.)

●Evaluation

•Height velocity – Calculation of height velocity (HV) is an important step in the assessment of a child with tall stature. HV above the following thresholds usually is abnormal and should prompt an evaluation for a growth abnormality:

-Age two to four years – HV more than 9 cm/year (>3.5 inches/year)

-Age four to six years – HV more than 8.5 cm/year (>3.3 inches/year)

-Age six years to puberty:

HV more than 6 cm/year for boys (>2.4 inches/year)

HV more than 6.5 cm/year for girls (>2.6 inches/year)

For a more precise assessment of linear growth, the child's HV can be plotted on an HV chart (figure 2A-B) to determine the HV percentile for the child's age and sex; an HV greater than the 90^th percentile is considered abnormal. (See 'Is the child's growth abnormally rapid?' above.)

•Height prediction – A general estimate of a child's genetic height potential can be obtained by calculation of the midparental height, which is based upon the heights of both biologic parents and adjusted for the sex of the child. The calculation can be performed using an equation or calculator (calculator 3). A tall child whose height is within the range expected for the biologic family is likely to have familial tall stature. (See 'Is the child's growth within the range for the family?' above.)

•Bone age determination – For children with abnormally rapid HV, and especially those whose projected height is tall for the biologic family, the evaluation for tall stature should also include radiographic determination of bone age. This result is used to predict height potential. This provides a more accurate estimate of the child's adult height than the midparental height method. It also identifies delayed or accelerated skeletal growth, which may be associated with certain endocrine disorders. (See 'Bone age' above.)

●Causes of tall stature

•Familial tall stature – Familial (constitutional) tall stature, a variant of the normal pattern of childhood growth and development, is defined as a condition in which the height of an individual is more than 2 standard deviations above the corresponding mean height for a normal subject of the same age and sex, in the absence of pathologic causes of tall stature. Distinguishing features are a family history of tall stature and lack of dysmorphic features, which permits distinction from pathologic causes of excessive growth. We do not recommend medical treatment for most children with familial tall stature (Grade 1B), because there is little evidence of psychosocial benefits and because of possible adverse effects, including increased risks for infertility. (See 'Familial tall stature' above.)

•Pathologic causes – The possibility of a disorder causing rapid growth should be considered in children with abnormal HV (as defined above), or in any child with rapid growth and features suggestive of an underlying disorder, including dysmorphic features, disproportionate growth (eg, long arms or legs compared with the trunk), precocious puberty or hypogonadism, or developmental delay (table 1). Abnormal HV should be evaluated even if the child has not developed tall stature.

-Causes of abnormally rapid growth during infancy include maternal diabetes mellitus, cerebral gigantism (Sotos syndrome), and Beckwith-Wiedemann syndrome. (See 'Statural overgrowth in infancy' above.)

-Endocrine causes of abnormally rapid growth during childhood and adolescence include precocious puberty (including virilizing congenital adrenal hyperplasia), growth hormone excess (pituitary gigantism), hyperthyroidism, and familial glucocorticoid deficiency or resistance. (See 'Statural overgrowth in childhood and adolescence' above.)

-Nonendocrine causes of abnormally rapid growth include Klinefelter syndrome and Marfan syndrome. Exogenous obesity is often associated with high-normal growth rates and relatively tall stature for age prior to puberty. However, bone age may be advanced so that adult height is not increased. A subset of patients with early onset obesity have pathogenic variants in the melanocortin 4 receptor (MC4R) and tend to have particularly tall stature as a child, which persists into adulthood. (See 'Nonendocrine disorders' above.)