Lawrence S. Neinstein, M.D., F.A.C.P.
Professor of Pediatrics and Medicine
USC Keck School of Medicine
Executive Director
University Park Health Center
Associate Dean of Student Affairs
   

 

 

Puberty - Abnormal Growth and Development (A2)

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Section A1 discusses normal pubertal growth and development. This section includes a discussion of disorders of growth and/or puberty and causal conditions as well as the ability to initiate specific diagnostic assessments and therapeutic management with the involvement of the adolescent, the family and, when appropriate, other health professionals.

Pubertal changes are highly variable from teen to teen including the age of pubertal onset, the duration of time between SMRs and the age of menarche. Table 1 below lists the normal variation in timing of adolescent secondary sexual development while Table 2 and Table 3 list pubertal growth characteristics in U.S. and European adolescents

Table 1: Means and normal variation in the timing of adolescent secondary sexual development (Males)

   
Time between stages (yr)
Percentile
Stage
Mean age at onset ( ± 2SD) (yr)
Stage Mean 5th 95th

G2
11.6 ± 2.1
G2-3 1.1 0.4
2.2
G3
12.9 ± 2.1
PH2-3 0.5 0.1 1.0
PH2
13.4 ± 2.2
G3-4 0.8 0.2 1.6
G4
13.8 ± 2.0
PH3-4 0.4 0.3 0.5
PH3
13.9 ± 2.1
G4-5 1.0 0.4 1.9
PH4
14.4 ± 2.2
PH4-5 0.7 0.2 1.5
G5
14.9 ± 2.2
G2-5 3.0 1.9 4.7
PH5
15.2 ± 2.1
PH2-5 1.6 0.8 2.7
Adapted from Barnes HV. Physical grwoth and development during puberty. Med Clin North Am 1975:59:1305

Table 2 : Pubertal growth characteristics in four U.S. longitudinal studies

Parameter University of California at Berkeley
Denver Child Research Center
Fels Research Institute Harvard School of Public Health

Girls
       
Age at peak height velocity (y)
11.01 (0.83) 11.01 (0.91) 10.96 (0.80) 11.13 (0.87)
Height at takeoff (cm)
141.79 (7.60) 137.25 (6.64) 138.57 (7.44) 140.33 (7.19)
Adult height (cm)
168.12 (6.23) 168.23 (6.69) 168.02 (5.15) 165.75 (5.07)
Pubertal gain (cm)
26.83 (5.69) 30.98 (4.04) 29.45 (6.80) 25.34 (5.64)
       
Boys
       
Age at peak height velocity (y)
13.06 (1.08) 13.31 (1.08) 12.99 (0.93) 12.90 (0.94)
Height at takeoff (cm)
150.60 (6.98) 149.42 (7.14) 149.95 (7.03) 147.39 (5.72)
Adult height (cm)
180.74 (6.58) 180.40 (5.41) 180.85 (5.79) 175.56 (6.11)
Pubertal gain (cm)
30.14 (5.43) 30.98 (4.66) 30.90 (4.34) 28.17 (5.51)

Values are mean (SD)
Adapted from Abbassi V. Growth and normal puberty. Pediatrics 1998;102:507-511

Table 3: Pubertal growth characteristics for European, white American, and British children

Parameter Boys Girls
American European and British American European and British

Age at takeoff (yr)
10.45 (1.47) 12.05 (12.05) 9.25 (1.15) 10.30 (0.95)
Height at takeoff (cm)
144.00 (-) 146.09 (6.33) 138.00 (-) 137.91 (7.02)
Age at peak height velocity (yr)
13.57 (1.11) 13.91 (0.84) 11.49 (1.17) 11.89 (0.90)
Peak height velocity (cm/yr)
9.49 (1.44) 8.80 (1.05) 8.14 (1.25) 8.13 (0.78)
Final adult height (cm)
177.00 (-) 173.64 (6.11) 163.00 (-) 163.16 (5.94)
Pubertal height gain (cm)
33.00 (-) 27.56 (3.54) 25.00 (-) 25.25 (4.14)

Data are mean (SD)
Adapted from Abbassi V. Growth and normal puberty. Pediatrics 1998;102:507-511

Sometimes an adolescent's growth falls outside the range of normal and they may be too short, too tall, or possibly not as sexually developed as their peers. These problems may lead to significant concerns for the adolescent and their family. The two main pubertal growth problems are delayed puberty and short stature.

DELAYED PUBERTY

Usually two standard deviations (SD) above and below the mean are used to define the range of normal variability. Adolescents that are beyond these limits should be considered for evaluation for hypothalamic, pituitary, gonadal dysfunction, or undiagnosed chronic illness. Some useful guidelines include:

Male Guidelines for delayed puberty

  • Genital (G) stage 1 persists beyond age 13.7 years, or pubic hair (PH) stage 1 persists beyond 15.1 years of age.
  • More than 5 years have elapsed from initiation to completion of genital growth.
  • The following sexual maturity ratings (SMRs) persist past the listed guidelines:
    • G2 > 2.2 years
    • G3 > 1.6 years
    • G4 > 1.9 years
    • PH2 > 1.0 year
    • PH3 > 0.5 year
    • PH4 > 1.5 years

Female Guidelines for delayed puberty

  • Breast (B) stage 1 persists beyond age 13.4, or pubic hair stage 1 persists beyond 14.1 years, or there is failure to menstruate beyond 16 years of age.
  • More than 5 years have elapsed between initiation of breast growth and menarche.
  • The following sexual maturity ratings persist past the listed guidelines:
    • B2 > 1.0 year
    • B3 > 2.2 years
    • B4 > 6.8 years
    • PH2 > 1.3 years
    • PH3 > 0.9 years
    • PH4 > 2.4 years

These general guidelines should always be taken in the context of the adolescent's family history of growth and pubertal development.

Differential Diagnosis

The differential diagnosis of delayed puberty can be divided between those processes associated with short stature and those associated with normal stature (listed below). In many cases, the function of the primary care physician will be to identify that there is a problem with growth and to identify common problems such as constitutional delay or thyroid dysfunction or a chronic disease state.

PUBERTAL DELAY WITHOUT SHORT STATURE
  • Constitutional delay of puberty
  • Acquired gonadotropin deficiency
    • Central Hypothalamic-Pituitary Tumors: Craniopharyngioma, hypothalamic glioma, astrocytoma, pituitary adenomas
    • Head Trauma
    • CNS Infections: Viral encephalitis, tuberculosis
    • Histiocytosis X
    • Sarcoidosis
  • Isolated gonadotropin deficiency
    • Kallmann syndrome
    • Other disorders with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) deficiency
  • Acquired gonadal disorders
    • Infections: Gonorrhea, tuberculosis, viral
    • Trauma
    • Postsurgical removal
    • Postradiation, chemotherapy
  • Congenital gonadal disorders
    • Klinefelter syndrome
    • Anorchism
    • Pure gonadal dysgenesis
    • Enzyme defects in androgen and estrogen production
  • Androgen receptor defects
    • Complete ( previously referred to as Testicular feminization)
    • Incomplete ( previously referred to as a variety of syndromes, including Reifenstein syndrome)
  • Chronic diseases
    • Congenital or acquired heart disease
    • Asthma
    • Inflammatory bowel disease
    • celiac disease
    • Juvenile rheumatoid arthritis
    • Systemic lupus erythematosus
    • Anorexia nervosa
    • Hyperthyroidism
    • Galactosemia (in girls)

PUBERTAL DELAY WITH SHORT STATURE

  • Constitutional delay of puberty and normal variant short stature
  • Panhypopituitarism
    • Congenital
    • Acquired
      • Infectious: Viral, tuberculosis
      • Posttraumatic
      • Central Tumors
      • Sarcoidosis
      • Histiocytosis
  • Congenital syndromes
    • Turner: Female
    • Noonan: s: Male or female
    • Mixed gonadal dysgenesis
    • Prader-Willi
    • Laurence-Moon-Biedl
    • Alström's
  • Glucocorticoid excess
  • Chronic diseases
    • Chronic heart disease
    • Asthma
    • Inflammatory bowel disease
    • celiac disease
    • Juvenile rheumatoid arthritis
    • Tuberculosis
    • Chronic renal failure
    • Renal tubular acidosis
    • Sickle cell anemia
    • Hypothyroidism
    • Diabetes mellitus
    • Systemic lupus erythematosus
    • Anorexia nervosa
    • Cystic fibrosis
    • Infection with human immunodeficiency virus (HIV)
    • Use of stimulants for attention deficit disorder

The most common cause of delayed maturation in adolescents is constitutional delay of puberty. However, it is important to consider other causes. Important items in the evaluation include:

History including growth record, family history of growth disorders and ages of maturation, review of systems, and nutritional history.

Physical examination should include a complete examination but particularly focus on:

  • nutritional status
  • body measurements
  • sexual maturity rating
  • thyroid exam
  • cardiac exam (for congenital heard disease)
  • chest exam (for chronic pulmonary disease)
  • abdominal exam (hepatosplenomegaly as sign of chronic system disease)
  • external vaginal examination (evaluate for presence of uterus and ovaries)
  • neurologic exam (for intracranial pathology)

Basic Laboratory tests might include:

  • complete blood count (anemia)
  • urinalysis (chronic renal disease)
  • sedimentation rate (screen for chronic systemic disease)
  • chemistry panel including glucose, creatinine, calcium phosphorus, albumin, protein and liver enzymes
  • A bone age is an essential part of the evaluation for delayed puberty. Delayed bone age will be seen in adolescents with hypopituitarism, hypothyroidism, chronic illness, and constitutional delay of puberty. Normal or delayed bone age may be seen in patients with Turner syndrome.
  • TSH: A screen for thyroid dysfunction with a TSH is important.

Other tests that might be used in specific cases include: MRI or CT of head, IGF-1 or IGFBP-3 levels, karyotype (if turner's is a concern), GI series or colonoscopy (if inflammatory bowel disease is a concern), celiac panel (if malabsorption is a concern), pelvic ultrasound (if question of normal uterus or ovaries) and gonadotropin levels (if gonadal failure is a concern). Even more advanced tests might include growth hormone measurements in conjunction with a stimulus such as glucagon (if growth hormone deficiency is a consideration), gonadotropin-releasing hormone (GnRH) stimulation test and human chorionic gonadotropin (hCG) test

Constitutional Delay of Puberty

Over 90% of delayed puberty is secondary to constitutional delay of puberty. The following items should be considered in making the diagnosis of constitutional delay of puberty:

  • The review of systems is negative for a chronic disease that could contribute to growth failure.
  • Nutritional status is normal
  • Growth has occurred at a rate of at least 3.7 cm/year
  • Physical examination if essentially normal including genital anatomy and sense of smell
  • There is a normal CBC, sedimentation rate, urinalysis result and TSH
  • There are non castrate levels of serum LH and FSH (may not be needed in all cases)
  • The bone age is delayed 1.5 to 4.0 years
  • Supportive evidence includes a family history of constitutional delay and a height between 3 rd and 25th percentiles for chronologic age

Adolescents with constitutional delay of puberty and their families will need support and reassurance that puberty and growth will occur. Follow-up is critical to make sure another abnormality has not been overlooked and that puberty does occur. Short courses of low dose testosterone have been used in adolescents with severe psychological problems secondary to a significant delay in maturation.

As most other causes of delayed puberty are irreversible, the health care provider must be prepared to help the adolescent with long term follow-up and psychological support including identification of the problem, potential for growth and sexual maturation, sexual identity and reproductive potential.

Short stature

As adult height is genetically determined; any evaluation of short stature must be assessed with family members' height as a guide. Generally, the 3rd percentile is used as the lower limit of normal. An adolescent should be considered for an evaluation of short stature if:

  • A linear growth rate of less than 4.0-5.0 cm/yr exists in the years before the normal age for peak linear growth velocity.
  • No evidence exists of a peak linear-growth-velocity year by age 16 in the male or age 14 in the female.
  • Distinct deceleration below the individual's established growth velocity occurs.
  • The adolescent's height is more than 2 SD from mid-parental height.
  • The adolescent's height is more than 3 SD below the mean. Adolescents whose height is between 2 and 3 SD below the mean deserve a careful history and physical examination, screening laboratory tests, and observation of growth for 6 months.

The differential diagnosis can be divided between those processes associated with normal puberty and those associated with simultaneous delay of puberty.

Short Stature without Pubertal Delay

  • Familial short stature
  • Isolated GH deficiency
  • Hypothyroidism (can also be associated with pubertal delay)
  • Congenital syndromes such as Down, Noonan, and Hurler's
  • Intrauterine growth retardation
  • Skeletal disorders; chondrodysplasias
  • Chronic illness
  • HIV infection

Short Stature with Pubertal Delay

  • Constitutional delay of puberty
  • Panhypopituitarism: Congenital and acquired
  • Congenital syndrome:
  • Turner and mixed gonadal dysgenesis
  • Syndromes associated with hypogonadotropic hypogonadism such as Prader-Willi and Laurence-Moon-Biedl
  • Glucocorticoid excess
  • Chronic illness
  • HIV infection

The evaluation of short stature is similar to that of delayed puberty listed above

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Questions

Question #1
What is the general guideline for determining significant concern in regards to delayed puberty or short stature?

Answer #1
In general there is more concern when an adolescent is two standard deviations from the mean. This may be slightly altered depending on the history of puberty and stature in the family.


Question #2
Should there be concern in a male who is a genital stage 1 or female who is a breast stage 1 and is 14.5 years of age?

Answer #2
Yes, as both males and females should have started genital development (males) and breast development (females) before the age of 14.


Question #3
What is the most common cause of delayed puberty in adolescents?

Answer #3
Constitutional delay of puberty. This condition accounts for over 90% of cases of delayed puberty in adolescents.


Question #4
An adolescent is being evaluated for delayed puberty and short stature. The teen is 14 and the bone age is 14. Is this consistent with constitutional delay of puberty?

Answer #4
No. In general, by definition a teen with constitutional delay of puberty must have a delayed bone age. However, usually the delay is between 1.5 and 4.0 years. A teen with a bone age that is delayed over 4.0 years should be evaluated much more closely for other causes.

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Cases

CASE #1

A 14 1/2 year old adolescent male comes to see you in the office with his parents. His parents complain that he is short.

Question
What are some of the key history points to obtain in this case?

Answer

  • Growth record - He has in general followed the 15 th percentile in growth until the age of 12 when he appears to have fallen from this curve to about the 5 th percentile.
  • Family history of growth disorders - There is no family history of any hormonal diseases or other chronic diseases but his father remembers being short in school, developing his puberty late and not shaving until after most of his friends. It is also important to explore an estimated height based on parental heights.
  • Review of systems - There are no positive findings on the review of systems.
  • Nutritional history - The teen has been taking a good diet and there is no history of nutritional problems at home.

Question
What are some of the key physical findings to be looking for?

Answer

  • Body measurements - The adolescents is at the 5th percentile for both height and weight. His blood pressure is 110/70 and his pulse at rest is 60.
  • Sexual maturity ratings - He is a SMR of 2 for both pubic hair and genital stage.
  • Neck/thyroid exam - There are no neck masses and no thyromegaly
  • Cardiac exam - There are no murmurs or abnormalities heard
  • Chest exam - Normal and no evidence of chronic respiratory diseases
  • Abdominal exam - No masses or hepatosplenomegaly
  • Neurologic exam - Normal

Question
What would be appropriate screening laboratory in this teen?

  • CBC - Hemoglobin is 12.5 with normal indices. His white blood cells count and platelet count are normal.
  • Urinalysis - No glucose or blood and microscopic exam is normal
  • Sed rate - 10 mm/hr.
  • Chemistry panel - Glucose, reatinine, calcium, albumin and liver enzymes are all normal.
  • TSH - Not absolutely necessary given this teens history but not inappropriate in screening short stature in an adolescent particularly if this was a female adolescent. TSH is normal.
  • Bone Age - The bone age in this teen is 13 and thus about 1.5 years delayed.

Question
What is the likely diagnosis in this teen?

Answer
The likely diagnosis given the recent delay in growth, the normal history of growth as a child, the delay of start of puberty in the father, the normal review of systems and screening laboratory and the delay in bone age would be constitutional delay of puberty. Reassurance to both the family and the teen would be important. However, it important to point out to the family and teen that a few teens do not have catch up growth and though it is likely his ultimate height will be close to that predicted by his midparental heights, it is possible that the teen will be shorter.

 

CASE #2

A 13 year old male presents to the office with history of short stature. His mother states that he has been short since about the age of 6. He has a normal birth history and grew normally until about age 5 or 6 and then seemed to stop growing normally. He was evaluated at a medical center in another area of the country and his mother states they told her he had a "growth hormone deficiency". His mother is an immigrant and speaks English poorly and does not understand his medical condition very well. She states that he only took the pills for a brief period of time and then stopped. They recently moved into the local area. He has continued to grow poorly. He is a B student in school and his only other complaint is dry skin.

The following is a photo of the teen and his skin.

Case 2 Teen and Skin
click for full-size image

The following is a growth curve similar to this teens

Growth Curve
click for full-size image

Key history

  • Body measurements: The adolescents is far below the first percentile for height but is above the 50th in weight. His blood pressure is 100/60 and his pulse at rest is 55.
  • Sexual maturity ratings: He is a SMR of 2 for both pubic hair and genital stage.
  • Physical examination: He appears to have dry skin and dry hair.

Question
What is the most likely diagnosis in this teen and what would be one of the most important blood tests?

Answer
The likely diagnosis is hypothyroidism and it would critical to measure a TSH and T4 level. A growth curve that shows a falling off in height but not weight is suggestive of endocrinopathies especially hypothyroidism and cortisol excess. The teen below is an example of a teen with similar growth curve and with diagnosis of cushings syndrome. Note the central obesity and slight buffalo hump. 

Teen with Cushing's Syndrome
click for full-size image

CASE #3

A 16 year old female presents with history of short stature. She has a history of always growing approximately on the 5 th percentile in height and 10 th percentile in weight. She has never fallen off that curve. Her parents are both average height. The teen has no history of any chronic medical problems or symptoms. Her screening CBC, ESR, chemistry panel and TSH are normal.

The teens height is 58 inches/147 cm tall. Her SMR is 5 for breast and 4 for pubic hair.

Question
What abnormalities are visible on exam and what is the most likely diagnosis?

Teen with short stature
click for full-size image

Answer:
The most likely diagnosis for a teen who has followed their growth curve but is short is either familial short stature (short parents) or a genetic/chromosomal abnormality. This teen has a slightly webbed neck, hyperpigmented nevi, a increased carrying angle (angle at elbow) and she is under 60 inches. That combination might suggest Turner's syndrome. However, it is unusual for a pure Turners to achieve this amount of breast development and in fact this teen had a Turner's mosaic pattern. A female adolescent who is under 60 inches, particularly with normal height parents has to be considered as possibly having Turner's syndrome.

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Web Sites

For Teenagers and Parents

http://www.magicfoundation.org
Magic foundation with information about growth disorders and brochures about many disorders

http://www.hgfound.org
Human Growth Foundation website with information and support for children and adults with growth disorders

http://www.keepkidshealthy.com/welcome/conditions/delayed_puberty.html
Information from keepkidshealty on delayed puberty

http://www.turnersyndrome.org/
Information about Turner syndrome

www.humatrope.com/index.jsp
Information from Eli Lilly Inc. about synthetic growth hormone

http://www.novonordisk.com/
Facts from novo on growth hormone deficiency and treatment

For Health Professionals

www.humatrope.com/index.jsp
Information from Eli Lilly Inc. about synthetic growth hormone

http://www.aafp.org/afp/990700ap/209.html
Review article from American Academy of Family Physicians on evaluation of Growth Disorders

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References

Neinstein L.S. Adolescent Health Care: A Practical Guide, Neinstein LS and Kaufman FR: Abnormal Growth and Development, Lippincott Williams and Wilkins 2002.

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Copyright (©) 2004-2013 Lawrence S. Neinstein, University of Southern California . All rights reserved. Republication or redistribution of the text, table, graphs and photos is expressly prohibited. The University of Southern California shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon.