McGraw-Hill Specialty Board Review Pediatrics, 2nd Edition

Chapter 5. ENDOCRINOLOGY

CASE 37: A 10-YEAR-OLD BOY WITH SHORT STATURE

A 10-year-old boy comes into your office for a routine physical examination. His only complaint is that he is shorter than all of his friends and he can’t ride the mega roller coaster at the local amusement park because he is shorter than the requirement. You have followed this child for many years, but most visits have been for illness, and his height has not been measured for the last few years. He is not on any medications. He reports occasional fatigue and occasional constipation. On physical examination, his height is less than the 3rd percentile and he is prepubertal.

SELECT THE ONE BEST ANSWER

1. Of the following, which is the least likely to help with his diagnosis?

(A) parental heights

(B) growth velocity

(C) actual height

(D) bone age

(E) weight for height

2. What is the most likely diagnosis if his growth rate is 5 cm/year, height age is 8 years, and bone age is 10 years?

(A) constitutional delay of growth and puberty

(B) undernutrition

(C) hypothyroidism

(D) growth hormone deficiency

(E) intrinsic short stature

3. What is the most likely diagnosis if his growth rate is 5 cm/year, height age is 8 years, and bone age is 8 years?

(A) intrinsic short stature

(B) growth hormone deficiency

(C) Cushing syndrome

(D) constitutional delay of growth and puberty

(E) hypothyroidism

4. What is the most likely diagnosis if his growth rate is 3 cm/year, height age is 8 years, and bone age is 8 years?

(A) exogenous obesity

(B) constitutional delay of growth and puberty

(C) growth hormone deficiency

(D) intrinsic short stature

(E) hypogonadism

5. What is the most likely diagnosis if he has abnormal body proportions and a narrow interpedicular distance in the lower lumbosacral area?

(A) Noonan syndrome

(B) Kallman syndrome

(C) hypochondroplasia

(D) Klinefelter syndrome

(E) Prader-Willi syndrome

6. Which of the following is one of the most common causes of short stature in children?

(A) hypothyroidism

(B) growth hormone deficiency

(C) poor nutrition

(D) chronic illness

(E) familial intrinsic short stature

7. Which of the following tests would you recommend to be included in an initial screen for a 10-year-old boy with an attenuated growth rate?

(A) complete blood count (CBC), karyotype

(B) sedimentation rate, thyroid function tests

(C) CBC, growth hormone level

(D) sedimentation rate, gonadotropin levels

(E) thyroid function tests, growth hormone level

8. Your initial screening tests are normal and you advise that the child return for follow-up so you can assess his growth velocity. When would you advise follow-up?

(A) 1-2 months

(B) 2-3 months

(C) 4-6 months

(D) 7-9 months

(E) 1 year

9. What is the normal growth velocity of a child between the ages of 3 and 10 years?

(A) 3-4.5 cm/year

(B) 4-5.5 cm/year

(C) 5-6.5 cm/year

(D) 6-7.5 cm/year

(E) 7-8.5 cm/year

10. Which of the following is the least accurate way to measure a child?

(A) on a scale equipped with a flexible height arm

(B) standing against a wall

(C) with a wall-mounted stadiometer

(D) with a portable stadiometer

(E) lying supine on a flat surface

11. What is this patient’s genetic height potential if his father is 5'10" and his mother 5'5"?

(A) 5'5"

(B) 5'7"

(C) 5'9"

(D) 5'10"

(E) 6'0"

12. You would be most concerned about a potential growth problem in a child who crossed from the 50th to the 25th percentile for height at what age?

(A) 8 months of age

(B) 2 years of age

(C) 7 years of age

(D) 13 years of age

(E) 15 years of age

13. Which of the following would be least helpful in differentiating between intrinsic short stature and constitutional delay of growth and puberty?

(A) growth rate from 0 to 3 years

(B) growth rate from 3 to 10 years

(C) growth rate from 11 to 14 years

(D) final stature

(E) bone age

14. Which of the following is not a classic feature of growth hormone deficiency?

(A) hypoglycemia during infancy

(B) delayed bone maturation

(C) central distribution of body fat

(D) low serum insulin-like growth factor (IGF)-1

(E) decreased arm span

15. Your patient eventually gets diagnosed with growth hormone deficiency and is started on growth hormone replacement therapy. He starts complaining of severe headaches. The pretreatment head magnetic resonance imaging (MRI) was normal. What would you be most concerned about?

(A) migraine headaches

(B) pseudotumor cerebri

(C) brain tumor

(D) tension headaches

(E) vision change

16. Which of the following conditions presents with an attenuated growth pattern?

(A) constitutional delay of puberty

(B) intrinsic short familial stature

(C) hypothyroidism

(D) A and C

(E) B and C

17. If this child were a 10-year-old girl, what test would you consider checking to help in your evaluation?

(A) karyotype

(B) estradiol

(C) gonadotropin levels

(D) chest radiograph

(E) pelvic ultrasound

18. Which of the following is not a feature of Turner syndrome?

(A) renal anomalies

(B) webbed neck

(C) lymphedema

(D) cubitus valgus

(E) right-sided cardiac anomalies

19. Your patient’s weight is greater than the 97th percentile and he has striae on the abdomen. What would be at the top of your differential diagnosis?

(A) genetic obesity syndrome

(B) exogenous obesity

(C) hypothyroidism

(D) growth hormone deficiency

(E) Cushing syndrome

20. Which of the following is not associated with tall stature as a child?

(A) Klinefelter syndrome

(B) exogenous obesity

(C) hyperthyroidism

(D) excess exogenous corticosteroids

(E) sexual precocity

ANSWERS

1. (C) Actual height. The actual height of a patient is least likely to help with the diagnosis because the only information it provides is that the patient is short for age. Statistically, 3% of the population will be below the normal growth curve. Data on parental heights offer information regarding the genetic height potential of the child. The growth velocity allows you to determine if the child is growing at a normal rate for his age. A predictable pattern of bone maturation occurs during bone growth, and a bone age radiograph is useful to determine the bone maturation and the growth potential of a child. Current weight-for-height is also important and helps to rule out a nutritional component to poor growth. Other important parts of the history include family growth and pubertal history, birth length and weight, and overall health history to rule out chronic disease as a cause of short stature.

2. (E) Intrinsic short stature. Children with intrinsic short stature typically grow at a normal rate but below the normal growth chart. Their bone age is usually equivalent to their chronological age, which are both greater than the height age (height age is the age at which the child’s height falls at the 50th percentile). They go through puberty at a normal time and end up on the shorter side of normal as an adult.

3. (D) Constitutional delay of growth and puberty. Children with constitutional delay of growth and puberty have normal growth rates during childhood, delayed puberty with a delayed pubertal growth spurt, and attainment of normal adult height. Their bone age is usually equivalent to their height age, and both are less than their chronological age. Children with intrinsic short stature also have a normal growth rate, but their bone age would approximate their chronological age. Children with growth hormone deficiency, Cushing syndrome, and hypothyroidism would have an attenuated growth pattern.

4. (C) Growth hormone deficiency. A growth rate of only 3 cm/year would be considered an attenuated growth rate, which is seen in endocrine causes of growth failure, such as growth hormone deficiency, hypothyroidism, and Cushing syndrome. Severe chronic disease and malnutrition can also cause an attenuated growth pattern. Children with exogenous obesity tend to be tall with a normal growth rate. Table 37-1 shows the classification of short stature as it relates to growth rate and bone age.

TABLE 37-1. Classification of Short Stature

 

TYPE

GROWTH RATE

BONE AGE

 

Intrinsic short stature

Normal

Normal

Constitutional delay

Normal

Delayed

Attenuated growth

Decreased

Delayed

 

5. (C) Hypochondroplasia. Hypochondroplasia is often described as a milder form of achondroplasia. However, although they are both transmitted via autosomal dominant transmission, they have not been reported to occur in the same family. Hypochondroplasia is a result of a mutation in the fibroblast growth factor receptor 3 gene. Patients present with short stature and dysmorphic features that are milder than in achondroplasia. They do not have the typical facial features of achondroplasia. These patients have radiologic evidence of a narrow interpedicular distance in the lower lumbosacral area. Children with Noonan syndrome often present with short stature, webbed neck, malformed ears, and right-sided cardiac abnormalities, such as pulmonic stenosis. They have a normal karyotype. Children with Kallman syndrome have hypogonadotropic hypogonadism and anosmia. Boys with Klinefelter syndrome (47,XXY) tend to be tall and often present in adolescence with small testicles. They tend to have school issues. Children with Prader-Willi syndrome present with hyperphagia, obesity, and short stature.

6. (E) Familial intrinsic short stature. The most frequent causes of short stature in children are the genetic normal variants, including familial intrinsic short stature and constitutional delay of growth and puberty.

7. (B) Sedimentation rate, thyroid function tests. General screening tests of overall health including a CBC to rule out anemia, a comprehensive metabolic panel to rule out kidney or liver problems, and a sedimentation rate to rule out underlying inflammation are an important first step in detecting a medical cause of short stature. Hormonal causes of short stature include hypothyroidism, which can be ruled out with thyroid function tests, and growth hormone deficiency. Growth hormone is secreted in a pulsatile fashion; thus a random growth hormone level would not be helpful. Measurements of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are often used to screen for growth hormone deficiency. Gonadotropin levels would not be helpful in a prepubertal 10-year-old child.

8. (C) Four to 6 months. A minimum interval of 4-6 months is typically needed for an accurate determination of growth velocity because seasonal variations in growth velocity have been reported. Although follow-up at 1 year would give the most accurate data on growth velocity, if this child had an attenuated growth pattern, valuable time would be lost in diagnosis and treatment of the growth disorder.

9. (C) The answer is 5-6.5 cm/year. Between the ages of 3 and 10 years, children tend to grow at a constant growth velocity, which averages 5 cm, or 2 inches, per year.

10. (A) On a scale equipped with a flexible height arm. The most reproducible way to measure children is using a wall-mounted stadiometer. In younger children, a supine stadiometer should be used that provides a stationary board at their head and a movable footboard. If a stadiometer is unavailable, the next best way to measure a child would be standing flat against a wall. The flexible height arm on a scale tends to be very unreliable.

11. (D) The answer is 5'10". A child’s genetic height potential can be estimated by calculating mid-parental height. For boys, 5 inches is added to the mother’s height and averaged with the father’s height, and for girls, 5 inches is subtracted from the father’s height and averaged with the mother’s height.

12. (C) Seven years of age. Typically between 3 and 10 years of age, children grow along a certain percentile for height. Any deviation from this percentile is a warning sign of a potential growth problem. During the first 3 years of life, it is not unusual for children to move upward or downward across growth channels toward their mid-parental height range. In addition, children who will go on to have constitutional delay of growth and puberty will often cross percentiles downward within the first 3 years of life. During puberty, children may again cross growth percentiles because the pubertal growth spurt of individuals is often out of phase. Thus a 13-year-old who has delayed puberty may cross percentiles downward even though he or she has a normal prepubertal growth rate.

13. (B) Growth rate from 3 to 10 years. Children with constitutional delay of growth and puberty and intrinsic short stature grow at normal rates between the ages of 3 and 10 years; thus growth velocity alone at these ages will not help differentiate among the causes of short stature. Children with constitutional delay in growth and puberty tend to fall off the normal growth curve between 0 and 3 years of age, grow slower than normal between the ages of 11 and 14 years because they are not yet in puberty, and end up at a normal stature as an adult. In contrast, children with intrinsic short stature tend to follow parallel but below the normal lines on the growth chart, and they end up shorter as adults. A bone age radiograph would help differentiate these two genetic variants.

14. (E) Decreased arm span. Arm span typically approximates height. Decreased arm span can be seen in conditions such as achondroplasia and hypochondroplasia, but it is not typically seen in growth hormone deficiency. Classic features of growth hormone deficiency include an attenuated growth pattern, short stature, hypoglycemia in infancy in cases of congenital growth hormone deficiency, delayed bone age, central distribution of body fat, and low IGF-1 levels.

15. (B) Pseudotumor cerebri. A potential adverse effect of growth hormone is fluid retention, which can lead to pseudotumor cerebri. This complication is typically reversed with a discontinuation of the growth hormone. Most children can be restarted on growth hormone at a lower dose without problems. Development of tumors in children without other predisposing factors has not been demonstrated.

16. (C) Hypothyroidism. Patients with constitutional delay of puberty and intrinsic short stature grow at a normal rate.

17. (A) Karyotype. Turner syndrome is the most common pathologic cause of short stature in girls. The incidence of Turner syndrome is approximately 1 in 2500 newborn girls. Turner syndrome is caused by the deletion of X chromosomal material. The most characteristic features of Turner syndrome are short stature and gonadal dysgenesis. In older girls, checking gonadotropin levels and estradiol is often used as a screen because these girls will have menopausal levels of gonadotropins and low estradiol as a result of primary ovarian failure.

18. (E) Right-sided cardiac anomalies. Left-sided cardiac anomalies such as coarctation of the aorta are more common in Turner syndrome; right-sided anomalies are more often seen in Noonan syndrome (in which patients present with a Turner-like phenotype but normal sex chromosomes). Other features of Turner syndrome include webbing of the neck, broad chest, widely spaced nipples, low posterior hairline, spooning of the nails, lymphedema, cubitus valgus, and renal anomalies, such as horseshoe kidney. Data have shown that growth hormone treatment increases growth velocity and final adult height in girls with Turner syndrome.

19. (E) Cushing syndrome. Children with Cushing syndrome present with short stature, excessive weight gain, and striae because of an increase in fragility of the skin as a result of excess cortisol.

20. (D) Excess exogenous corticosteroids. Supraphysiologic levels of exogenous steroids can attenuate growth and cause short stature and obesity in children. This contrasts with exogenous obesity in which children tend to be tall. Klinefelter syndrome is associated with tall stature. The most common cause of tall stature in a child is intrinsic familial tall stature.


SUGGESTED READING

Botero D, Evliyaoglu O, Cohen LE. Hypopituitarism. In: Radovick S, MacGillivray MH, eds. Pediatric EndocrinologyA Practical Clinical Guide. Totowa, NJ: Humana Press; 2003:3-36.

Cuttler L, Rosenfield RL. Somatic growth and maturation. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 5th ed. Philadelphia, PA: WB Saunders; 2006:697-732.

Rosenfeld RG, Cohen P. Disorders of growth hormone/insulinlike growth factor secretion and action. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:254-334.

CASE 38: AN 81/2-YEAR-OLD WITH PUBERTAL DEVELOPMENT

An 81/2-year-old patient is brought into your office because of concerns of early pubertal development. The mother noted the development of breast buds approximately 2 months before the visit. There is no report of pubic hair development or acne. The child is otherwise healthy and has been on no medications. On physical examination, the child is friendly and in no distress. Height and weight are at the 50th percentile. The child has Tanner stage 2 breast development and stage 1 pubic and axillary hair.

SELECT THE ONE BEST ANSWER

1. If this child is a girl, the most likely diagnosis would be which of the following?

(A) gynecomastia

(B) precocious puberty

(C) normal puberty

(D) premature thelarche

(E) premature pubarche

2. On physical examination of the girl, you note that her breast development is asymmetric. What would you do next?

(A) breast ultrasound

(B) breast biopsy

(C) consult a surgeon

(D) assure her that it is normal

(E) mammogram

3. If this were a 6-year-old girl, which of the following would be the most important history to ask to help narrow your differential diagnosis?

(A) birth size

(B) developmental history

(C) birth history

(D) parental heights

(E) history of medications in the house

4. If this child is an 81/2-year-old girl who instead has Tanner stage 2 pubic hair development with Tanner stage 1 breast development, the most likely diagnosis would be which of the following?

(A) precocious puberty

(B) normal puberty

(C) premature thelarche

(D) premature pubarche

(E) congenital adrenal hyperplasia

5. If this child were a boy with testicles measuring 2 cm in long diameter, the most likely diagnosis would be which of the following?

(A) precocious puberty

(B) pubertal gynecomastia

(C) premature thelarche

(D) prepubertal gynecomastia

(E) Klinefelter syndrome

6. The first sign of puberty in a girl is which of the following?

(A) menarche

(B) axillary hair development

(C) pubic hair development

(D) growth spurt

(E) appearance of breast buds

7. The first sign of puberty in boys is which of the following?

(A) growth spurt

(B) testicular enlargement

(C) appearance of pubic hair

(D) appearance of facial hair

(E) voice change

8. If this child is a 4-year-old girl, the differential diagnosis includes which of the following?

(A) precocious puberty

(B) normal puberty

(C) premature thelarche

(D) premature adrenarche

(E) A and C

9. A 6-year-old boy with precocious puberty is more likely to have which of the following than a 6-yearold girl with precocious puberty?

(A) neurologic disorder

(B) idiopathic precocious puberty

(C) congenital adrenal hyperplasia

(D) gonadal tumor

(E) adrenal tumor

10. At which Tanner stage of breast development in girls does the areola and papilla form a secondary mound above the level of the breast?

(A) Tanner stage 1

(B) Tanner stage 2

(C) Tanner stage 3

(D) Tanner stage 4

(E) Tanner stage 5

11. The Tanner stage of breast development at which a girl is most likely to get menarche is which of the following?

(A) Tanner stage 1

(B) Tanner stage 2

(C) Tanner stage 3

(D) Tanner stage 4

(E) Tanner stage 5

12. The normal time range in girls from breast budding until the appearance of menarche is which of the following?

(A) 2-2.5 years

(B) 0.5-1 year

(C) 3-3.5 years

(D) 1-1.5 years

(E) 2.5-3 years

13. The average age of menarche for North American white girls is which of the following?

(A) 10.7 years

(B) 11.5 years

(C) 12 years

(D) 12.7 years

(E) 13.3 years

14. The average growth remaining once a girl has experienced menarche is which of the following?

(A) 0.5 inch

(B) 1 inch

(C) 2 inches

(D) 3 inches

(E) 4 inches

15. A boy experiences his maximal pubertal growth spurt at which of the following times?

(A) before testicular enlargement

(B) shortly after pubic hair development

(C) shortly after axillary hair development

(D) before penile enlargement

(E) in late puberty

16. Which of the following is a gonadotropin-dependent process?

(A) premature thelarche

(B) central precocious puberty

(C) premature adrenarche

(D) premature pubarche

(E) B and C

17. Which of the following would you expect in a girl with premature thelarche?

(A) growth spurt

(B) tall stature

(C) pubic hair

(D) normal growth velocity

(E) advanced bone age

18. Which of the following would you not expect in a child with premature pubarche?

(A) signs of virilization

(B) normal bone age

(C) pubic hair development

(D) normal growth velocity

(E) axillary hair development

19. Which of the following would not be expected as a consequence of untreated, rapidly progressive, central precocious puberty?

(A) tall stature as a child

(B) tall stature as an adult

(C) short stature as an adult

(D) advanced bone maturation

(E) psychological difficulties

20. Pubertal gynecomastia occurs in what percentage of boys?

(A) less than 10%

(B) 20%

(C) 25%

(D) 35%

(E) more than 40%

ANSWERS

1. (C) Normal puberty. The appearance of any signs of puberty before the age of 8 years in a girl is considered precocious. Thus an 81/2-year-old girl with breast development would be in the early range of normal for pubertal onset. Recent studies suggest that girls may be going into puberty at a younger age. Premature thelarche is the early appearance of breast development without any other signs of early puberty, and premature pubarche is the early appearance of pubic hair alone. The term premature adrenarche is used when there is isolated pubic hair development and biochemical evidence of maturation of the adrenal gland (increase in dehydroepiandrosterone [DHEA]-sulfate level).

2. (D) Assure her it is normal. It is not unusual for breast development to begin unilaterally in both boys and girls. In addition, most women have asymmetric breasts. If the breast anlage (breast bud) is removed surgically, no breast will form on that side. Simple assurance that this is a normal process is the proper way to proceed.

3. (E) History of medications in the house. Estrogencontaining creams and contraceptive pills can cause isolated thelarche in girls. Thus it is important to determine if the child could have been exposed to these as a cause of the breast development.

4. (B) Normal puberty. The appearance of pubic hair after the age of 8 in girls would not be considered precocious.

5. (D) Prepubertal gynecomastia. A boy with 2-cm testicles is not yet in puberty; thus this would not be considered precocious puberty or pubertal gynecomastia. Prepubertal gynecomastia is rare and almost always abnormal. Etiologies include testicular, adrenal, and human chorionic gonadotropin (hCG)-secreting tumors, exogenous estrogen exposure, familial aromatase excess syndrome, or idiopathic gynecomastia.

6. (E) Appearance of breast buds. The typical sequence of development of secondary sexual characteristics in girls is breast budding, appearance of pubic hair, peak height velocity, and menarche. Pubic or axillary hair can occur before breast budding as a normal variant.

7. (B) Testicular enlargement. Enlargement of the testicles in boys to 2.5 cm in long diameter (or 4 mL in volume) is the first sign of puberty. Testicular enlargement is largely due to an increase in Sertoli cells and seminiferous tubular volume with a small contribution by Leydig cells. Pubic hair typically develops approximately 1 year after testicular enlargement. The growth spurt, appearance of facial hair, and voice change occur later in puberty in boys.

8. (E) A and C. Both precocious puberty and premature thelarche can present with isolated breast development. Thus this child would need to be followed closely for the appearance of other signs of puberty.

9. (A) Neurologic disorder. Boys are more likely to have a neurologic disorder leading to precocious puberty than girls. Approximately 95% of true precocity in girls is idiopathic. However, it is important to rule out a neurologic disorder as a cause of precocious puberty in both sexes.

10. (D) Tanner stage 4. The Tanner staging system consists of five categories describing the sequence of puberty, from a prepubertal child to adult development. Tanner staging of breast development in girls is shown in Table 38-1.

11. (D) Tanner 4. Girls typically are at stage 4 for breast development (areolar mounding) when they experience menarche.

12. (A) The answer is 2-2.5 years. Although the timing of pubertal onset is variable, the timing from breast budding to menarche in girls is typically between 2 and 2.5 years.

13. (D) The answer is 12.7 years.

14. (C) The answer is 2 inches.

15. (E) In late puberty. The difference between the mean height of men and women is related to the timing and peak of the pubertal growth spurt in boys and girls. Because the pubertal growth spurt is later for boys, they are taller on average once they start the growth spurt in late puberty. In addition, boys experience a greater peak height velocity than girls, leading to their greater adult stature. The typical sequence of development of secondary sexual characteristics in boys is testicular growth, pubarche, penile growth, and peak height velocity.

16. (B) Central precocious puberty, which results from early activation of the hypothalamic-pituitarygonadal axis.

17. (D) Normal growth velocity. Premature thelarche is the isolated appearance of breast development with a peak prevalence in the first 2 years of life. It is not associated with any other signs of puberty, such as a growth spurt, pubic hair development, or advanced bone maturation. The early breast development usually spontaneously regresses. These girls need to be followed closely for evidence of early puberty because breast development is the first sign of puberty in girls.

TABLE 38-1. Tanner Stages of Breast Development

 

TANNER STAGE

CLINICAL APPEARANCE

 

1

Prepubertal

2

Appearance of a palpable (but not always visible) breast bud

3

Enlargement and elevation of the breast with no separation of the contour of the breast and areola

4

Areola forms a separate mound above the breast

5

Adult breast

 

18. (A) Signs of virilization. Premature pubarche describes the isolated appearance of pubic hair before the age of 8 in girls and 9 in boys in the absence of other signs of puberty or virilization. Although this is thought of as a benign problem that does not need treatment, more recent studies suggest that many girls with a history of early pubic hair development go on to have problems with hirsutism, acne, and irregular menstrual periods during adolescence.

19. (B) Tall stature as an adult. One of the most significant consequences of untreated, rapidly progressive precocious puberty is rapid advancement of bone maturation with early epiphyseal fusion and short stature as an adult. Predicted adult height is a major factor in the decision as to which children will need therapy for precocious puberty.

20. (E) More than 40%. Pubertal gynecomastia occurs in greater than 40% of boys in mid-puberty. It can vary from breast buds to significant breast tissue. It typically resolves within 2-3 years. The cause of pubertal gynecomastia has been studied for decades, with conflicting results. It may be due to an imbalance in the ratio of testosterone to estrogen. It is more prevalent in obese boys, likely related to increased aromatase in adipose tissue. Aromatase converts testosterone to estradiol, thus leading to increased estradiol in peripheral tissues. Other pathologic etiologies include acquired testicular failure, biosynthetic defects in testosterone production, testicular or liver tumors, and hyperthyroidism. Gynecomastia can also be a consequence of several drugs, including spironolactone, cimetidine, digitalis, phenothiazine, and marijuana. Treatment usually consists of reassurance and psychosocial support, with weight loss in obese boys. Surgical removal of excess breast tissue is indicated in those boys in whom the gynecomastia does not regress in 3 years. Medical therapy is usually not indicated.


SUGGESTED READING

Hughes IA. The testes: disorders of sexual differentiation and puberty in the male. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:662-685.

Muir A. Precocious puberty. Pediatr Rev. 2006;27:373-381.

Rodriguez H, Pescovitz OH. Precocious puberty: clinical management. In: Radovick S, MacGillivray MH, eds. Pediatric EndocrinologyA Practical Clinical Guide. Totowa, NJ: Humana Press; 2003:399-428.

Rosenfield RL, Cooke DW, Radovick S. Puberty and its disorders in the female. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:530-609.

CASE 39: A 14-YEAR-OLD WITHOUT ANY SIGNS OF PUBERTY

A 14-year-old child is brought into your office because of concerns of lack of pubertal development. The parents report that the child has otherwise been healthy, but the child has been complaining that all of his/her friends seem to be getting much taller than him/her. The child’s father is 6 feet tall and could not recall when he went through puberty, but he did remember being shorter than all of his friends in high school. The mother is 5'6" and had menarche at age 14 years. On physical examination, the child’s height is less than the 5th percentile, and weight for height is at the 30th percentile. The child is entirely prepubertal.

SELECT THE ONE BEST ANSWER

1. What is the most likely diagnosis if this is a boy with a bone age of 11 years and his father grew 4 inches after high school?

(A) hypergonadotropic hypogonadism

(B) constitutional delay of puberty

(C) hypogonadotropic hypogonadism

(D) Klinefelter syndrome

(E) Kallmann syndrome

2. What is the most likely diagnosis if this is a boy with a bone age of 14 years, who reports that he can’t smell well?

(A) Kallmann syndrome

(B) Noonan syndrome

(C) Klinefelter syndrome

(D) panhypopituitarism

(E) pituitary tumor

3. What would be in your differential diagnosis if this were a boy with a bone age of 10 years and prepubertal gonadotropin levels?

(A) constitutional delay of puberty

(B) hypergonadotropic hypogonadism

(C) hypogonadotropic hypogonadism

(D) A and C

(E) all of the above

4. If this were a girl with a bone age of 13 years, which diagnosis would be least likely?

(A) constitutional delay of puberty

(B) hypergonadotropic hypogonadism

(C) Turner syndrome

(D) hypogonadotropic hypogonadism

(E) panhypopituitarism

5. Which of the following would be ruled out as a diagnosis if this child had pubic hair?

(A) constitutional delay in puberty

(B) hypergonadotropic hypogonadism

(C) hypogonadotropic hypogonadism

(D) Turner syndrome

(E) none of the above

6. Which of the following issues in the medical history will help with your diagnosis of delayed puberty?

(A) nutritional habits

(B) exercise intensity

(C) prior medical history

(D) parents’ pubertal history

(E) all of the above

7. Which of the following is the most common cause of delayed puberty in boys?

(A) Kallmann syndrome

(B) hypergonadotropic hypogonadism

(C) constitutional delay of puberty

(D) Klinefelter syndrome

(E) panhypopituitarism

8. You want to order a bone age radiograph to assess skeletal maturation. What would you order?

(A) a radiograph of the right foot and ankle

(B) a radiograph of the left hand and wrist

(C) a radiograph of the right hand and wrist

(D) a radiograph of the left foot and ankle

(E) a radiograph of the skull

9. At what age in a boy would you be concerned about delayed puberty?

(A) 12-year-old

(B) 13-year-old

(C) 14-year-old

(D) 15-year-old

(E) 16-year-old

10. At what age in a girl would you be most concerned about delayed puberty?

(A) 11-year-old

(B) 12-year-old

(C) 13-year-old

(D) 14-year-old

(E) 15-year-old

11. The first biochemical sign of maturation of the hypothalamic-pituitary-gonadal axis is which of the following?

(A) early morning rise of luteinizing hormone (LH) secretion

(B) late morning rise of LH secretion

(C) late afternoon rise of LH secretion

(D) early evening rise of LH secretion

(E) sleep-associated rise of LH secretion

12. What should be included in your workup of delayed puberty?

(A) early morning gonadotropin levels

(B) late morning testosterone (boy) or estradiol (girl) levels

(C) afternoon testosterone (boy) or estradiol (girl) levels

(D) early evening gonadotropin levels

(E) early evening testosterone (boy) or estradiol (girl) levels

13. Which of the following is a cause of primary hypogonadism?

(A) panhypopituitarism

(B) craniopharyngioma

(C) Kallmann syndrome

(D) anorexia nervosa

(E) Turner syndrome

14. Which of the following is not a cause of hypogonadotropic hypogonadism?

(A) hypothyroidism

(B) hypothalamic dysfunction

(C) gonadal abnormality

(D) hypopituitarism

(E) anorexia nervosa

15. Which of the following is not a feature of Turner syndrome?

(A) webbed neck

(B) low posterior hairline

(C) right-sided cardiac defects

(D) spooned nails

(E) renal anomalies

16. Which of the following is not a feature of Klinefelter syndrome?

(A) short stature

(B) seminiferous tubule dysgenesis

(C) 47,XXY

(D) normal onset of puberty

(E) language difficulties

17. The age at which a child goes into puberty dependents most on which of the following?

(A) chronological age

(B) height age

(C) weight age

(D) bone age

(E) B and C

18. Which of the following is not a goal of therapy for lack of sexual development?

(A) age-appropriate secondary sex characteristics

(B) advancement of bone maturation

(C) growth spurt

(D) relieve concerns of immature appearance

(E) B and C

ANSWERS

1. (B) Constitutional delay of puberty. This represents the extreme of normal physiologic variation in timing of onset of puberty. Typically the patient is shorter than the mean with a delay in bone maturation (which is usually equal to the height age). They have a normal growth velocity. There is usually a family history of delayed puberty and late growth spurt. Patients will eventually go into puberty and progress through puberty normally. Treatment usually consists of reassurance. Boys can be treated with a short course of low-dose testosterone to give them pubic hair and a slight growth spurt if there is significant psychological distress about their lack of puberty. They need to be monitored closely on treatment to avoid significant advancement of their bone maturation, which could limit their growth potential because of premature epiphyseal closure.

2. (A) Kallmann syndrome. In Kallmann syndrome, hyposmia or anosmia is associated with gonadotropin deficiency. It is caused by improper migration of the gonadotropin-releasing hormone (GnRH) neurons and olfactory bulb across the cribriform plate. It is frequently inherited as an X-linked recessive trait but occasionally can be caused by autosomal dominant or recessive inheritance with variable penetrance. There can be significant heterogeneity within the same family with this condition. Associated anomalies may include renal agenesis, midline facial defects, cryptorchidism, microphallus, sensorineural deafness, and visual abnormalities.

3. (E) All of the above. Onset of puberty typically depends more on the bone age than the chronological age. A boy with a bone age of 10 would not be expected to be in puberty; thus his gonadotropin levels would be in the prepubertal range in all conditions listed. Once the bone age advances to a pubertal age, gonadotropin levels in boys with hypergonadotropic hypogonadism will become elevated.

4. (A) Constitutional delay of puberty. Because puberty corresponds more closely with bone age than with chronological age, a girl with a bone age of 13 years should be in puberty, and lack of puberty at this bone age would suggest hypogonadism. The correlation between bone age and pubertal onset is less clear in obese children because overnutrition often causes an advancement in bone age.

5. (E) None of the above. Gonadarche (maturation of the hypothalamic-pituitary gonadal axis) and adrenarche (maturation of the adrenal gland) are two separate processes. Therefore, adrenarche leading to the development of pubic hair can occur without gonadarche.

6. (E) All of the above. Nutritional disorders, intense exercise, and occult chronic illness can all affect the hypothalamic GnRH pulse generator and cause delayed puberty. In addition, constitutional delay of growth and puberty tends to run in families.

7. (C) Constitutional delay of puberty. Constitutional delay in puberty is the most common cause of delayed puberty in boys. Children with panhypopituitarism causing delayed puberty usually come to attention because of other hormonal deficiencies.

8. (B) A radiograph of the left hand and wrist. The several accepted techniques of assessing bone maturation include the Tanner-Whitehouse method and the method of Greulich and Pyle. Both methods focus on the left hand and wrist.

9. (C) A 14-year-old. Delayed puberty is defined as the absence of signs of puberty in a child at a chronological age greater than 2 standard deviations above the mean of pubertal development for a given population. In boys, this age is 14 years. This is also the age at which most boys will be starting high school where communal showering is common; thus their concerns regarding lack of puberty increase.

10. (C) A 13-year-old

11. (E) Sleep-associated rise of LH secretion. The first biochemical sign of puberty is a sleep-associated rise in LH secretion. Puberty begins with pulsatile GnRH secretion, which is followed by pulsatile gonadotropin secretion, which is eventually followed by maturation of the gonads with a gradual increase in sex hormones. The pulsatile GnRH and gonadotropin secretion begins at night and eventually extends throughout the day in later puberty.

12. (A) Early morning gonadotropin levels. In very early puberty, levels of gonadotropins and sex steroids are first detectable at night. Thus the best time to check outpatient laboratory tests would be early morning. Gonadotropin levels and sex steroid levels should be checked in a laboratory with very sensitive assays appropriate for children.

13. (E) Turner syndrome. Turner syndrome in girls presents with primary ovarian failure because of atresia of the ovaries in fetal life. Many girls with Turner syndrome first present in early adolescence because of short stature and delayed puberty. In Kallmann syndrome, isolated gonadotropin deficiency and anosmia is found because of failure of the GnRH neurons and olfactory bulb to migrate properly. Craniopharyngioma and the subsequent treatment can lead to panhypopituitarism, and anorexia nervosa can lead to hypothalamic hypogonadism.

14. (C) Gonadal abnormality. Secondary hypogonadism is a result of disorders that decrease gonadotropin secretion. Lack of thyroid hormone has been shown to interfere with gonadotropin secretion. An abnormality in the gonad would lead to elevated gonadotropin levels.

15. (C) Right-sided cardiac defects. Girls with Turner syndrome usually present with short stature and delayed puberty because of primary ovarian failure. Occasionally, girls are diagnosed at birth because of puffy hands and feet, and a webbed neck because of lymphedema. They have a 45,XO karyotype (or a mosaic karyotype, ie, 45,XO/ 46,XX). Associated features include webbed neck, low posterior hairline, cubitus valgus, spooned nails, renal anomalies, and left-sided cardiac defects including coarctation of the aorta. Right-sided cardiac defects are found in Noonan syndrome, which has similar phenotypic findings as Turner syndrome with a normal karyotype. Girls with Noonan syndrome have normal ovarian function, but boys typically have cryptorchidism and abnormal Leydig cell function.

16. (A) Short stature. Klinefelter syndrome is the most frequent form of hypogonadism in males with an incidence of 1 in 500-1000 males. In all cases, seminiferous tubule function is impaired. Patients have variable Leydig cell function and thus can have testosterone levels from low to normal. Patients often have the onset of puberty at a normal age, but secondary sexual changes do not progress to the adult stage. Karyotype is 47,XXY, or variants including 48,XXXY, 49,XXXXY and male 46,XX. The typical phenotype includes tall stature with long arms and legs, small firm testes, small phallus, poor muscular development, language difficulties, and poor social adaptation.

17. (D) Bone age. The age at which children go into puberty varies widely. Bone age has been shown to be a better predictor of pubertal milestones than chronological age. Thus an 8-year-old girl with a bone age of 12 would be expected to be in puberty. Conditions that cause an advancement of bone maturation (such as undertreated congenital adrenal hyperplasia) can lead to precocious puberty.

18. (B) Advancement of bone maturation. The goals of therapy for delayed puberty include inducing the development of age-appropriate secondary sex characteristics, a growth spurt, and psychosocial benefits. Psychosocial concerns tend to be more pronounced in boys than girls because of societal pressures and can lead to low self-esteem and poor body image. If the therapy advances the bone maturation too quickly, children can have premature epiphyseal fusion and end up short as an adult.


SUGGESTED READING

Hughes IA. The testes: disorders of sexual differentiation and puberty in the male. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:662-685.

Rosen DS, Foster C. Delayed puberty. Pediatr Rev. 2001;22:309–315.

Rosenfield RL, Cooke DW, Radovick S. Puberty and its disorders in the female. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:530-609.

Stafford DEJ. Delayed puberty. In: Radovick S, MacGillivray MH, eds. Pediatric EndocrinologyA Practical Clinical Guide. Totowa, NJ: Humana Press; 2003:383-397.

CASE 40: A 10-YEAR-OLD WITH A GOITER

A 10-year-old child is brought into your office for a routine school physical. On review of systems, the child has been complaining of fatigue but is doing well at school. The child is not taking any medications and has otherwise been healthy. There is a history of some type of thyroid problem in the maternal grandmother and paternal aunt. On physical examination you notice that the child has a goiter with no palpable nodules (see Figure 40-1).

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FIGURE 40-1. A child with a prominent goiter.


SELECT THE ONE BEST ANSWER

1. What other information would be most helpful to narrow your differential diagnosis?

(A) birth history

(B) newborn screen

(C) developmental history

(D) growth pattern

(E) pubertal history

2. Which of the following tests would you order first?

(A) total thyroxine (TT4), free thyroxine index (FTI), thyrotropin (TSH), and thyroid antibodies

(B) total triiodothyronine (T3), reverse T3, TSH

(C) TT4, reverse T3, TSH, thyroid antibodies

(D) thyroid ultrasound

(E) thyroid scan

3. The thyroid gland is tender to palpation, and the child reports that he/she has had an upper respiratory tract infection the last few days. What would be at the top of your differential diagnosis?

(A) Hashimoto thyroiditis

(B) hyperthyroidism

(C) Graves disease

(D) subacute thyroiditis

(E) euthyroid sick syndrome

4. What would the most likely diagnosis be if the TT4 was 4.5 μg/dL (normal: 5-11.5) and FTI 3 (normal: 6.0-10.5)?

(A) Hashimoto thyroiditis

(B) Graves disease

(C) low thyroxin-binding globulin (TBG)

(D) subacute thyroiditis

(E) euthyroid sick syndrome

5. What would you expect the TSH to be for the child described in question 4? (normal: TSH 0.4-6.4 mU/L)

(A) less than 0.01 mU/L

(B) 0.01 mU/L

(C) 1.0 mU/L

(D) 6.0 mU/L

(E) 15 mU/L

6. What would the most likely diagnosis be if the TT4 was 3 μg/dL, FTI 7, and the child did not have a goiter?

(A) Hashimoto thyroiditis

(B) Graves disease

(C) low TBG

(D) subacute thyroiditis

(E) euthyroid sick syndrome

7. What would be the most likely diagnosis if the TT4 was 10 μg/dL, FTI 10, TT3 180 ng/dL (normal: 80-195), and thyroid antibodies were positive?

(A) Hashimoto thyroiditis

(B) Graves disease

(C) high TBG

(D) subacute thyroiditis

(E) none of the above

8. Which of the following is not a symptom or sign of hypothyroidism in children?

(A) growth retardation

(B) bradycardia

(C) polyphagia

(D) pubertal disorder

(E) delayed bone maturation

9. Which of the following depends on thyroid hormone?

(A) somatic growth

(B) bone growth

(C) tooth eruption

(D) A and B

(E) all of the above

10. Which of the following is not a cause of acquired hypothyroidism?

(A) autoimmune thyroiditis

(B) late-onset thyroid dysgenesis

(C) TSH deficiency

(D) subacute thyroiditis

(E) C and D

11. Most circulating triiodothyronine is derived from

(A) peripheral conversion from thyroxine

(B) thyroid gland

(C) pituitary gland

(D) parathyroid glands

(E) hypothalamus

12. Which of the following is the biologically active form of thyroid hormone?

(A) TRH (thyrotropin-releasing hormone)

(B) TSH

(C) T4

(D) T3

(E) Reverse T3

13. Which of the following is true regarding newborn screening for congenital hypothyroidism?

(A) Programs that use TT4 can miss central hypothyroidism.

(B) The optimum time to collect the sample is within the initial 24 hours of life.

(C) Transient hypothyroidism can be missed.

(D) Programs that use TSH can miss central hypothyroidism.

(E) Programs that use TT3 can miss central hypothyroidism

14. Which of the following is the leading cause of congenital hypothyroidism in iodine-sufficient areas?

(A) TRH deficiency

(B) TSH deficiency

(C) thyroid dyshormonogenesis

(D) transient hypothyroidism

(E) thyroid dysgenesis

15. What is the most worrisome consequence of untreated congenital hypothyroidism?

(A) prolonged physiologic jaundice

(B) retarded central nervous system development

(C) delayed bone maturation

(D) soft tissue myxedema

(E) poor growth

16. You notice that the patient has exophthalmos. What diagnosis would be most likely?

(A) Hashimoto thyroiditis

(B) Hashitoxicosis

(C) Graves disease

(D) iodine deficiency

(E) TSH-secreting pituitary tumor

17. All of the following are signs or symptoms of hyperthyroidism except

(A) delayed deep tendon reflexes

(B) nervousness

(C) fatigue

(D) palpitations

(E) A and C

18. Which of the following statements is true regarding the treatment of Graves disease?

(A) antithyroid drugs can cause granulocytopenia

(B) radioactive iodine should only be used in thyroid storm

(C) subtotal surgical thyroidectomy is the preferred initial treatment in children

(D) corticosteroids inhibit release of T4 from the thyroid gland

(E) thyroid storm is a common complication

19. Which of the following is true regarding neonatal Graves disease?

(A) neonatal Graves occurs in 20% of neonates born to mothers with Graves

(B) the onset of signs and symptoms can be delayed for 8-9 days

(C) no treatment is necessary because it tends to be self-limited

(D) neonates are typically asymptomatic

(E) the disease is caused by transplacental passage of thyroid hormone

20. What would the most likely diagnosis be if this child was in the intensive care unit following cardiac surgery and had a TT4 of 4 μg/dL, FTI 4, TT3 of 50 ng/dL, reverse T3 450 ng/dL, and TSH 4 mU/L (normal: 0.4-6.4)?

(A) TRH deficiency

(B) TSH deficiency

(C) TBG deficiency

(D) Hashimoto thyroiditis

(E) euthyroid sick syndrome

ANSWERS

1. (D) Growth pattern. Children with hypothyroidism often manifest slowing of their growth, whereas children with hyperthyroidism eventually have accelerated growth if the disorder is not detected and treated appropriately.

2. (A) TT4, FTI, TSH, and thyroid antibodies. Serum TT4 is the major thyroid hormone in the blood, and laboratory tests measure both bound and unbound T4. Because most T4 is bound to thyroxin-binding globulin (TBG), transthyretin, or albumin, levels of binding proteins affect the TT4 concentration. Thus the levels of free and total thyroid hormone may not be concordant. Free thyroxin index is a calculation that reflects bioavailable thyroid hormone because it takes into account the amount of binding protein. TSH is secreted from the pituitary under the control of thyrotropin-releasing hormone (TRH) from the hypothalamus, and through negative feedback from thyroid hormones. Several antibodies against thyroid antigens have been demonstrated in chronic autoimmune thyroiditis, and these levels should be determined in a child with a goiter. TT3 is the active form of thyroid hormone, but it is usually not measured with the initial screen. Reverse T3 is an inactive metabolite of TT4, and measurement is important in the diagnosis of euthyroid sick syndrome. Thyroid ultrasound or thyroid scan would be indicated if nodules were detected.

3. (D) Subacute thyroiditis. Subacute thyroiditis is a self-limited inflammation of the thyroid gland that usually follows an upper respiratory tract infection. The thyroid gland can be very tender to palpation. There is often a pattern of hyperthyroidism secondary to inappropriate release of thyroid hormone. Signs and symptoms of hyperthyroidism can persist for 1-4 weeks, after which transient hypothyroidism typically develops with recovery of the gland. The total course of illness can last 2-9 months. Treatment is typically with anti-inflammatory drugs. Children with euthyroid sick syndrome do not present with a goiter, and the presentation usually does not follow a mild illness.

4. (A) Hashimoto thyroiditis. The most common abnormality of thyroid function in children is hypothyroidism, usually caused by autoimmune (Hashimoto) thyroiditis. Hashimoto thyroiditis is characterized by circulating thyroid antibodies and varying degrees of thyroid dysfunction. It can present with or without a goiter. It is more prevalent in girls, and many patients have a family history of autoimmune thyroid disease. Spontaneous remission has been reported. Other causes of acquired hypothyroidism include late-onset thyroid dysgenesis or dyshormonogenesis, TSH deficiency, thyroid damage, and iodine deficiency. T4 replacement is the treatment of choice for hypothyroidism.

5. (E) The answer is 15 mU/L. In hypothyroidism secondary to Hashimoto thyroiditis, the TSH will be elevated.

6. (C) Low TBG. TT4 measures both bound and free T4. In cases where the TBG is low, measured T4 levels will be low, even though free thyroid hormone levels are normal. High-dose glucocorticoids can lower TBG levels, and low TBG levels can also run in families. In contrast, pregnancy or estrogen administration is a common cause of high TBG levels.

7. (A) Hashimoto thyroiditis. There is a spectrum of presentation for Hashimoto thyroiditis. Patients can present with a picture of hyperthyroidism (hashitoxicosis), euthyroidism, or hypothyroidism. Patients typically have a nontender goiter and evidence of thyroid antibodies.

8. (C) Polyphagia, which is a symptom of hyperthyroidism. The most common manifestation of hypothyroidism in children is subnormal growth velocity leading to short stature. The growth retardation can be present for many years before other symptoms occur. Other manifestations of hypothyroidism specific to children include delayed bone maturation and sexual disorders, including both delayed and precocious puberty. Other symptoms of hypothyroidism include bradycardia, cold intolerance, fatigue, constipation, muscle aches, and dry skin.

9. (E) All of the above.

10. (D) Subacute thyroiditis. Patients with subacute thyroiditis may present initially with hyperthyroidism, which is followed by transient hypothyroidism associated with recovery. Thyroid function then typically returns to normal with resolution of the inflammation.

11. (A) Peripheral conversion from thyroxine (T4). Approximately 70-90% of circulating T3 is derived from monodeiodination of T4 in peripheral tissues, with the remainder derived from the thyroid gland. Thus the activity of the deiodination enzymes is critical to the production of intracellular T3 and critical for the maintenance of normal cellular activity. In contrast, most T4 is made in the thyroid gland.

12. (D) T3, which is the active form of thyroid hormone. T4 is the major thyroid hormone in the blood and metabolized to T3 and reverse T3, which is not biologically active. TSH is secreted from the pituitary gland under the control of TRH from the hypothalamus and controls thyroid hormone production and release from the thyroid gland.

13. (D) Programs that use TSH can miss central hypothyroidism. Most children with central hypothyroidism have normal to low normal serum TSH concentrations, and thus they will be missed if only TSH is measured. Neonates with congenital hypothyroidism typically have no specific signs at birth. The possibility of central hypothyroidism needs to be considered in any infant with other signs of pituitary deficiency, such as hypoglycemia, prolonged neonatal jaundice, micropenis, midline facial defects, or poor growth.

14. (E) Thyroid dysgenesis. Congenital hypothyroidism occurs in approximately 1 in 4000 newborns and is the most preventable cause of mental retardation, if detected and treated early. Neonates with congenital hypothyroidism usually have very few signs and symptoms, thus underlining the importance of the neonatal screen for diagnosis. Thyroid dysgenesis (agenesis, hypoplasia, or ectopic thyroid) is the leading cause of congenital hypothyroidism in iodine-sufficient areas, followed by, in order of decreasing incidence: transient hypothyroidism, thyroid dyshormonogenesis, and TSH deficiency.

15. (B) Retarded central nervous system development. Thyroid hormones exert effects that are most obvious during infancy and early childhood. Brain development depends on thyroid function in the first 3 years of life. The early detection of congenital hypothyroidism and early treatment prevents the development of mental retardation that would occur in untreated cases. The initial goal of treatment of congenital hypothyroidism is to restore the T4 concentration to the upper half of the normal range as rapidly as possible.

16. (C) Graves disease. Virtually all children with Graves disease have a goiter, and 50-75% have mild ophthalmopathy. Severe ophthalmopathy is much less common in children than in adults. Eye findings may include lid lag, infrequent blinking, appearance of a stare because of retraction of the upper lid, exophthalmos, and ophthalmoplegia. Graves disease occurs most commonly in the 11- to 15-year age group, and girls are affected more frequently than boys.

17. (A) Delayed deep tendon reflexes. The development of hyperthyroidism in children can be insidious. Typical symptoms include nervousness and jitteriness, sleep disorders leading to fatigue, heat intolerance, tachycardia and palpitations, and a decline in school performance. Children with Graves disease tend to have greater emotional lability and behavioral disturbances than adults. In prolonged hyperthyroidism in children, accelerated linear growth and advanced bone maturation can be seen. Delayed deep tendon reflexes are seen in hypothyroidism.

18. (A) Antithyroid drugs can cause granulocytopenia. Blocking thyroid hormone synthesis with methimazole is typically the initial therapy of hyperthyroidism in a young child. Most children need to be on antithyroid drugs for many years, and close supervision is necessary to monitor thyroid function tests. Side effects of these drugs include rash, granulocytopenia, and liver failure. Ablation of the thyroid gland with radioactive iodine is another treatment option for Graves disease but usually not the preferred initial treatment in children. This treatment option is used extensively in adults. Subtotal surgical thyroidectomy is another treatment option but is usually reserved for children who fail medical therapy or experience serious side effects of antithyroid medications. The availability of an experienced thyroid surgeon is an important criterion for the success of this treatment option. Serious complications of subtotal thyroidectomy include hypoparathyroidism and recurrent laryngeal nerve damage. Corticosteroids can be used in thyroid storm to prevent the peripheral conversion of T4 to T3.

19. (B) The onset of signs and symptoms can be delayed for 8-9 days. Neonatal Graves disease occurs in approximately 2% of neonates born to mothers with Graves hyperthyroidism. It can be severe, and even life threatening, if not treated properly. It occurs following the transplacental passage of TSH receptor–stimulating antibody. The time of onset and severity of symptoms is variable and depends on the transplacental passage of blocking antibodies and antithyroid drugs. The characteristic manifestations of neonatal Graves disease include irritability, tachycardia, poor weight gain, diarrhea, thyromegaly, and exophthalmus. The treatment consists of iodine or antithyroid drugs, corticosteroids, and propranolol. Neonatal Graves typically resolves spontaneously in 3-12 weeks.

20. (E) Euthyroid sick syndrome, which is an alteration of thyroid hormone levels seen in severe illness. Patients have a decrease in T3 because of an increased metabolism of TT4 to the bioinactive reverse T3, which is characteristically elevated. The lowest levels of T3 and T4 have been associated with increased mortality. It is controversial whether euthyroid sick syndrome is an adaptive phenomenon to decrease metabolic rate, an important contributor of the disease process, or just an associated marker of disease severity. It is controversial whether treatment with thyroid hormone is beneficial or harmful.


SUGGESTED READING

Counts D, Varma SK. Hypothyroidism in children. Pediatr Rev. 2009;30:251-258.

Fisher DA, Grueters A. Disorders of the thyroid in the newborn and infant. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:198-226.

Fisher DA, Grueters A. Thyroid disorders in childhood and adolescence. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:227-253.

Huang SA, Larsen PR. Autoimmune thyroid disease. In: Radovick S, MacGillivray MH, eds. Pediatric EndocrinologyA Practical Clinical Guide. Totowa, NJ: Humana Press; 2003:291-307.

Larsen CA. Congenital hypothyroidism. In: Radovick S, MacGillivray MH, eds. Pediatric EndocrinologyA Practical Clinical Guide. Totowa, NJ: Humana Press; 2003:p 275-290.

CASE 41: A 14-MONTH-OLD WITH A SEIZURE

A 14-month-old child presents to the emergency department following a brief tonic-clonic seizure. The child has no previous history of seizures. He has not been ill recently and has had a normal appetite. He was exclusively breastfed until 6 months of age when his mother added in cereal (mixed with breast milk) and some jar baby foods. He continues to breast-feed. It is early spring, and it has been a particularly dark and dreary winter. His mother has concerns that the child is not yet walking. He is afebrile on physical examination and is normal size for both height and weight.

SELECT THE ONE BEST ANSWER

1. On physical examination, the patient has a positive Chvostek sign. This is typical in which of the following circumstances?

(A) hypophosphatasia

(B) hypoglycemia

(C) hypocalcemia

(D) hypophosphatemia

(E) hypomagnesemia

2. Which of the following are clinical features of hypocalcemia?

(A) laryngospasm, shortened QT interval on electrocardiogram (ECG), and a positive Trousseau sign

(B) laryngospasm, prolonged QT interval on ECG, and a positive Trousseau sign

(C) paresthesias, prolonged QT interval on ECG, and a negative Trousseau sign

(D) paresthesias, shortened QT interval on ECG, and a positive Trousseau sign

(E) paresthesias, normal QT interval on ECG, and a positive Trousseau sign

3. The patient’s total calcium is low at 6 mg/dL, with a low ionized calcium of 3 mg/dL. What is the most likely diagnosis if the serum phosphate is 2.5 mg/dL?

(A) nutritional rickets

(B) hypoparathyroidism

(C) X-linked hypophosphatemic rickets

(D) pseudohypoparathyroidism (PHP)

(E) pseudopseudohypoparathyroidism (PPHP)

4. What is the most likely diagnosis if the total calcium is 6 mg/dL, ionized calcium of 3 mg/dL, and serum phosphate 8 mg/dL?

(A) nutritional rickets

(B) hypoparathyroidism

(C) X-linked hypophosphatemic rickets

(D) PPHP

(E) low serum albumin

5. What is the most likely diagnosis if the total calcium is 6 mg/dL, ionized calcium of 3 mg/dL, serum phosphate 8 mg/dL, and PTH 130 pg/mL (normal: 9-52)?

(A) nutritional rickets

(B) hypoparathyroidism

(C) X-linked hypophosphatemic rickets

(D) PHP

(E) PPHP

6. In nutritional rickets, which of the following laboratory values would you expect to be low?

(A) parathyroid hormone (PTH)

(B) 1,25-dihydroxyvitamin D

(C) 25-hydroxyvitamin D

(D) alkaline phosphatase

(E) B and C

7. The radiograph shown in Figure 41-1 is most representative of which of the following?

(A) hypoparathyroidism

(B) PHP

(C) nutritional rickets

(D) PPHP

(E) hyperparathyroidism

art

FIGURE 41-1. Radiograph of the wrist (left) and knee (right) in a 14-month-old child with a seizure.


8. Rachitic bone deformities include which of the following?

(A) craniotabes

(B) rachitic rosary

(C) Harrison grooves

(D) A and B

(E) all of the above

9. You start the child on intravenous (IV) calcium replacement, but the serum calcium does not normalize. Which of the following should you look for?

(A) hypokalemia

(B) hypoglycemia

(C) hypomagnesemia

(D) hypophosphatasia

(E) hypophosphatemia

10. PTH controls serum calcium levels through its action on all of the following organs except which of the following?

(A) bone

(B) kidney

(C) liver

(D) intestinal tract

(E) C and D

11. The active form of vitamin D is which of the following?

(A) 25-hydroxyvitamin D

(B) 24,25-dihydroxyvitamin D

(C) vitamin D(D) vitamin D(E) 1,25-dihydroxyvitamin D

12. The major impact of the active form of vitamin D is on which organ?

(A) parathyroid glands

(B) kidney

(C) intestinal tract

(D) bone

(E) liver

13. Which of the following is not a typical cause of early neonatal hypocalcemia (within the first 72 hours of life)?

(A) prematurity

(B) infant of a diabetic mother

(C) congenital hypoparathyroidism

(D) asphyxia

(E) small for gestational age

14. Late neonatal hypocalcemia (between 5 and 10 days of life) is most likely caused by each of the following except

(A) asphyxia

(B) transient hypoparathyroidism

(C) hyperphosphatemia

(D) infant of a mother with marginal vitamin D intake

(E) hypomagnesemia

15. You diagnose your patient with nutritional rickets because of vitamin D deficiency. You would likely use all of the following except which in your management of the patient?

(A) calcium supplementation

(B) phosphate supplementation

(C) calcitriol (1,25-dihydroxy vitamin D)

(D) ergocalciferol (vitamin D2)

(E) B and D

16. Your patient has a low calcium, low phosphate, and elevated alkaline phosphatase. You acutely start the child on IV calcium, calcitriol (1,25-dihydroxyvitamin D), and oral ergocalciferol. The calcium normalizes quickly with your therapy. After several days, you stop the calcitriol, and to your surprise, the calcium level falls. What is the most likely cause?

(A) laboratory error

(B) development of hyperphosphatemia

(C) patient remains hypophosphatemic

(D) the patient received too much calcium

(E) patient has 1-α-hydroxylase deficiency

17. You diagnose your patient with hypoparathyroidism, and once the serum calcium is stabilized, you discharge him home on calcitriol and supplemental calcium. The mother calls in 1 week complaining that she is changing her child’s urine-soaked diaper every 2 hours. What should you be most concerned about?

(A) hypermagnesemia

(B) hypomagnesemia

(C) hypocalcemia

(D) hypercalcemia

(E) hyperphosphatemia

18. What test(s) would help in the diagnosis if your patient was an infant with hypocalcemia and cardiac defects?

(A) chest radiograph

(B) analysis of chromosome 15q11

(C) analysis of chromosome 22q11

(D) A and B

(E) A and C

ANSWERS

1. (C) Hypocalcemia. Chvostek sign is a twitching of the circumoral muscles in response to gentle tapping on the facial nerve just anterior to the ear. It is a sign of hypocalcemia; however, up to 10% of normal individuals have a slight twitch in response to this maneuver.

2. (B) Laryngospasm, prolonged QT interval on ECG, and a positive Trousseau sign. The signs and symptoms of acute hypocalcemia typically result from increased neuromuscular irritability. This can be elicited by checking for a positive Chvostek or Trousseau sign. Trousseau sign is carpal spasm seen with hypoxia. To test for Trousseau sign, a blood pressure cuff should be inflated to 20 mm Hg above the patient’s systolic blood pressure for 3 minutes. Figure 41-2 shows the classic response of a positive Trousseau sign. Unlike Chvostek sign, which can be seen in patients with normal calcium levels, a positive Trousseau sign is rare in the absence of hypocalcemia. Patients often complain of paresthesias of the fingers, toes, and circumoral region. Muscle cramps are also seen and may progress to tetany (spontaneous carpopedal spasm). Laryngospasm and bronchospasm can be seen. Other signs and symptoms include seizures, irritability, impaired school performance, and behavioral changes. With severe hypocalcemia, patients can have prolongation of their QT interval and can be prone to arrhythmias.

3. (A) Nutritional rickets. Children with nutritional rickets usually present with both low serum calcium and phosphate because of a deficiency of vitamin D, leading to a decrease of both calcium and phosphate absorption in the gut. Rickets can also develop with a deficiency of either calcium or phosphate, especially in the rapidly growing premature infant. Hypoparathyroidism and PHP usually present with hyperphosphatemia because of a lack of PTH action on the kidney where PTH typically stimulates excretion of phosphate. Children with PPHP have the phenotypic features of Albright hereditary osteodystrophy (PHP type 1a) without the biochemical abnormalities. X-linked hypophosphatemic rickets occurs because of a defect in the kidney causing a loss of phosphate, but these children do not present with hypocalcemia.

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FIGURE 41-2. An example of the Trousseau sign. The photo on the right demonstrates flexion of the wrist and metacarpophalangeal joints, with extension of the interphalangeal joints and adduction of the finger after insufflation of the blood pressure cuff. (Reprinted with permission from Meininger ME, Kendler JS. Trousseau’s sign. N Engl J Med. 2000;343:1855. Copyright 2000 Massachusetts Medical Society. All rights reserved.)


4. (B) Hypoparathyroidism. Hypoparathyroidism occurs when the PTH produced by the parathyroid glands is insufficient to maintain the serum calcium in the normal range. Because PTH causes renal calcium absorption and renal phosphate excretion, insufficient PTH causes both hypocalcemia and hyperphosphatemia. Serum PTH is low, serum 1,25-dihydroxyvitamin D is usually low to low normal (PTH enhances the conversion of 25-hydroxy- to 1,25-dihydroxyvitamin D), and alkaline phosphatase is usually normal.

5. (D) PHP, which is a syndrome characterized by target tissue unresponsiveness to the actions of PTH. Biochemical abnormalities of hypoparathyroidism are seen including hypocalcemia and hyperphosphatemia in the face of elevated PTH levels. PHP type 1a is also called Albright hereditary osteodystrophy, which presents with PTH resistance with other somatic defects including short stature, round facies, obesity, and developmental delay.

6. (C) 25-Hydroxyvitamin D. In nutritional rickets, hypocalcemia causes a secondary hyperparathyroidism, and thus PTH levels will be elevated. Because PTH and hypophosphatemia stimulate renal production of 1,25-dihydroxyvitamin D, levels of this hormone will be normal to high. Alkaline phosphatase is a marker of bone turnover that tends to be elevated in nutritional rickets. 25-Hydroxyvitamin D reflects the nutritional component of vitamin D, and these levels would be low in vitamin D–deficient rickets.

7. (C) Nutritional rickets. The radiograph demonstrates typical findings of nutritional rickets including widening with cupping and fraying of the metaphyses. The bones are often demineralized in general. In general, no bone changes are seen in hypoparathyroidism and PHP. Occasionally, bone changes consistent with hyperparathyroidism such as subperiosteal and endosteal bone resorption can be seen in PHP because of the bones not being resistant to PTH.

8. (E) All of the above. Craniotabes is a generalized softening of the calvaria that can be seen in younger infants with rickets, along with frontal bossing and parietal flattening. Rachitic rosary is caused by prominence of the costochondral junction of the ribs. This is typically palpable on the lateral aspect of the chest in a young child because the ribs are not fully formed. Harrison groves are indentations of the lower ribs from the vessels that run under the ribs and indent the soft bone. Genu varum (bowleg deformity) is also a common rachitic bone deformity, which becomes more pronounced with weight bearing. Children also present with thickening of the wrists and ankles. There is an increased risk of fracture in children with rickets.

9. (C) Hypomagnesemia. Low magnesium levels inhibit both PTH secretion and action of PTH at bone and kidney, which will hinder the correction of serum calcium. Serum magnesium should be corrected.

10. (C) Liver. PTH promotes calcium mobilization from bone by osteoblast-mediated activation of bone resorbing osteoclasts. In the proximal tubule of the kidney, PTH increases the reabsorption of calcium while inhibiting phosphate reabsorption, and it activates the enzyme 1-α-hydroxylase, which catalyzes the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. PTH indirectly promotes the absorption of calcium and phosphate in the intestinal tract through the action of 1,25-dihydroxyvitamin D. PTH does not control calcium through effects on the liver.

11. (E) 1,25-Dihydroxyvitamin D. The skin produces vitamin Dfrom 7-deoxycholesterol after exposure to the sun. People with increased skin melanin pigmentation have decreased photosynthesis of vitamin D, and thus they require more time in the sun to make the same amount of vitamin D as those with lighter skin color. Season of the year and geographic latitude can greatly affect the production of vitamin D in the skin. The natural sources of vitamin D include fatty fish, such as salmon, and fatty fish oils, such as cod liver oil. Most vitamin D obtained from the diet comes from fortified foods, such as milk and bread. Vitamin Dis biologically inert and must undergo 25-hydroxylation in the liver, with subsequent 1-α-hydroxylation in the kidney to form the biologically active form of vitamin D, 1,25-dihydroxyvitamin D. 24,25-Dihydroxyvitamin D is biologically inert and one of the first steps of vitamin D degradation.

12. (C) Intestinal tract. 1,25-Dihydroxyvitamin D has its major impact in the gut because it promotes the reabsorption of calcium and phosphate in the duodenum and jejunum.

13. (C) Congenital hypoparathyroidism. Early neonatal hypocalcemia is characteristically seen in premature infants, infants with asphyxia at birth, and infants of diabetic mothers. Premature infants often have an exaggerated postnatal depression of serum calcium. In addition, both premature infants and asphyxiated infants tend to have an exaggerated rise in calcitonin, which antagonizes the effect of PTH on bone and kidney and may provoke hypocalcemia. Infants of mothers with diabetes may also have an exaggerated postnatal depression of serum calcium, and maternal glycosuria is accompanied by significant losses of magnesium, which predisposes the infant to total body magnesium losses. Hypomagnesemia in turn inhibits both PTH secretion and action.

14. (A) Asphyxia. An asphyxiated infant is more likely to present with early neonatal hypocalcemia rather than late neonatal hypocalcemia.

15. (B) Phosphate supplementation. Children with rickets because of vitamin D deficiency typically require calcium supplementation and calcitriol acutely to raise their calcium into the normal range. Ergocalciferol is used to replenish the vitamin D stores, but its effects are typically not seen for 4-7 days, hence the use of the biologically active calcitriol acutely. Phosphate supplementation is typically not used unless the rickets is caused by phosphate depletion (as is sometimes seen in premature infants or patients on total parenteral nutrition) or if the patient has hypophosphatemic rickets (in which case the patient would not have hypocalcemia).

16. (E) Patient has 1-α-hydroxylase deficiency. In 1-α-hydroxylase deficiency, or what is also termed vitamin D–dependent rickets (VDDR) type I, 25-hydroxyvitamin D is not converted into the biologically active 1,25-dihydroxyvitamin D in the kidney because of a deficiency of 1-α-hydroxylase. These patients cannot make biologically active vitamin D when treated with ergocalciferol, and they must be maintained on calcitriol. This disorder usually presents between 3 and 12 months of life, and children have similar symptoms and signs as children with nutritional rickets. Vitamin D–resistant rickets or vitamin D–dependent rickets (VDDR) type II is caused by a defect in the vitamin D receptor, leading to resistance to vitamin D. They can present with both hypocalcemia and hypophosphatemia.

17. (D) Hypercalcemia. Mild hypercalcemia can present with generalized weakness, anorexia, constipation, and polyuria. More severe hypercalcemia can present with nausea, vomiting, dehydration, seizures, and coma. Patients who are hypercalcemic can also present with significant psychological changes such as depression or paranoia.

18. (E) A and C. Children with DiGeorge syndrome typically present with transient or permanent hypocalcemia because of hypoplasia of the parathyroid glands, hypoplasia or aplasia of the thymus leading to impaired cell-mediated immunity, and anomalies of the outflow tract of the heart. Abnormalities in the chest radiograph are common, and absence of the thymic shadow should be looked for. Mutations in chromosome 22q11 have been described in DiGeorge syndrome. Other clinical characteristics include facial malformations, short stature, and developmental delay. Mutations in chromosome 15q11 are seen in Prader-Willi syndrome.


SUGGESTED READING

Diaz R. Abnormalities in calcium homeostasis. In: Radovick S, MacGillivray MH, eds. Pediatric EndocrinologyA Practical Clinical Guide. Totowa, NJ: Humana Press; 2003:343-363.

Levine B-S, Carpenter TO. Rickets: the skeletal disorders of impaired calcium or phosphate availability. In: Radovick S, MacGillivray MH, eds. Pediatric EndocrinologyA Practical Clinical Guide. Totowa, NJ: Humana Press; 2003:365-379.

Root AW, Diamond FB. Disorders of mineral homeostasis in the newborn, infant, child and adolescent. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:686-769.

Rosen CJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism 7th ed. Washington, DC: American Society for Bone and Mineral Research; 2008.

CASE 42: A 12-YEAR-OLD GIRL WITH NAUSEA, ABDOMINAL PAIN, AND VOMITING

A 12-year-old girl comes to your office with complaints of nausea, abdominal pain, and emesis for the past 24 hours. She has previously been healthy, but her parents believe she has lost weight over the summer despite a very good appetite. She has been drinking more water during the day, which her parents relate to it being summertime. She also complains of nocturia for the last few months. She is not taking any medications. On examination, she appears ill, with dry mucous membranes. She is afebrile. Respirations are deep and rapid.

SELECT THE ONE BEST ANSWER

1. What diagnosis would be at the top of your differential?

(A) appendicitis

(B) gastroenteritis

(C) diabetes insipidus

(D) diabetes mellitus

(E) psychogenic polydipsia

2. What test would you do first?

(A) serum amylase

(B) abdominal ultrasound

(C) liver function tests

(D) hemoglobin A1c

(E) urinalysis

3. Diabetic ketoacidosis (DKA) is typically characterized by all of the following except

(A) hyperkalemia

(B) hyperglycemia

(C) ketosis

(D) acidosis

(E) osmotic diuresis

4. The following hormones play a role in DKA except

(A) cortisol

(B) growth hormone

(C) epinephrine

(D) prolactin

(E) B and D

5. Your patient has a serum blood glucose of 900 mg/dL, pH 7.0, large serum ketones, sodium 126, potassium 4.2, chloride 102, bicarbonate less than 5, and phosphate 4.2 mEq/L. Which of the following is true?

(A) she should be treated for hyponatremia

(B) the blood glucose should be lowered to normal as quickly as possible

(C) she should receive an ampule of sodium bicarbonate

(D) she should have additional potassium in the intravenous (IV) fluids

(E) further monitoring of phosphate is not necessary

6. Potential drawbacks to the use of sodium bicarbonate in DKA include each of the following except

(A) cerebral edema

(B) rebound alkalosis

(C) sodium overload

(D) hypokalemia

(E) rise in cerebrospinal fluid (CSF) pH

7. What would the most appropriate initial management be if her serum blood sugar was 800 mg/dL, serum and urine ketones were large, and pH was 7.12?

(A) bolus of normal saline

(B) sodium bicarbonate drip

(C) bolus of IV insulin

(D) bolus of IV sodium bicarbonate

(E) a subcutaneous dose of insulin

8. What would the most appropriate initial management be if her serum blood sugar was 250 mg/dL, serum ketones small, pH 7.38, and she appeared well hydrated?

(A) a subcutaneous dose of insulin

(B) bolus of IV insulin

(C) start an oral hypoglycemic medication

(D) watch and repeat serum glucose in 6-24 hours

(E) bolus of normal saline

9. What would the most appropriate initial management be if her serum blood sugar was 180 mg/dL, ketones negative, pH 7.38, and she has had an illness with a fever for the last week?

(A) a subcutaneous dose of insulin

(B) bolus of IV insulin

(C) start an oral hypoglycemic medication

(D) watch and repeat serum glucose in 6 hours

(E) none of the above

10. Her mother, maternal aunt, maternal grandmother, and maternal great-grandmother all have a history of diabetes. This family history would worry you most about what type of diabetes?

(A) type 1 diabetes

(B) type 2 diabetes

(C) atypical diabetes

(D) gestational diabetes

(E) maturity-onset diabetes of youth

11. In a child in DKA, when would you worry most about the development of cerebral edema?

(A) before any treatment

(B) immediately after the initial bolus of normal saline

(C) with the start of insulin therapy

(D) several hours after the institution of therapy

(E) once the ketosis clears

12. Which of the following is not a manifestation of cerebral edema?

(A) tachycardia

(B) papilledema

(C) widened pulse pressure

(D) headache

(E) coma

13. Which of the following would not be an appropriate initial treatment for cerebral edema associated with DKA?

(A) decrease IV fluids

(B) stop insulin therapy

(C) hyperventilation

(D) mannitol

(E) all of the above are appropriate treatments

14. You diagnose your patient with type 1 diabetes and start her on subcutaneous insulin. Several months later the mother calls you to inform you that her daughter is ill and has vomited 4 times in the last 2 hours. She has not been eating well, and her mother is unsure of what to do. You would advise she do which of the following first?

(A) hold the insulin since she is not eating

(B) check urine ketones

(C) come directly to the emergency department

(D) push fluids and call you back in 4 hours

(E) administer glucose tablets

15. Several months later you get a page at 6 am from the child’s mother because the child is having a seizure. You would advise the mother to do which of the following first?

(A) administer glucose tablets

(B) administer glucose gel

(C) give orange juice

(D) hold the insulin dose

(E) administer glucagon

16. On a routine follow-up 2 years later, your patient reports that she checks her blood sugar 4 times daily (they range from 80 to 120), and she follows her meal plan consistently. She does all of her own care. You note on examination that she has lost 10 lb in the past 3 months and is now below the 5th percentile for weight. Her hemoglobin A1c is elevated at 12%. What should be your main concern at this time?

(A) anorexia

(B) poor compliance

(C) insulin resistance

(D) celiac disease

(E) hyperthyroidism

17. On your initial examination, you notice that the patient is obese and has acanthosis nigricans. This can be a marker for which of the following?

(A) hyperglycemia

(B) type 1 diabetes

(C) autoimmunity

(D) hyperandrogenism

(E) hyperinsulinism

18. On hospital follow-up in 3 months, your patient has gained 10 kg and now has a body mass index (BMI) of 36. Which of the following would be most helpful with distinguishing between type 1 and type 2 diabetes in your patient?

(A) reported blood glucose

(B) required insulin dosage

(C) hemoglobin A1c level

(D) C-peptide

(E) family history

ANSWERS

1. (D) Diabetes mellitus. Typical clinical symptoms of diabetes mellitus include polyuria, polydipsia, and polyphagia. Vomiting is often seen in DKA associated with ketosis. Abdominal pain is also present in many cases and may mimic appendicitis or pancreatitis. The abdominal pain usually resolves within a few hours of fluid and insulin therapy. Cerebral obtundation can be present and is usually related to the degree of hyperosmolarity. Kussmaul respirations (deep, sighing, and rapid) are often seen with profound acidosis.

2. (E) Urinalysis. A urinalysis is an important first step to detect glucosuria. A serum amylase and abdominal ultrasound would only be required if the patient’s abdominal pain did not subside after several hours of fluid resuscitation and improvement of the patient’s metabolic state. A hemoglobin A1c is important to confirm the presence of hyperglycemia over the last several months and is important in long-term follow-up of the patient, but it does not usually help in the acute management of the patient.

3. (A) Hyperkalemia. Measured serum potassium is usually normal to high; however, patients are usually depleted of total body potassium for the following reasons: insulin deficiency causes decreased Na/K adenosine triphosphatase (ATPase) activity, and decreased Na/K exchange leading to increased extracellular K, acidosis causes exchange of K from intracellular to extracellular compartment in exchange for H+ ions, which move into the cell along a concentration gradient, and K+ is then lost in part via osmotic diuresis and vomiting, and in part via the actions of aldosterone, which is elevated secondary to volume depletion. Blood glucose in DKA is typically greater than 300 mg/dL. However, the blood glucose can be less than 300 mg/dL in known diabetics because of vomiting with decreased carbohydrate intake and continued insulin administration. The primary mode of ketoacid production in DKA is from free fatty acid. The ketoacids relative to DKA are betahydroxybutyric acid and acetoacetic acid. Acetone has no effect on blood pH but is clinically important because of its characteristic odor. Most laboratories measure acetoacetate in blood and urine. However, the ratio of acetoacetate to beta-hydroxybutyrate is 1:3 in the fasted state and 1:7-1:15 in DKA. Thus the degree of ketosis in DKA is typically underestimated. Acidosis is defined as a blood pH less than 7.3 or serum bicarbonate less than 15 mEq/L. In DKA, acidosis is predominantly because of the accumulation of ketoacids, and thus patients have an increased anion gap. Other mechanisms contributing to acidosis include lactic acidosis from tissue hypoperfusion and hyperchloremic acidosis during fluid replacement. In general, the degree of acidosis in DKA bears no relation to the degree of hyperglycemia.

4. (D) Prolactin. The cardinal hormonal alterations seen in diabetic ketoacidosis include an absolute or relative insulin deficiency, with an excess of the stress hormones epinephrine, cortisol, and growth hormone (GH). Epinephrine activates glycogenolysis, gluconeogenesis, and lipolysis, and it inhibits insulin release by the pancreas. Cortisol decreases glucose use in muscle and stimulates gluconeogenesis. GH increases lipolysis and impairs insulin action on muscle. The catabolic and metabolic effects of each of the stress hormones are accentuated during insulin deficiency. Prolactin plays no known role in DKA.

5. (D) She should have additional potassium in the IV fluids. The serum sodium is usually factitiously low because of the hyperglycemia. For every 100 mg/dL glucose increment over 100 mg/dL, there is a decrease of 1.6 mEq/L sodium. Thus this patient’s true sodium is closer to 139 mEq/L. Measured serum potassium is usually normal or high, but patients are usually depleted of total body potassium (see answer to question 3). It is therefore important to treat with 30-40 mEq/L K+ once the child urinates because correction of acidosis, restoration of intravascular volume, insulin, and improvement of renal function tend to decrease extracellular K+. Approximately a fourth to a half of K+ administered during fluid replacement is lost in the urine. Hypokalemia is one of the avoidable causes of fatality in DKA. It is also important to monitor and replace phosphate because these patients can have a total body depletion of phosphate as a result of extracellular shifting and subsequent loss in the urine because of the catabolic state. Furthermore, with insulin treatment and fluid replacement, phosphate shifts back into the intracellular compartment, and a hypophosphatemic state occurs if phosphate is not replaced. Hypophosphatemia impairs insulin action and results in a decrease in synthesis of adenosine triphosphate (ATP) and other energy intermediates. Sodium bicarbonate should only be used if the serum pH is less than 7.1 and if the patient is unstable. Sodium bicarbonate should never be administered as a bolus. Serum blood glucose should be lowered slowly to avoid osmotic shifts.

6. (E) Rise in CSF pH. The use of sodium bicarbonate in DKA may increase the risk of cerebral edema because of osmotic shifts. Other drawbacks include hypokalemia, impaired tissue oxygenation with left shift of the oxyhemoglobin dissociation curve, rebound alkalosis, sodium overload, and the potential for a paradoxical fall in CSF pH while correcting peripheral acidosis.

7. (A) Bolus of normal saline. Dehydration is virtually universal in patients with DKA, and if unrecognized or mismanaged, it contributes significantly to the morbidity and mortality of DKA. The degree of dehydration varies from patient to patient, and the extent of the losses is unpredictable in any given patient. In DKA, there is an osmotically driven shift of water from intracellular to extracellular compartments. This results in underestimation of the extent of dehydration and is responsible for the unusual laboratory finding of hyponatremia despite dehydration and hyperosmolarity. The three main mechanisms of water and electrolyte loss in DKA include osmotic diuresis secondary to hyperglycemia, losses via the respiratory tract secondary to hyperventilation from metabolic acidosis, and losses from the gastrointestinal (GI) tract from vomiting. Serum blood sugar typically decreases with a normal saline bolus. To avoid rapid shifts in osmolality, the serum glucose should be lowered by 100 mg/dL per hour. Thus a continuous insulin drip is preferred to a bolus of either IV or subcutaneous insulin because it allows titration of the insulin based on the blood glucose response. Sodium bicarbonate should be avoided as discussed in the answer to question 6.

8. (A) A subcutaneous dose of insulin. In this situation, the patient is not in DKA with the lack of acidosis and will respond to subcutaneous insulin.

9. (D) Watch and repeat serum glucose in 6 hours. In this situation, the child may have stress-induced hyperglycemia rather than diabetes mellitus, which warrants close following and treatment if worsening hyperglycemia or ketosis develops. There are no current data to suggest that children with stressinduced diabetes in the absence of islet cell and GAD-65 autoimmunity are a greater risk of developing diabetes in the future.

10. (E) Maturity-onset diabetes of youth. Maturityonset diabetes of youth is a rare group of disorders with characteristics of type 2 diabetes mellitus caused by monogenic defects of beta cell function. Clinical criteria include the onset of type 2 diabetes at an early age (<25 years of age) and autosomal dominant inheritance.

11. (D) Several hours after the institution of therapy. Cerebral edema is usually not seen until the patient has been treated with fluids and insulin and laboratory data have shown improvement.

12. (A) Tachycardia. Manifestations of cerebral edema include headache, deepening coma, fever, bradycardia, widened pulse pressure, papilledema, and unequal pupils. The exact cause of cerebral edema is still controversial, but it is likely related to overtreatment with hypotonic solutions and rapid changes in plasma osmolality.

13. (B) Stop insulin therapy. A decrease of IV fluids, mannitol administration, and hyperventilation are all appropriate measures to decrease intracranial pressure to avoid brain herniation. Insulin therapy would still be indicated to correct the metabolic state.

14. (B) Check urine ketones. Children with diabetes are prone to develop DKA in times of illness because of the secreted stress hormones associated with illness (see question 4), which makes them relatively insulin resistant. Furthermore, the production of ketones can be the result of gastroenteritis or can cause a child to feel ill and vomit. If the child does have ketones, holding the insulin will make the situation worse, and additional insulin is required to reverse the catabolic state. Although pushing fluids is important in children who are vomiting to prevent dehydration, determination of urine ketone status is the most important first step in caring for this child.

15. (E) Administer glucagon. Glucagon will rapidly increase the blood sugar and get the child to a point where he or she is conscious enough to ingest oral glucose. Nothing should be put into the mouth of a seizing child to avoid aspiration. Depending on the cause of the hypoglycemia, the child may need an adjustment to the insulin dose.

16. (B) Poor compliance. Weight loss and an elevated hemoglobin A1c in a diabetic suggest foremost a deficiency of insulin. Unfortunately, it is not uncommon to detect poor compliance in an adolescent with diabetes. The hemoglobin A1c measures how much glucose is irreversibly bound to hemoglobin and thus is a marker of blood sugar levels over the last 3 months (lifespan of red blood cells).

17. (E) Hyperinsulinism. Acanthosis nigricans is characterized by hyperpigmented, thick, velvety lesions that occur most commonly on the posterior neck, groin, and axilla. It is commonly seen in obese patients who have insulin resistance.

18. (D) C-peptide. C-peptide is generated from the cleavage of proinsulin, and one molecule of C-peptide is released into the circulation for every molecule of insulin. Thus C-peptide can be used as an index of insulin secretion. C-peptide levels are generally low in type 1 diabetes associated with insulin deficiency and normal to high in type 2 diabetes associated with insulin resistance.


SUGGESTED READING

Cooke DW, Plotnick L. Type 1 diabetes mellitus in pediatrics. Pediatr Rev. 2008;29:374-385.

Cowell KM. Type 2 diabetes mellitus. Pediatr Rev. 2008;29:289-292.

Sperling MA, Weinzimer SA, Tamborlane WV. Diabetes mellitus. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:374-421.

CASE 43: A NEONATE WITH AMBIGUOUS GENITALIA

You are called to the newborn nursery emergently to see a full-term baby with ambiguous genitalia. The pregnancy and delivery were unremarkable. On physical examination, the baby is in no distress. The baby has a phallus that is 2 cm in stretched length. There is a 1-mm orifice at the base of the phallus, no obvious vaginal opening, and no palpable gonads (Figure 43-1).

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FIGURE 43-1.


SELECT THE ONE BEST ANSWER

1. If the karyotype is 46,XX, what would be the most likely diagnosis?

(A) maternal androgen exposure

(B) ovotesticular disorder of sex development (DSD)

(C) congenital adrenal hyperplasia (CAH)

(D) 5-alpha-reductase deficiency

(E) gonadal dysgenesis

2. Which of the following is the most frequent enzymatic defect in congenital adrenal hyperplasia?

(A) 3-beta-hydroxysteroid dehydrogenase deficiency

(B) 11-beta-hydroxylase deficiency

(C) 21-hydroxylase deficiency

(D) 17-hydroxylase deficiency

(E) steroidogenic acute regulatory protein (StAR) deficiency

3. What would your immediate concern be for the baby in question 1?

(A) hypokalemia

(B) surgical correction of the genital abnormality

(C) assigning a sex

(D) renal anomalies

(E) possibility of salt-wasting crisis

4. You diagnose the patient with CAH as a result of 21-hydroxylase deficiency. What are the mother’s chances of having another baby with CAH?

(A) Less than 5%

(B) 25%

(C) 50%

(D) 75%

(E) 100%

5. Which of the following is measured as part of the newborn screen to detect CAH?

(A) 17-hydroxyprogesterone

(B) 17-hydroxypregnenolone

(C) 21-hydroxylase

(D) testosterone

(E) androstenedione

6. What would be the most likely diagnosis if the baby has palpable gonads, a phallic urethra, and also has other midline defects such as cleft lip and palate?

(A) CAH

(B) panhypopituitarism

(C) ovotesticular DSD

(D) androgen insensitivity syndrome

(E) 5-alpha-reductase deficiency

7. The initial evaluation of an infant with ambiguous genitalia should include which of the following?

(A) karyotype, abdominal radiograph, measurement of adrenal steroids

(B) pelvic ultrasound, measurement of adrenal steroids, biopsy of gonads

(C) karyotype, measurement of adrenal steroids, biopsy of gonads

(D) karyotype, abdominal radiograph, measurement of sex steroids

(E) karyotype, pelvic ultrasound, measurement of adrenal steroids

8. Which of the following disorders does not usually have associated external genital abnormalities?

(A) Smith-Lemli-Opitz syndrome

(B) Prader-Willi syndrome

(C) Turner syndrome

(D) trisomy 18

(E) B and C

9. What is the role of the sex-determining region Y (SRY) chromosome?

(A) initiate external male genitalia formation

(B) initiate testis formation

(C) inhibit formation of internal female genitalia

(D) inhibit formation of external female genitalia

(E) initiate ovarian formation

10. 5-alpha-reductase has what function?

(A) converts testosterone into estradiol

(B) converts testosterone into dihydrotestosterone

(C) converts dihydrotestosterone into testosterone

(D) converts estradiol into testosterone

(E) converts androstenedione into testosterone

11. Abnormalities in which of the following genes lead to abnormalities in sexual differentiation?

(A) sex-determining region on the Y chromosome

(B) 5-alpha-reductase

(C) androgen receptor

(D) 21-hydroxylase

(E) all of the above

12. What structures do the Müllerian ducts form?

(A) fallopian tubes, uterus, and upper vagina

(B) ovaries, fallopian tubes, and uterus

(C) fallopian tubes, uterus, and upper and lower vagina

(D) ovaries, uterus, and upper vagina

(E) ovaries, uterus, and cervix

13. What structures do the Wolffian ducts form?

(A) epididymis, vas deferens, penile urethra

(B) testes, epididymis, vas deferens

(C) testes, epididymis, seminal vesicles

(D) epididymis, seminal vesicles, penile urethra

(E) epididymis, vas deferens, seminal vesicles

14. What is the role of Leydig cells in sexual differentiation?

(A) cause testicular enlargement

(B) produce testosterone, which stabilizes the Wolffian ducts

(C) enhance Sertoli cell formation

(D) cause regression of the Müllerian ducts

(E) spermatogenesis

15. Growth and differentiation of the external genitalia in males depends most on which of the following?

(A) testosterone

(B) Müllerian-inhibiting hormone

(C) LH and follicle-stimulating hormone (FSH)

(D) SRY

(E) dihydrotestosterone

16. Infants born with 5-alpha-reductase deficiency have which of the following features?

(A) 46,XX, male internal genitalia, female external genitalia

(B) 46,XY, male internal genitalia, female external genitalia

(C) 46,XX, female internal genitalia, male external genitalia

(D) 46,XY, female internal genitalia, male external genitalia

(E) 46,XY, female internal genitalia, female external genitalia

17. At what age do females need to be exposed to excess androgens to cause labial fusion and development of a urogenital sinus (Figure 43-2)?

(A) before 4 weeks’ gestation

(B) between 4 and 12 weeks’ gestation

(C) between 12 and 16 weeks’ gestation

(D) between 16 and 24 weeks’ gestation

(E) after 24 weeks’ gestation

art

FIGURE 43-2. Retrograde urethrogram of the internal genitalia of a virilized female infant with congenital adrenal hyperplasia as a result of 21-hydroxylase deficiency. With early exposure to androgens, the urethra and vagina do not extend to the perineum to form separate openings. An internal connection between the urethra and vagina forms a urogenital sinus, which results in only a single opening on the perineum.


18. What is the lower limit of normal penile length in a male term newborn?

(A) 1.5 cm

(B) 2.0 cm

(C) 2.5 cm

(D) 3.0 cm

(E) 3.5 cm

19. In females, the genital tubercle becomes which of the following?

(A) clitoris

(B) labia minora

(C) labia majora

(D) vaginal opening

(E) vagina

ANSWERS

1. (C) CAH, which is the most common diagnosis in virilized 46,XX infants. The ambiguous genitalia in female infants is caused by excess androgen exposure in utero and can range from mild virilization with posterior fusion to complete virilization. Maternal androgen exposure and ovotesticular DSD can both cause excess virilization in girls, but they are not as common as CAH. 5-alpha-reductase deficiency and gonadal dysgenesis cause genital ambiguity in males.

2. (C) 21-Hydroxylase deficiency. 21-Hydroxylase deficiency caused by mutations in the 21-hydroxylase gene accounts for most of CAH. A deficiency of 21-hydroxylase impairs the conversion of 17-hydroxyprogesterone to 11-deoxycortisol, resulting in decreased cortisol production, and impairs the conversion of progesterone to deoxycorticosterone, resulting in defects in aldosterone production. Males with 21-hydroxylase deficiency do not present with genital ambiguity. However, males with 3-beta-hydroxysteroid dehydrogenase deficiency, 17-alpha-hydroxylase deficiency, and StAR deficiency are undervirilized.

3. (E) Possibility of a salt-wasting crisis. Children with CAH as a result of 21-hydroxylase deficiency can produce inadequate aldosterone leading to a salt-wasting crisis. Infants with a salt-wasting crisis present with failure to thrive, lethargy, vomiting, hypotension, hypovolemia, hyponatremia, and hyperkalemia. If CAH is not diagnosed and treated promptly, it can be fatal. Newborn screening programs have allowed the early detection of CAH as a result of 21-hydroxylase deficiency, especially in boys who do not present with ambiguous genitalia, and mildly virilized girls. Stress doses of hydrocortisone should be given to all infants in whom a diagnosis of CAH is considered. This will provide both glucocorticoid and mineralocorticoid coverage. Once infants with salt-wasting CAH are put on maintenance hydrocortisone, a mineralocorticoid must be added. Approximately two-thirds of infants with CAH are salt wasters.

4. (B) 25%. Congenital adrenal hyperplasia as a result of 21-hydroxylase deficiency is transmitted as an autosomal recessive trait. Thus, assuming she has more children with the same father, there is a 25% chance that they will inherit both mutant alleles and be affected with CAH. It is possible to diagnose children prenatally. In subsequent pregnancies, this mother can be started on dexamethasone early in the pregnancy (by 5-6 weeks) to attempt to lessen the degree of genital ambiguity in affected female offspring by lowering the excess androgen production. Screening for CAH is done either by chorionic villus sampling or amniocentesis. Dexamethasone is only continued in women carrying affected female fetuses. The excess androgen production in affected males in utero currently has no known detrimental effect.

5. (A) 17-Hydroxyprogesterone. The most common enzyme deficiency causing CAH is deficiency of 21-hydroxylase, which converts 17-hydroxyprogesterone to 11-deoxycortisol. Thus a deficiency of 21-hydroxylase will lead to a buildup of the precursor, 17-hydroxyprogesterone.

6. (B) Panhypopituitarism. This describes a baby with micropenis. The presence of other midline defects suggests panhypopituitarism. Pituitary gonadotropins are necessary for phallic enlargement after the external genitalia are formed. This baby must be screened for other pituitary hormone deficiencies. CAH is a less likely cause of genital ambiguity when other nongenital anomalies are present. Patients with ovotesticular DSD have the presence of both female and male internal genitalia with dysgenetic or mixed gonads.

7. (E) Karyotype, pelvic ultrasound, measurement of adrenal steroids. Determination of the karyotype can help classify the infant as an undervirilized male, a virilized female, or a mixed sex chromosome pattern. Ultrasound of the pelvis can help determine the presence of the gonads, uterus, and vagina. Measurement of adrenal steroids is necessary because CAH is a common cause of ambiguous genitalia, and patients can have life-threatening adrenal insufficiency if not diagnosed and treated. Biopsy of the gonads is not indicated in the initial evaluation. An abdominal radiograph does not help much in the initial diagnosis.

8. (C) Turner syndrome. Girls with Turner syndrome are usually born with normal female external and internal female genitalia but have streak ovaries as a result of accelerated ovarian atresia. Boys with Smith-Lemli-Opitz syndrome (a disorder of cholesterol biosynthesis caused by a deficiency of 7-dehydrocholesterol reductase) often present with hypospadias, a bifid scrotum, and cryptorchidism among other phenotypic abnormalities. Patients with Prader-Willi syndrome can present with micropenis in boys or hypoplasia of the labia majora in girls. They often have hypogonadism. Patients with trisomy 18 can have cryptorchidism and hypoplasia of the labia majora.

9. (B) Initiate testis formation. SRY is a transcription factor expressed in gonads with a Y chromosome, which is thought to initiate the molecular events of testis formation. Mutations within SRY have been associated with 46,XY sex reversal because of testicular failure.

10. (B) Converts testosterone into dihydrotestosterone. The enzymatic conversion of testosterone to dihydrotestosterone is critical for virilization of external male genitalia.

11. (E) All of the above. Expression of SRY is thought to be the initiating factor in testis formation. Thus deletion of SRY will cause sex reversal in 46,XY infants. 5-alpha-reductase is the enzyme that converts testosterone into the more biologically active dihydrotestosterone, and a deficiency results in undervirilization of male infants. Abnormality in the androgen receptor will cause undervirilization of males because of androgen insensitivity. 21-Hydroxylase deficiency blocks cortisol production, leading to androgen excess that causes overvirilization of female infants.

12. (A) Fallopian tubes, uterus, and upper vagina. In males, Müllerian-inhibiting hormone is secreted from the testicular Sertoli cells beginning at approximately the seventh week of gestation, and it causes regression of the Müllerian ducts.

13. (E) Epididymis, vas deferens, seminal vesicles. The Wolffian ducts differentiate into the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts in 46,XY males.

14. (B) Produce testosterone that stabilizes the Wolffian ducts. Differentiation of the Wolffian ducts depends on local testosterone production from the Leydig cells of the testes.

15. (E) Dihydrotestosterone. Whereas development of the Wolffian ducts and internal genitalia depends on local production of testosterone, development of the external genitalia in males depends on dihydrotestosterone.

16. (B) 46,XY, male internal genitalia, female external genitalia. 5-alpha-reductase deficiency is an autosomal recessive disorder in which 46,XY infants have bilateral testes and normal male internal genitalia (a result of normal testosterone production and production of Müllerian-inhibiting hormone that causes female internal genitalia to regress), but with undervirilized external genitalia because of defective conversion of testosterone to dihydrotestosterone. They typically present with microphallus, perineal hypospadias, and a blind vaginal pouch. At puberty, 46,XY patients undergo progressive virilization with phallic enlargement and muscular development because of testosterone production.

17. (B) Between 4 and 12 weeks’ gestation. The separation of the vagina and urethra is complete in females by 12 weeks. Exposure to excess androgens before this time can interfere with this process. Exposure to excess androgens once the vagina and urethra are separate causes clitoromegaly and rugation of the labial folds only. Formation of a urogenital sinus is common in virilized females with CAH.

18. (C) 2.5 cm. A phallus smaller that 2.5 cm in a term newborn would be considered a micropenis. This measurement should be adjusted for gestational age. Micropenis can be caused by decreased testosterone exposure in the second and third trimester, which can be caused by LH deficiency or partial androgen insensitivity. Growth hormone deficiency can also cause micropenis. These infants should be screened for the possibility of panhypopituitarism.

19. (A) Clitoris. In females the genital tubercle forms the clitoris; in males it forms the phallus.


SUGGESTED READING

Antal Z, Ping Z. Congenital adrenal hyperplasia: diagnosis, evaluation and management. Pediatr Rev. 2009;30:e49-e57.

Lee PA, Houk CP, Ahmed SF, Hughes IA. Consensus statement on management of intersex disorders. Pediatrics. 2006;188:e488-500.

MacGillivray MH, Mazur T. Management of infants born with ambiguous genitalia. In: Radovick S, MacGillivray MH, eds. Pediatric EndocrinologyA Practical Clinical Guide. Totowa, NJ: Humana Press; 2003:429-449.

Witchell SF, Lee PA. Ambiguous genitalia. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:127-164.

CASE 44: A 13-YEAR-OLD GIRL WITH RAPID WEIGHT GAIN

A 13-year-old girl comes into your clinic with the complaint of rapid weight gain over the last 2 years. She claims that she does not eat more than others in the family, and she has gym class 3 times weekly. Her typical day consists of going to school, doing homework, and then watching television or playing video games for several hours daily. Other family members are also overweight. On physical examination, she is overweight but in no apparent distress.

SELECT THE ONE BEST ANSWER

1. Which formula would you use to calculate BMI?

(A) kg/m

(B) kg/m(C) kg2/m

(D) kg/cm

(E) kg/cm2

2. Which BMI defines an overweight (but not obese) child?

(A) between 55th and 65th percentile

(B) between 65th and 75th percentile

(C) between 75th and 85th percentile

(D) between 85th and 95th percentile

(E) higher than 95th percentile

3. BMI is not a good estimate of adiposity in which of the following situations?

(A) body builder

(B) endogenous obesity

(C) short stature

(D) exogenous obesity

(E) tall stature

4. Which of the following is not an adequate method of measuring the degree of obesity?

(A) dual-energy x-ray absorptiometry (DEXA) scan

(B) weight greater than the 90th percentile of normal

(C) skinfold thickness

(D) bioelectrical impedance analysis

(E) waist circumference

5. You calculate the patient’s BMI as greater than the 95th percentile for age. On further questioning, she has always been “chubby” with a very large appetite except when she was an infant when she had feeding difficulty and hypotonia. What would be the likely diagnosis?

(A) Cushing syndrome

(B) exogenous obesity

(C) Prader-Willi syndrome

(D) Laurence-Moon-Bardet-Biedl syndrome

(E) hypothyroidism

6. Which of the following features would you not expect to find in the child described in question 5?

(A) tall stature

(B) developmental delay

(C) hyperphagia

(D) relatively small hands and feet

(E) almond-shaped eyes

7. Her mother is convinced that her daughter has hypothyroidism as a cause of her obesity. Which of the following would mitigate against this diagnosis?

(A) normal growth velocity

(B) delayed bone maturation

(C) fatigue

(D) family history

(E) coarse hair

8. On physical examination, your patient is short and has purple striae on the abdomen. Which of the following would you be most concerned about?

(A) hypothyroidism

(B) genetic obesity syndrome

(C) exogenous obesity

(D) Cushing syndrome

(E) Prader-Willi syndrome

9. On physical examination, the patient’s BMI is greater than the 95th percentile and you notice that she has darkening and thickening of the skin on the posterior neck and in the axilla. Which of the following would you be most concerned about?

(A) Addison disease

(B) hypothyroidism

(C) prolactinoma

(D) Cushing syndrome

(E) hyperinsulinism

10. Your patient reports that she has had several vaginal yeast infections recently. Which of the following tests is most important in your workup?

(A) CBC

(B) cortisol

(C) immunoglobulin levels

(D) fasting blood sugar

(E) urine culture

11. Which of the following is not a feature of the metabolic syndrome?

(A) hypertension

(B) insulin resistance

(C) dyslipidemia

(D) type 1 diabetes mellitus

(E) hypercoagulability

12. On physical examination, your patient is of normal stature, but you notice hirsutism and moderate inflammatory acne. What part of the history will be important to narrow your differential diagnosis?

(A) nutrition history

(B) menstrual history

(C) developmental history

(D) school performance

(E) growth history

13. Which of the following is the best test to diagnose the condition in question 12?

(A) fasting insulin level

(B) hemoglobin A1c

(C) free testosterone

(D) FSH

(E) estradiol

14. Excess body fat in which area of the body has been associated more strongly with health risks than fat stored elsewhere?

(A) neck

(B) chest

(C) abdomen

(D) buttocks

(E) thighs

15. How likely is a 13-year-old child with a BMI at the 90th percentile (who has an overweight parent) to remain overweight as an adult?

(A) less than 30%

(B) 40%

(C) 50%

(D) 60%

(E) more than 70%

16. Which of the following is not a comorbid condition associated with exogenous childhood obesity?

(A) short stature

(B) sleep apnea

(C) type 2 diabetes mellitus

(D) slipped capital femoral epiphysis

(E) pseudotumor cerebri

17. Which of the following is true regarding the prevalence of obesity in children?

(A) it has been stable in the last 10 years

(B) it has been stable in the last 5 years

(C) it has been increasing in all children aged 2-19 years in the last 10 years

(D) it has been increasing only in children aged 12-19 years in the last 5 years

(E) There is no difference in prevalence among various racial/ethnic groups

18. Which of the following statements regarding obesity is true?

(A) genes have a more important role than environment in the obesity epidemic

(B) BMI is a direct measure of adiposity

(C) obese children can easily lose weight if they eat properly

(D) obesity occurs when energy intake is balanced by energy expenditure

(E) severe obesity can result from human gene mutations

ANSWERS

1. (B) kg/m2. Body mass index provides a satisfactory index of adiposity.

2. (D) Between 85th and 95th percentile. Cutoff criteria for overweight and obese children are based on the 2000 Centers for Disease Control and Prevention (CDC) BMI for age growth charts. If a child’s BMI falls between the 85th and 95th percentile, he or she is considered to be overweight. If their BMI is higher than the 95th percentile, they are defined as obese. Obesity implies excess body fat. Body fat mass reflects the long-term balance between energy expenditure and energy intake.

3. (A) Body builder. The major limitation to BMI is that it does not differentiate between weight that is fat and weight that is muscle. Thus very muscular people may be improperly classified as overweight or obese.

4. (B) Weight greater than the 90th percentile of normal. Tall children who are proportional will have weights greater than the 90th percentile of normal and not be obese. However, if a child’s weight is on the height curve, they are likely obese. DEXA scans can demonstrate the distribution and extent of adiposity, but the disadvantage is that sophisticated equipment is necessary. Skinfold thickness is measured with the use of specific calipers. Age- and sex-specific percentiles for triceps and subscapular skinfolds are available, and skinfold thickness more than 85th percentile for age and sex suggests obesity. The disadvantage of using skinfold thickness to classify obesity is that there is significant interobserver error and the measurement becomes less reliable as body fatness increases. Bioelectrical impedance estimates adiposity by measuring resistance to a low-frequency electrical current. The advantage of this method is that it is portable, noninvasive, and reliable in many populations. Disadvantages are that it can be variable, and measurements are compromised with altered hydration and extreme obesity. Measurement of waist circumference is an indirect measure of visceral adiposity. This measurement may help identify those children with an elevated BMI who have the highest metabolic risk.

5. (C) Prader-Willi syndrome. A history of feeding difficulty and hypotonia as an infant is found in Prader-Willi syndrome, which is the most common genetic syndrome associated with obesity. Impaired paternal imprinting in the chromosomal region 15q11–13 is found in Prader-Willi syndrome. Laurence-Moon-Bardet-Biedl syndrome, an autosomal recessive disorder characterized by retinal degeneration, mental retardation, obesity, polydactyly, renal dysplasia, and short stature, is a rare cause of pediatric obesity.

6. (A) Tall stature. One of the characteristic features of Prader-Willi syndrome is short stature for the genetic background. Patients present with hyperphagia, relatively small hands and feet, developmental delay, almond-shaped eyes, and a characteristic behavioral disorder.

7. (A) Normal growth velocity. Children with a hormonal cause of obesity are typically short with a poor growth velocity. Long-standing hypothyroidism would cause short stature, delayed bone age, coarse hair, dry skin, and fatigue. With hypothyroidism secondary to autoimmune thyroiditis, there is often a family history of thyroid dysfunction.

8. (D) Cushing syndrome. Short stature associated with obesity should raise the concern of an endocrinologic cause of obesity such as Cushing syndrome or hypothyroidism. Cushing syndrome describes any form of glucocorticoid excess. In children, the first signs of Cushing syndrome are typically growth attenuation and weight gain. The attenuation of growth often occurs before the excessive weight gain. In addition, purple striae are often seen in Cushing syndrome due to stretching of fragile skin.

9. (E) Hyperinsulinism. Acanthosis nigricans, or hyperpigmented, thick, velvety areas of skin most commonly on the posterior neck, groin, and axilla, often occurs among obese patients and is a marker of insulin resistance. Although hyperpigmentation occurs in Addison disease, it is most prominent in areas of the skin exposed to the sun and in flexor surfaces such as knees, elbows, and knuckles. In addition, Addison disease presents with anorexia and weight loss, not gain.

10. (D) Fasting blood sugar. Obese children are at risk of developing type 2 diabetes mellitus, which usually has an insidious onset. History of frequent vaginal yeast infections should raise the concern of hyperglycemia.

11. (D) Type 1 diabetes mellitus. The metabolic syndrome combines atherogenic risk factors with underlying insulin resistance. Key features include hyperinsulinemia, abnormal glucose metabolism (impaired glucose tolerance or type 2 diabetes), hypertension, dyslipidemia, obesity (especially visceral) hyperuricemia, microalbuminuria, and hypercoagulability. With the marked increase in the prevalence of obesity in children, this syndrome will become much more common and eventually lead to increased mortality overall.

12. (B) Menstrual history. Obesity in a girl is a feature of polycystic ovary syndrome (PCOS) and is often the presenting complaint. Other features include menstrual irregularity, hirsutism, acne, and insulin resistance.

13. (C) Free testosterone. PCOS is the most common cause of hyperandrogenism and typically presents after the onset of puberty. The best way to screen for PCOS is by measuring androgens, including total testosterone, free testosterone, and DHEA sulfate. Measurement of free testosterone is the most sensitive test for the detection of androgen excess.

14. (C) Abdomen. Many studies have shown that excess abdominal fat increases the risk of complications independent of and additive to that caused by the degree of obesity.

15. (E) More than 70%. Overweight children (age 10-16 years) with at least one overweight parent have more than a 70% likelihood of being overweight as an adult. The persistence of obesity into adulthood is among the most serious consequences of pediatric obesity because there is a tight association between length of time spent at an abnormal body weight as an adult and atherosclerosis, cardiovascular disease, type 2 diabetes mellitus, and dyslipidemia.

16. (A) Short stature. Most children with exogenous obesity are tall for age and may appear older than their chronological age. Obese children are more likely to have high fasting insulin levels, and in the past few years, there has been a significant increase in type 2 diabetes. This tends to correlate with the increase in prevalence of obesity in children. Few organ systems are unaffected by excessive adiposity in childhood.

17. (C) It has been increasing in all children of age 2-19 years in the past 10 years. The prevalence of childhood obesity has been increasing rapidly in the past 20 years and shows no evidence of slowing. There are significant differences in the prevalence of obesity in various ethnic groups, with non-Hispanic black girls and Mexican American boys having the highest prevalence of obesity.

18. (E) Severe obesity can result from human gene mutations. Many factors can result in an imbalance between energy intake and energy expenditure, leading to the promotion of excess fat deposition. Although genes play an important role in the regulation of body weight, behavioral and environmental factors are likely primarily responsible for the dramatic increase in obesity in the past two decades. BMI is an indirect measure of adiposity. A number of human gene mutations have been described that result in severe obesity, including mutations in leptin and melanocortin 4 receptor.


SUGGESTED READING

Barlow SE. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120(suppl 4):S164-192.

O’Rahilly S. Insights into obesity and insulin resistance from the study of extreme human phenotypes. Eur J Endocrinol. 2002;147:435-441.

Speiser PW, Rudolf MC, Anhalt H, et al. Childhood obesity. J Clin Endocrinol Metab. 2005;90(3):1871-1887.

CASE 45: A 16-YEAR-OLD BOY WITH FATIGUE, ANOREXIA, INTERMITTENT VOMITING, AND WEIGHT LOSS

A 16-year-old patient presented to the emergency department with the complaints of fatigue, anorexia, intermittent vomiting, and weight loss. He had no diarrhea or fever but did complain of right upper quadrant abdominal pain. He was previously healthy and was not taking any medications. An abdominal computerized tomography (CT) scan was performed that revealed hepatosplenomegaly, and a presumptive diagnosis of mononucleosis was made. He was treated with prednisone for 4 days with marked improvement of his symptoms. His symptoms eventually returned, and following further tests, he was diagnosed with delayed emptying of the gallbladder. He underwent a cholecystectomy 4 months after his initial presentation. He tolerated the surgery well, but on postoperative day 1 he became very sleepy and began to have mental status changes. He improved slightly and was discharged. He now presents back to the emergency department and you find him to be hypotensive with a blood glucose of 50 mg/dL. Further history revealed that he has lost 35 pounds in the last 4 months. On physical examination, he appears dehydrated, and you notice marked hyperpigmentation on the neck, elbows, knuckles, and lower abdomen. In addition, he appears tan even though he has not recently been in the sun.

SELECT THE ONE BEST ANSWER

1. Which of the following would be the most appropriate initial management of this patient?

(A) IV fluids and stress dose glucocorticoids

(B) oral glucocorticoids

(C) emergency exploratory laparotomy

(D) consult to the pediatric oncology team

(E) insulin drip

2. Which of the following laboratory results would you expect to find in this patient?

(A) serum sodium 127, potassium 2.5 mEq/L; urine potassium 200 mEq/day

(B) serum sodium 127, potassium 3.5 mEq/L; urine potassium 15 mEq/day

(C) serum sodium 127, potassium 7.5 mEq/L; urine potassium 100 mEq/day

(D) serum sodium 147, potassium 7.5 mEq/L; urine potassium 5 mEq/day

(E) serum sodium 127, potassium 7.5 mEq/L; urine potassium 5 mEq/day

3. What would you expect this patient’s adrenocorticotropic hormone (ACTH) and cortisol level to be before treatment?

(A) low ACTH, low cortisol

(B) low ACTH, high cortisol

(C) high ACTH, low cortisol

(D) high ACTH, high cortisol

(E) normal ACTH, low cortisol

4. All of the following signs and symptoms except which one should clue you in to a diagnosis of primary adrenal insufficiency?

(A) hyperpigmentation

(B) anorexia

(C) weight loss

(D) hepatosplenomegaly

(E) vomiting

5. Which of the following is not a clinical manifestation of Addison disease?

(A) unexplained hypoglycemia

(B) vitiligo

(C) neutropenia

(D) nausea

(E) weakness

6. Which of the following statements regarding adrenal insufficiency is (are) true?

(A) adrenal crisis is rare in patients with secondary adrenal insufficiency

(B) hyperpigmentation is common in secondary adrenal insufficiency

(C) hyperkalemia is commonly seen at presentation in secondary adrenal insufficiency

(D) the major cause of adrenal crisis is glucocorticoid deficiency

(E) all of the above

7. Which of the following would be the preferable treatment for a child in adrenal crisis?

(A) IV methylprednisolone

(B) IV hydrocortisone

(C) IV dexamethasone

(D) A or B

(E) any of the above

8. On physical examination, the patient has candidiasis in the mouth and noticeable vitiligo on the face and trunk. Which of the following tests should you check to help with your diagnosis?

(A) magnesium

(B) CBC

(C) immunoglobulin levels

(D) urinalysis

(E) calcium

9. Your patient also describes neurologic symptoms. What would be at the top of the differential?

(A) adrenoleukodystrophy

(B) infectious adrenalitis

(C) drug-induced adrenal failure

(D) autoimmune adrenalitis

(E) tuberculosis

10. Which of the following has been associated with adrenal hemorrhage in children?

(A) Pseudomonas aeruginosa sepsis

(B) Escherichia coli sepsis

(C) meningococcemia

(D) neonatal asphyxia

(E) all of the above

11. Addison disease is most commonly caused by which of the following?

(A) infectious adrenalitis

(B) autoimmune adrenalitis

(C) adrenal hemorrhage

(D) metastatic cancer

(E) trauma

12. Which of the following statements regarding serum cortisol concentrations is true?

(A) serum cortisol concentrations are highest in the early morning

(B) serum cortisol concentrations are highest in the early afternoon

(C) serum cortisol concentrations are highest in the early evening

(D) serum cortisol concentrations are highest in the late evening

(E) serum cortisol concentrations do not vary during the day

13. You diagnose your patient with Addison disease. Which of the following is true regarding outpatient treatment?

(A) he should be discharged on fludrocortisone but only needs glucocorticoid during times of stress

(B) he should be discharged on an oral glucocorticoid but only needs fludrocortisone during times of stress

(C) he only needs glucocorticoid at discharge

(D) he only needs glucocorticoids and fludrocortisones during times of stress

(E) he should be discharged on glucocorticoid and fludrocortisone

14. Your patient is doing well at home on his medications and his skin pigmentation has faded. His mother calls because he has developed a low-grade fever with diarrhea. Which of the following would be the most appropriate initial management?

(A) he should double his fludrocortisone dose

(B) he should come directly to your clinic

(C) he should double his hydrocortisone dose

(D) he should make no changes in his medications

(E) he should come directly to the emergency department

15. One year after discharge, the patient notes that his skin pigmentation is beginning to darken again. What would be your major concern?

(A) poor compliance with the glucocorticoid

(B) poor compliance with fludrocortisone

(C) development of ACTH resistance

(D) development of insulin resistance

(E) development of cortisol resistance

16. Which of the following is (are) not a cause of secondary adrenal insufficiency?

(A) panhypopituitarism

(B) autoimmune adrenalitis

(C) isolated ACTH deficiency

(D) megestrol acetate ingestion

(E) A and D

17. Which of the following statements regarding secondary adrenal insufficiency is (are) not true?

(A) hyponatremia can occur

(B) hyperkalemia can occur

(C) skin hyperpigmentation does not occur

(D) weakness and fatigue are common symptoms

(E) A and B

18. Which of the following is the most common cause of tertiary adrenal insufficiency?

(A) cranial radiation

(B) hypothalamic tumors

(C) head trauma

(D) pituitary tumor

(E) chronic administration of high doses of glucocorticoids

ANSWERS

1. (A) IV fluids and stress dose glucocorticoids. This adolescent can have many clinical manifestations of Addison disease and is likely to manifest an adrenal crisis. Thus it is imperative to treat him with IV fluids and stress doses of glucocorticoids before any other management. Normal saline with additional glucose should be used as the IV fluids to replace sodium loss and correct hypoglycemia. An emergency exploratory laparotomy without pretreatment with stress dose glucocorticoids could lead to a catastrophic outcome.

2. (E) Serum sodium 127, potassium 7.5 mEq/L; urine potassium 5 mEq/day. Hyponatremia is a common feature of primary adrenal insufficiency secondary to mineralocorticoid deficiency and inappropriate vasopressin secretion caused by glucocorticoid deficiency. Mild hyponatremia can also occur in secondary or tertiary adrenal insufficiency because of inappropriate vasopressin secretion. Hyperkalemia is only seen in primary adrenal insufficiency.

3. (C) High ACTH, low cortisol. In adrenal insufficiency of any cause, the serum cortisol will be low. The ACTH level will help distinguish between primary adrenal insufficiency (in which ACTH levels will be high) and secondary or tertiary adrenal insufficiency (in which ACTH levels will be low).

4. (D) Hepatosplenomegaly. The onset of adrenal insufficiency is often insidious. The presenting signs and symptoms depend on how quickly adrenal function is diminished and whether mineralocorticoid production is affected along with glucocorticoid production. Adrenal insufficiency is often first detected when a stress precipitates an adrenal crisis. Hyperpigmentation in areas exposed to sunlight, areas such, as the palmar creases, axilla, areola, and areas exposed to friction such as the elbows, knees, belt line, and knuckles, is the most characteristic finding of Addison disease and is present in most patients. Anorexia and weight loss are also seen in primary adrenal insufficiency along with other GI symptoms such as vomiting, abdominal pain, diarrhea, and constipation. Dehydration caused by vomiting and diarrhea can often precipitate an adrenal crisis. Although splenomegaly can be seen in primary adrenal insufficiency, hepatomegaly is not a common finding.

5. (C) Neutropenia. Unexplained hypoglycemia is found in Addison disease but tends to be more common in younger patients. In adults, it can be precipitated by fever or infection. Although hyperpigmentation is the major manifestation of Addison disease, vitiligo can be seen in patients with autoimmune causes of adrenal insufficiency because of autoimmune destruction of dermal melanocytes. Patients can have eosinophilia. Neutropenia is not a typical clinical manifestation of Addison disease. Other clinical manifestations include generalized weakness, fatigue, postural dizziness, diffuse myalgia, behavioral changes, and splenomegaly.

6. (A) Adrenal crisis is rare in patients with secondary adrenal insufficiency. The major cause of adrenal crisis is mineralocorticoid deficiency and not glucocorticoid deficiency. Secondary adrenal insufficiency occurs because of ACTH deficiency, which affects only the glucocorticoid production. Patients with secondary or tertiary adrenal insufficiency typically have normal aldosterone production, which is under the control of the renin-angiotensin system. Thus they have normal serum potassium and rarely present in adrenal crisis. The hyperpigmentation is found only in primary adrenal insufficiency and occurs because of chronic ACTH hypersecretion.

7. (B) IV hydrocortisone. In a patient in adrenal crisis, it is important to replace both the deficient glucocorticoid as well as the deficient mineralocorticoid. Of the above, only hydrocortisone has significant mineralocorticoid activity if given at stress doses IV. Unfortunately, currently no IV form of mineralocorticoid is available. Fludrocortisone is a potent oral synthetic mineralocorticoid that can be used once the patient is stable and ready to discontinue IV saline.

8. (E) Calcium. The presence of vitiligo with primary adrenal insufficiency suggests an autoimmune etiology. Autoimmune polyglandular syndrome type 1 is a rare autosomal recessive disorder in which primary adrenal insufficiency is associated with chronic mucocutaneous candidiasis and hypoparathyroidism. The candidiasis and hypoparathyroidism typically appear first in early to mid-childhood, and adrenal insufficiency usually develops in mid to late adolescence. Thus it would be important to screen this patient for hypocalcemia. Other common associated manifestations include primary hypogonadism and malabsorption syndromes. Patients rarely develop diabetes mellitus and autoimmune thyroiditis. In contrast, in autoimmune polyglandular syndrome type 2, adrenal insufficiency is typically the initial manifestation. Hypoparathyroidism does not occur in this disorder, and diabetes mellitus and autoimmune thyroiditis are common.

9. (A) Adrenoleukodystrophy. The presence of X-linked adrenoleukodystrophy needs to be ruled out in any young man with primary adrenal insufficiency. Not all patients have neurologic symptoms when the adrenal insufficiency is diagnosed. Very long-chain fatty acid concentrations are increased in affected males. If a patient is diagnosed with adrenoleukodystrophy, all male siblings should be screened.

10. (E) All of the above. Adrenal hemorrhage in children has been associated with Pseudomonas aeruginosa sepsis, meningococcemia and E coli sepsis (Waterhouse-Friderichsen syndrome), and in neonates following a difficult labor or asphyxia. Patients may have a sudden fall in hemoglobin with hyponatremia and hyperkalemia.

11. (B) Autoimmune adrenalitis. Autoimmune adrenalitis accounts for greater than 70% of cases of Addison disease. The most common detectable antibody is against 21-hydroxylase. Autoimmune destruction of other endocrine glands is often seen. In the past, infectious adrenalitis caused by tuberculosis was the most common cause of Addison disease, but now infectious adrenalitis occurs in less than 20% of new cases of Addison disease. Adrenal insufficiency occurs at a low incidence in metastatic cancer because a significant proportion of the adrenal gland must be destroyed for adrenal insufficiency to become evident.

12. (A) Serum cortisol concentrations are highest in the early morning. There is a diurnal rhythm of serum cortisol, and concentrations are typically highest in the early morning between 4 and 8 AM. In patients with normal adrenal function, cortisol levels typically increase markedly with stress.

13. (E) He should be discharged on glucocorticoid and fludrocortisone. Patients with Addison disease are deficient in both glucocorticoid and mineralocorticoid and thus need daily replacement of both. The importance of diligence taking the medications needs to be stressed to avoid adrenal crisis. Patients with secondary or tertiary adrenal insufficiency typically only need treatment with hydrocortisone because ACTH is not an important regulator of aldosterone release.

14. (C) He should double his hydrocortisone dose. The major risk to the patient with primary adrenal insufficiency is the lack of an appropriate adrenal response to stress. Thus patients who are ill or undergoing any type of procedure should be treated with additional glucocorticoid. The dose of mineralocorticoid is typically not adjusted during illness. If patients are unable to keep down the medications and fluids, they need to come to the emergency department for IV therapy to avert an adrenal crisis. It is important that patients with adrenal insufficiency wear a MedicAlert tag.

15. (A) Poor compliance with the glucocorticoid regimen. Darkening of the skin pigmentation in a patient with primary adrenal insufficiency would suggest that treatment with glucocorticoids is not adequate and ACTH levels are elevated. Either the child has outgrown the glucocorticoid dose and will need an adjustment or, more commonly in an adolescent, they have not been as compliant as desired.

16. (B) Autoimmune adrenalitis. Secondary adrenal insufficiency is caused by any process that affects the pituitary gland and interferes with ACTH secretion. Autoimmune adrenalitis is a disorder of the adrenal gland and causes primary adrenal insufficiency. Isolated ACTH deficiency is rare. Megestrol acetate is a progestin with some glucocorticoid activity that is used in children with cancer or cystic fibrosis to increase appetite. Withdrawal of megestrol acetate can be associated with secondary adrenal insufficiency in some patients.

17. (B) Hyperkalemia can occur. Hyponatremia can be seen in secondary adrenal insufficiency because glucocorticoid action is required for appropriate renal free water clearance. However, hyperkalemia does not occur because the renin-angiotensin-aldosterone system remains intact. Hyperpigmentation of the skin occurs typically only in primary adrenal insufficiency.

18. (E) Chronic administration of high doses of glucocorticoid. With the widespread use of supraphysiologic doses of glucocorticoids, suppression of the hypothalamic-pituitary-adrenal axis is a frequent cause of adrenal insufficiency in children. Tertiary adrenal insufficiency can be seen with prolonged use of high-dose glucocorticoids (>7 days), and the timing of recovery of hypothalamic-pituitaryadrenal function can be variable. Glucocorticoids should never be discontinued abruptly in patients who have been on a prolonged course but rather should be weaned slowly.


SUGGESTED READING

Bethin KE, Muglia LJ. Adrenal insufficiency. In: Radovick S, MacGillivray MH, eds. Pediatric EndocrinologyA Practical Clinical Guide. Totowa, NJ: Humana Press; 2003:203-226.

Brenner K, Frohna JG. Index of suspicion. Case 3. Diagnosis: acute adrenal insufficiency. Pediatr Rev. 2001;22:245-250.

Miller WL, Achermann JC, Fluck CE. The adrenal cortex. In: Sperling MA, ed. Pediatric Endocrinology. 3rd ed. Philadelphia, PA: WB Saunders; 2008:444-511.