eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Constitutional Growth Delay

Pamela A Clark, MD, Consulting Staff, McLeod Physician Associates; Consulting Staff, McLeod Pediatric Subspecialties

Updated: Aug 5, 2009

Introduction

Background

Children with constitutional growth delay (CGD), the most common cause of short stature and pubertal delay, typically have retarded linear growth within the first 3 years of life. In this variant of normal growth, linear growth velocity and weight gain slows beginning as young as age 3-6 months, resulting in downward crossing of growth percentiles, which often continues until age 2-3 years. At that time, growth resumes at a normal rate, and these children grow either along the lower growth percentiles or beneath the curve but parallel to it for the remainder of the prepubertal years.

Comparison of the growth patterns between idiopathic short stature and constitutional growth delay.

At the expected time of puberty, the height of children with constitutional growth delay begins to drift further from the growth curve because of delay in the onset of the pubertal growth spurt. Catch-up growth, onset of puberty, and pubertal growth spurt occur later than average, resulting in normal adult stature and sexual development. Although constitutional growth delay is a variant of normal growth rather than a disorder, delays in growth and sexual development may contribute to psychological difficulties, warranting treatment for some individuals. Studies have suggested that referral bias is largely responsible for the impression that normal short stature per se is a cause of psychosocial problems; nonreferred children with short stature do not differ from those with more normal stature in school performance or socialization. A recent study determined that constitutional growth delay was the most common cause of short stature in children.¹

Pathophysiology

Constitutional growth delay is a global delay in development that affects every organ system. Delays in growth and sexual development are quantified by skeletal age, which is determined from bone age radiographic studies of the left hand and wrist. Growth and development are appropriate for an individual's biologic age (skeletal age) rather than for their chronologic age. Timing and tempo of growth and development are delayed in accordance with the biologic state of maturity. Constitutional growth delay may be inherited as an autosomal dominant, recessive, or x-linked trait.²

Frequency

United States

Approximately 15% of patients with short stature referred for endocrinologic evaluation have constitutional growth delay. Individuals with constitutional growth delay and familial short stature represent another 23%. The frequency of constitutional growth delay may be underestimated because individuals with milder delays and those who are not psychologically stressed may not be seen by subspecialists. In a study of 555 (out of 80,000) schoolchildren below the third percentile in height for age with growth rates below normal (<5 cm/y), twice as many boys as girls were affected. Constitutional growth delay was found in 28% of boys and 24% of girls, and another 18% of boys and 16% of girls had familial short stature in combination with constitutional growth delay.

Mortality/Morbidity

Constitutional growth delay is not associated with increased mortality because it is a variant of normal growth rather than a disease. However, in some affected individuals, it can be associated with significant psychological stress, resulting in poor self-image and social withdrawal. Researchers have also found that individuals with constitutional growth delay may be at increased risk for reduced bone mass in adulthood because of the delay in sex steroid influence on bone accrual during adolescence.

A recent study compared associations between bone formation markers and resorption and bone mineral density in healthy children and in children with constitutional growth delay. The study concluded that parathyroid hormone was a valuable marker in bone mineralization during puberty and that accelerated bone mineralization was reflected by high serum parathyroid hormone levels during puberty.³

Race

No racial bias has been identified.

Sex

Although the epidemiologic data indicate that all variants of normal growth are twice as common in boys as in girls, referrals for short stature reflect an even more divergent sex ratio. This likely reflects greater concern about males who are shorter than their peers or who have delayed sexual development.

Age

Patterns of growth consistent with constitutional growth delay occur in infants as young as 3-6 months. However, individuals often do not seek medical attention until puberty, when lack of sexual development becomes a concern and discrepancy in height from peers is magnified by the delay in pubertal growth spurt.

Clinical

History

Individuals with constitutional growth delay (CGD) are usually of normal size at birth. Deceleration in both height and weight velocity typically occurs within the first 3-6 months of life. This shift downward is similar to that observed in infants experiencing normal lag-down growth but tends to be more severe and prolonged. Individual variation is substantial; however, most children resume a normal growth velocity by age 2-3 years. During childhood, these individuals grow along or parallel to the lower percentiles of the growth curve.

Skeletal age, which is estimated from radiographic studies of the left hand and wrist, is usually delayed (typically 2-4 y by late childhood) and is most consistent with the child's height age (age for which a child's height is at the 50th percentile) rather than the child’s chronologic age.

Because the timing of the onset of puberty, pubertal growth spurt, and epiphyseal fusion are determined by a child's skeletal age (biologic age), children with constitutional growth delay are often referred to as "late bloomers."

At the usual age for puberty, these children continue to grow at a prepubertal rate appropriate for their biologic stage of development. Natural slowing of linear growth just before onset of puberty may be exaggerated, emphasizing the difference in size from peers who are accelerating in growth. The timing of the pubertal growth spurt is delayed, and the spurt may be prolonged with a lower peak height velocity. In patients with both constitutional growth delay and familial short stature, the degree of growth retardation may appear more severe, but the adult height is appropriate for the genetic background.

Physical

Physical examination findings in patients with constitutional growth delay are essentially normal, with the exception of immature appearance for age. Body proportions may reflect the delay in growth. During childhood, the upper-to-lower body ratio may be greater than normal, reflecting more infantile proportions. In adults, the ratio is often reduced (ie, <1 in whites, <0.9 in blacks) as a result of the longer period of leg (long bone) growth.

Causes

Constitutional growth delay is thought to be inherited from multiple genes from both parents. The strong role of heredity is reflected in the 60-90% likelihood of this growth pattern in a family member of the same or opposite sex. A delay in the reactivation of the hypothalamic-pituitary pulse generator results in a later onset of puberty.

Differential Diagnoses

Other Problems to Be Considered

Systemic disease

Inflammatory bowel disease
Renal tubular acidosis
Cystic fibrosis
Occult malignancy
Autoimmune disease

Syndromes associated with short stature, pubertal delay, and lack of spontaneous pubertal development

Turner syndrome
Noonan syndrome
Kallmann syndrome
Prader-Willi syndrome
Klinefelter syndrome
Russell-Silver syndrome
Pseudohypoparathyroidism

Other

Growth hormone (GH) insensitivity
Idiopathic short stature (ISS)

Workup

Laboratory Studies

• Constitutional growth delay (CGD) in children with slow growth or delayed puberty is a diagnosis of exclusion. Evaluation excludes hormonal deficiencies, occult systemic illness, or syndromes associated with growth impairment as potential underlying causes.
• Hormonal evaluation includes the following:
  • Thyroid function: Thyroxine (T4) and thyroid-stimulating hormone (TSH) levels are within the reference range in patients with constitutional growth delay.
  • GH production: Random growth hormone (GH) values are of little use because of the pulsatile fashion in which GH is secreted by the pituitary. Rather, levels of insulinlike growth factor-1 (IGF-1) and its major binding protein (IGFBP-3) are measured. They are a reliable reflection of GH production if malnutrition is not a concern. IGF-1 and IGFBP-3 levels are sex and age specific; they should be interpreted using skeletal age (see Radiography) rather than chronologic age. GH production is normal for bone age (biologic age) in constitutional growth delay but may appear decreased if interpreted in the context of chronologic age because of the natural increment in GH production with advancing age and pubertal stage. GH provocative testing may also yield falsely low values in some prepubertal individuals with constitutional growth delay unless they are primed with sex steroids (ie, testosterone, estrogen).
  • Gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) secretion: LH and FSH are helpful only if the skeletal maturation is advanced to the stage consistent with puberty (ie, at least age 10 y in girls and age 12 y in boys). Low levels of these hormones are expected in young children and adolescents with younger skeletal age. This is defined as physiologic hypogonadotropic hypogonadism. Extremely elevated LH and FSH levels are indicative of gonadal dysfunction (ie, pathologic hypergonadotropic hypogonadism) and convey a poor prognosis for spontaneous pubertal development and future sexual function. Such levels are found in patients with Turner syndrome and in patients with Kallmann syndrome (see below) and gonadal damage from chemotherapy and irradiation.
• Routine laboratory studies: Abnormal routine laboratory study findings may suggest the presence of diseases such as inflammatory bowel disease, renal tubular acidosis, occult malignancy, infections, and autoimmune disorders. Routine screening to rule out occult systemic disease as a cause for growth impairment or pubertal delay includes the following tests:
  • CBC count with differential
  • Chemistries including renal and hepatic indices
  • Erythrocyte sedimentation rate
  • Urinalysis
• If syndromes are suspected based on physical examination findings or family history, a karyotype or referral for genetic evaluation may be indicated. Syndromes that may mimic constitutional growth delay include, but are not limited to, the following:
  • Turner syndrome (females) - Short stature and gonadal failure; abnormality of X chromosome
  • Noonan syndrome - Turner phenotype but normal karyotype; often with abnormalities of pubertal development
  • Kallmann syndrome - Hyposmia or anosmia and hypogonadotropic hypogonadism
  • Russell-Silver syndrome - Marked growth retardation of prenatal onset

Imaging Studies

• Radiography: A radiographic study of the left hand and wrist to assess skeletal maturation is critical in diagnosing constitutional growth delay. Typically, the bone age begins to lag behind chronologic age during early childhood and is delayed in adolescence by an average of 2-4 years. Because the timing of puberty, the pubertal growth spurt, and epiphyseal fusion are dependent on biologic age (skeletal maturation) rather than chronologic age, all of these events are delayed in accordance with bone age. Lateral skull radiographs are rarely obtained because they are only helpful in the context of intracranial calcifications, such as those associated with craniopharyngiomas.
• MRI: MRI of the pituitary gland is indicated if pituitary dysfunction is found upon hormonal evaluation or when physical symptoms (eg, visual changes, severe headaches) are present in the context of growth failure or pubertal delay.

Treatment

Medical Care

Medical care in constitutional growth delay (CGD) is aimed at obtaining several careful growth measurements at frequent intervals, often every 6 months. These measurements are used to calculate linear height velocities and establish a trajectory on the growth curve. Medical treatment of this variation of normal growth is not necessary but may be initiated in adolescents experiencing psychosocial distress (see Medication).

Diet

No special dietary requirements are necessary, although a balanced diet with adequate calories and calcium intake is recommended to support normal growth and bone development.

Activity

No restrictions on activity are necessary. However, adolescents with constitutional growth delay who participate in contact sports must realize their limitations in competition with larger, stronger peers. Adolescents who wish to participate in weight lifting or resistance-training activities should use lower weights with greater repetitions to avoid undue stress on immature growth plates.

Medication

Because constitutional growth delay (CGD) is not a disorder but rather a variation of normal growth, medical treatment is not necessary. However, short courses of sex hormones are an option for those patients experiencing psychological distress because of their delay in growth and development. In males, androgens can be used to accelerate linear growth and onset of pubertal changes. When used appropriately, no detrimental effects on adult height are evident. Therapy does not increase adult stature. Guidelines have been established for children in whom growth hormone (GH) therapy is indicated.⁴

Anabolic steroids

These agents promote growth and sexual maturation.

Testosterone (Delatestryl, Depo-Testosterone)

Depot preparation of testosterone available as enanthate or cypionate salt. Available in multiuse vial for IM injection. Transdermal preparations are available and have been used successfully in this context, although no established protocols are available.

Dosing

Adult

300 mg IM q2-3wk is adult replacement dose

Pediatric

50-100 mg IM qmo starting dose; dose can be increased by 50 mg q3-4mo; total duration of therapy 6-18 mo; discontinue when endogenous testosterone production evident (when early-morning testosterone level >150 mg/dL is determined right before an injection would be due)

Interactions

Increase effects of warfarin

Contraindications

Documented hypersensitivity; severe renal, hepatic, or cardiac disease; hypercalcemia; pregnancy; boys with a skeletal age <11.5-12 y (potential lessening of adult height because of more rapid skeletal maturation rather than acceleration in height)

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

Advance dose slowly; do not administer more frequently than monthly to minimize suppression of hypothalamic-pituitary-gonadal axis; anabolic effects may alter serum glucose; not for IV administration; use of oral preparations of testosterone are not appropriate because they have been associated with hepatic toxicity

Follow-up

Further Outpatient Care

• Periodic evaluation of height, weight, and stage of sexual development should be performed in children and adolescents with constitutional growth delay (CGD). Plotting of growth parameters on standard growth charts, calculation of growth velocities, and documentation of Tanner stages for genital or breast and pubic hair development should be included.
• In addition to the above, adolescent males undergoing testosterone therapy should have an early morning testosterone level obtained a day or so before an injection is due when therapy may need to be discontinued. If the adolescent's endogenous testosterone level is 150 mg/dL or greater, therapy can be stopped and pubertal development can be expected to proceed normally.

Inpatient & Outpatient Medications

• Testosterone enanthate or cypionate (optional for males)

Complications

• Short-term complications of constitutional growth delay are primarily limited to psychosocial issues resulting from differences in stature and sexual development from peer groups. As infants, delay in bone age may also manifest as delays in motor skills and control of bowel or bladder function as a result of immature muscular development.
• Long-term consequences of constitutional growth delay are now recognized and may include height at the lower end of the reference range for an individual's family and osteopenia. The height deficit at the onset of puberty, shorter period between the onset of puberty and the adolescent growth spurt, and lower peak height velocity can contribute to a slightly lower adult height. Data on bone density are more conflicting. Osteopenia during adulthood is a concern because of the potential for reduced bone accrual during adolescence. Bone mineralization increases most in girls aged 11-14 years and in boys aged 14-17 years. More than half of adult bone calcium accumulates during this pubertal period. Delays in circulating sex steroids and resultant increases in growth hormone concentrations may lead to permanent deficiencies in bone mass. Some studies show that, although decreases in total bone that may be related to reduced limb bone mass and size may be present, volumetric density is normal.

Prognosis

• Most children with constitutional growth delay attain a normal adult height; however, stature tends to be at the lower end of the reference range for that individual's family because of the lower peak height velocity during the pubertal growth spurt. This observation may also reflect a bias in the individuals studied (more significantly delayed children referred to endocrinologists). Adult height is in contrast to individuals with idiopathic short stature (ISS), in whom stature and growth rate are likely to result in a low adult height (<61 in for males or <57 in for females).
• Predictions for adult height can be obtained through the use of tables designed to take into consideration current height and skeletal maturation. The Bayley-Pinneau tables are most commonly used to offer predictions for adult stature from a bone age in children aged 6-7 years and older. Different tables are available for normal, early, and late maturers because differences in the tempo of puberty and peak height velocity influence growth potential. Patients and parents should be aware that these predictions are estimates that become more accurate with advancing skeletal maturation.

Patient Education

• Education of patients and their families about normal growth patterns and the role of skeletal age as a predictor of onset and progression of puberty and ultimate height potential are important. Once patients realize that their growth pattern is not pathologic, anxiety is often ameliorated and they are less likely to perceive a need for pharmacologic intervention.
• For excellent patient education resources, visit eMedicine's Growth Hormone Deficiency Center. Also, see eMedicine's patient education articles Growth Failure in Children, Growth Hormone Deficiency, Understanding Growth Hormone Deficiency Medications, and Growth Hormone Deficiency FAQs.

Multimedia

Media file 1: Comparison of the growth patterns between idiopathic short stature and constitutional growth delay.

References

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2. Banerjee I, Hanson D, Perveen R, Whatmore A, Black GC, Clayton PE. Constitutional delay of growth and puberty is not commonly associated with mutations in the acid labile subunit gene. Eur J Endocrinol. Apr 2008;158(4):473-7. [Medline].

3. Doneray H, Orbak Z. Association between bone turnover markers and bone mineral density in puberty and constitutional delay of growth and puberty. West Indian Med J. Jan 2008;57(1):33-9. [Medline].

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9. Horner JM, Thorsson AV, Hintz RL. Growth deceleration patterns in children with constitutional short stature: an aid to diagnosis. Pediatrics. Oct 1978;62(4):529-34. [Medline].

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14. Racine MS, Symons KV, Foster CM, Barkan AL. Augmentation of growth hormone secretion after testosterone treatment in boys with constitutional delay of growth and adolescence: evidence against an increase in hypothalamic secretion of growth hormone-releasing hormone. J Clin Endocrinol Metab. Jul 2004;89(7):3326-31. [Medline]. [Full Text].

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Keywords

constitutional growth delay, CGD, delayed puberty, physiologic hypogonadotropic hypogonadism, short stature, idiopathic short stature, ISS, delayed sexual development, physiologic hypogonadotropic hypogonadism, gonadal dysfunction, growth retardation, delayed puberty, diagnosis, treatment

Contributor Information and Disclosures

Author

Pamela A Clark, MD, Consulting Staff, McLeod Physician Associates; Consulting Staff, McLeod Pediatric Subspecialties
Pamela A Clark, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Arlan L Rosenbloom, MD, Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology
Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Barry B Bercu, MD, Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital
Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Lawson-Wilkins Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

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